2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Cognitive-Dysfunction

The mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE), which in turn confounds the estimation of perfusion into a specific tissue of interest such as gray or white matter. This confound occurs because the image voxels contain a mixture of tissues with disparate perfusion properties, leading to estimated perfusion values that reflect primarily the volume proportions of tissues in the voxel rather than the perfusion of any particular tissue of interest within that volume. It is already recognized that PVE influences studies of brain perfusion, and that its effect might be even more evident in studies where changes in perfusion are co-incident with alterations in brain structure, such as studies involving a comparison between an atrophic patient population vs control subjects, or studies comparing subjects over a wide range of ages. However, the application of PVE correction (PVEc) is currently limited and the employed methodologies remain inconsistent. In this article, we outline the influence of PVE in ASL measurements of perfusion, explain the main principles of PVEc, and provide a critique of the current state of the art for the use of such methods. Furthermore, we examine the current use of PVEc in perfusion studies and whether there is evidence to support its wider adoption. We conclude that there is sound theoretical motivation for the use of PVEc alongside conventional, 'uncorrected', images, and encourage such combined reporting. Methods for PVEc are now available within standard neuroimaging toolboxes, which makes our recommendation straightforward to implement. However, there is still more work to be done to establish the value of PVEc as well as the efficacy and robustness of existing PVEc methods.

Topics: Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Carbon Radioisotopes; Cerebral Arteries; Cognitive Dysfunction; Entorhinal Cortex; Hippocampus; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Membrane Glycoproteins; Nerve Tissue Proteins; Neuroimaging; Organ Size; Perfusion; Positron-Emission Tomography; Pyridines; Pyrrolidinones; Radiopharmaceuticals; Spin Labels; Synaptic Vesicles; Thiazoles

We conducted a meta-analysis of positron emission tomography (PET) findings in Alzheimer's disease (AD) and mild cognitive impairment (MCI) to clarify the changes underpinning these conditions. All studies that utilised the PET tracers Pittsburgh Compound-B (PIB) or 2-[18F]fluoro-2-deoxy-D-glucose (FDG) to investigate patients with MCI or AD, were considered for the meta-analysis. Meta-analyses of PIB-PET and FDG-PET changes between patients and controls were undertaken with the effect-size signed differential mapping (ES-SDM) voxel-based meta-analytic method. A total of 24 studies were included involving 728 AD patients, 211 MCI patients and 658 healthy controls. Individuals with AD showed a significant PIB retention in bilateral precuneus and temporal, supramarginal, cingulate and fusiform gyri, as well as right insula and putamen. In addition, AD patients showed significant glucose hypometabolism in bilateral precuneus and temporal, supramarginal, cingulate, fusiform, angular, inferior parietal and middle frontal gyri, as well as left precentral and parahippocampal gyri and right superior frontal gyrus and thalamus. An exploratory meta-analysis of the few studies on MCI showed mildly decreased glucose metabolism with a similar regional distribution than in patients with AD. We suggest that our results can be used for further region-of-interest studies of AD and MCI patients.

Topics: Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Fluorodeoxyglucose F18; Glucose; Humans; Positron-Emission Tomography; Thiazoles

Subjective cognitive impairment (SCI) refers to concerns regarding one's cognitive functioning in the absence of objective evidence of impairment, and may represent an early stage of Alzheimer's disease. However, as not all individuals with SCI cognitively decline, there is growing interest in the early identification of those individuals with SCI who are most at risk of developing Alzheimer's disease. One promising method of early identification involves the use of biomarkers that are known to be associated with the pathophysiology of the disease; in particular, markers of amyloid and tau accumulation. While there has been substantial research on amyloid and tau biomarkers in the context of mild cognitive impairment (MCI), only recently has attention shifted to SCI, which may represent an even earlier stage in the disease course. The purpose of this paper is to qualitatively review the literature on amyloid and tau biomarkers in SCI. A brief discussion of non-amyloid/tau biomarkers is also included. Not surprisingly, we found that amyloid and tau biomarker profiles become increasingly abnormal from SCI, to MCI, to Alzheimer's disease. Additionally, although amyloid and tau biomarkers appear to be unable to differentiate between SCI and healthy controls, there is some evidence to suggest that they may be able to differentiate between those individuals with SCI who cognitively decline over time and those who do not. While this finding has potential clinical implications, achieving optimal predictive value will likely require further research into the use of numerous biomarkers in combination.

Topics: Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Databases, Bibliographic; Humans; Longitudinal Studies; Positron-Emission Tomography; tau Proteins; Thiazoles

Our aim was to conduct a meta-analysis of longitudinal studies assessing the association between Pittsburgh compound B (PiB) retention and the progression of cognitive status in healthy elderly, in patients with mild cognitive impairment (MCI) and in patients with Alzheimer's disease (AD). PubMed, MEDLINE, Embase and the Cochrane Library up to April 2013 were searched for studies reporting PiB retention at baseline and conversion of clinical status at follow-up, with manual searches of bibliographies of key retrieved articles and relevant reviews. Two independent reviewers extracted data on individual numbers with PiB positive or negative status at baseline and corresponding numbers of patients with cognitive decline at follow-up (conversion from healthy elderly to MCI or AD, or from MCI to AD, or a Mini-Mental State Examination decline >3 for AD patients). Relative risks were pooled using fixed-effects or random-effects models as appropriate. Associations were tested in subgroups representing three different phases of AD. Publication bias was evaluated with funnel plots. Twelve cohort studies including 1275 participants were included with a follow-up period ranging from 1 to 3.8 years. The pooled adjusted relative risks were 3.75 (95% confidence interval 2.76-5.09; P for heterogeneity 0.16; fixed-effects model) for disease progression, 1.73 (0.63-4.75; P for heterogeneity 0.27; fixed-effects model) for AD patients (four studies), 4.03 (2.68-6.07; P for heterogeneity 0.49; fixed-effects model) for MCI patients (eight studies) and 3.67 (2.25-5.99; P for heterogeneity 0.26; fixed-effects model) for disease progression in healthy elderly (six studies). Baseline PiB positive status is associated with a significantly increased risk of cognitive progression in healthy elderly and MCI patients.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Disease Progression; Humans; Middle Aged; Positron-Emission Tomography; Thiazoles

Use of biomarkers in the detection of early and preclinical Alzheimer's disease (AD) has become of central importance following publication of the NIA-Alzheimer's Association revised criteria for the diagnosis of AD, mild cognitive impairment (MCI) and preclinical AD. The use of in vivo amyloid imaging agents, such a Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) is able to detect early AD pathological processes and subsequent neurodegeneration. Imaging with PiB and FDG thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other etiologies in patients presenting with mild or atypical symptoms or confounding comorbidities in which the diagnostic distinction is difficult to make clinically. From a research perspective, this allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to MCI to AD. The present review focuses on use of PiB and FDG-PET and their relationship to one another.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Fluorodeoxyglucose F18; Glucose; Humans; Positron-Emission Tomography; Thiazoles

Abstract Recent advances have made possible the in vivo detection of beta-amyloid (Aβ) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aβ among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Asymptomatic Diseases; Benzothiazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Dementia; Ethylene Glycols; Fluorine Radioisotopes; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

According to the latest revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) (NINCDS-ADRDA) diagnostic criteria for Alzheimer's disease dementia, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of imaging biomarkers. These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, the accuracy of biomarkers in the diagnosis of Alzheimer's disease dementia and other dementias has not yet been systematically evaluated. A formal systematic evaluation of the sensitivity, specificity, and other properties of positron emission tomography (PET) imaging with the (11)C-labelled Pittsburgh Compound-B ((11)C-PIB) ligand was performed.. To determine the diagnostic accuracy of the (11)C- PIB-PET scan for detecting participants with MCI at baseline who will clinically convert to Alzheimer's disease dementia or other forms of dementia over a period of time.. The most recent search for this review was performed on 12 January 2013. We searched MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science and Conference Proceedings (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We also requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies (managed by the Cochrane Renal Group).No language or date restrictions were applied to the electronic searches and methodological filters were not used so as to maximise sensitivity.. We selected studies that had prospectively defined cohorts with any accepted definition of MCI with baseline (11)C-PIB-PET scan. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis for example NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria.. We screened all titles generated by electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. The identified full papers were assessed for eligibility and data were extracted to create two by two tables. Two independent assessors performed quality assessment using the QUADAS 2 tool. We used the hierarchical summary receiver operating characteristic (ROC) model to produce a summary ROC curve.. Conversion from MCI to Alzheimer's disease dementia was evaluated in nine studies. The quality of the evidence was limited. Of the 274 participants included in the meta-analysis, 112 developed Alzheimer's dementia. Based on the nine included studies, the median proportion converting was 34%. The studies varied markedly in how the PIB scans were done and interpreted.The sensitivities were between 83% and 100% while the specificities were between 46% and 88%. Because of the variation in thresholds and measures of (11)C-PIB amyloid retention, we did not calculate summary sensitivity and specificity. Although subject to considerable uncertainty, to illustrate the potential strengths and weaknesses of (11)C-PIB-PET scans we estimated from the fitted summary ROC curve that the sensitivity was 96% (95% confidence interval (CI) 87 to 99) at the included study median specificity of 58%. This equated to a positive likelihood ratio of 2.3 and a negative likelihood ratio of 0.07. Assuming a typical conversion rate of MCI to Alzheimer's dementia of 34%, for every 100 PIB scans one person with a negative scan would progress and 28 with a positive scan would not actually progress to Alzheimer's dementia.There were limited data for formal investigation of heterogeneity. We performed two sensitivity analyses to assess the influence of type of reference standard and the use of a pre-specified threshold. There was no effect on our findings.. Although the good sensitivity achieved in some included studies is promising for the value of (11)C-PIB-PET, given the heterogeneity in the conduct and interpretation of the test and the lack of defined thresholds for determination of test positivity, we cannot recommend its routine use in clinical practice.(11)C-PIB-PET biomarker is a high cost investigation, therefore it is important to clearly demonstrate its accuracy and standardise the process of the (11)C-PIB diagnostic modality prior to it being widely used.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Carbon Radioisotopes; Cognitive Dysfunction; Dementia; Disease Progression; Early Diagnosis; Humans; Positron-Emission Tomography; Prospective Studies; Sensitivity and Specificity; Thiazoles

In vivo imaging of amyloid-β (Aβ) with positron emission tomography has moved from the research arena into clinical practice. Clinicians working with cognitive decline and dementia must become familiar with its benefits and limitations. Amyloid imaging allows earlier diagnosis of Alzheimer disease and better differential diagnosis of dementia and provides prognostic information for mild cognitive impairment. It also has an increasingly important role in therapeutic trial recruitment and for evaluation of anti-Aβ treatments. Longitudinal observations are required to elucidate the role of Aβ deposition in the course of Alzheimer disease and provide information needed to fully use the prognostic power of this investigation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Asymptomatic Diseases; Brain; Carbon Radioisotopes; Chromosome Aberrations; Cognitive Dysfunction; Diagnosis, Differential; Disease Progression; DNA Mutational Analysis; Fluorine Radioisotopes; Genetic Carrier Screening; Humans; Positron-Emission Tomography; Prognosis; Statistics as Topic; Thiazoles

In recent years, the role of PET imaging in the prediction of mild cognitive impairment (MCI) to Alzheimer's disease (AD) conversion has been the subject of many longitudinal studies. The purpose of this study was to perform a meta-analysis to estimate the diagnostic accuracy of (18) F-fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) and (11) C-Pittsburgh Compound B-positron emission tomography (PIB-PET) for prediction of short-term conversion to AD in patients with MCI. The MEDLINE and EMBASE databases were systematically searched for relevant studies. Methodological quality of the included studies was assessed. Sensitivities and specificities of PET in individual studies were calculated and meta-analysis was undertaken with a random-effects model. A summary receiver operating characteristic (SROC) curve was constructed with the Moses-Shapiro-Littenberg method. Heterogeneity was tested, and the presence of publication bias was assessed. Potential sources for heterogeneity were explored by assessing whether or not certain covariates significantly influenced the relative diagnostic odds ratio (DOR). Pooled estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), DOR and the SROC curve of each PET imaging were determined. A total of 13 research studies (seven FDG-PET and six PIB-PET) met inclusion criteria and had sufficient data for statistical analysis. FDG-PET pooled estimates had 78.7% sensitivity (95% CI, 68.7-86.6%),74.0% specificity (95% CI, 67.0-80.3%), 18.1 LR+(95% CI, 7.3-45.0) and 0.32 LR-(95% CI, 0.16-0.61); and PIB-PET pooled estimates had 93.5% sensitivity (95%CI, 71.3-99.9%), 56.2% specificity (95% CI, 47.2-64.8%), 2.01 LR+ (95% CI, 1.57-2.58) and 0.17 LR-(95% CI, 0.08-0.36). Overall DOR was 17.3 (95% CI, 5.08-59.2) for FDG-PET and 12.8 (95% CI, 5.35-30.54) for PIB-PET. Area under the SROC curve was 0.88 ± 0.05 for FDG-PET and 0.85 ± 0.04 for PIB-PET. The data from FDG-PET research studies had high heterogeneity and funnel plot suggested a publication bias. The diagnostic accuracy determined for both FDG-PET and PIB-PET in this meta-analysis suggests that they are potentially valuable techniques for prediction of progression in patients with MCI. Both have their advantages and their combined use is a promising option for prediction purposes depending on availability and experience.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Clinical Trials as Topic; Cognitive Dysfunction; Cross-Sectional Studies; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; Sensitivity and Specificity; Thiazoles

Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15% per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of (18)F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Humans; Plaque, Amyloid; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Stilbenes; Thiazoles

Many researchers argue that Alzheimer's disease is at least partly caused by deposition of amyloid beta (Aβ) in the brain. Ferulic acid (FA) and Angelica archangelica (AA) are candidate agents for reducing Aβ and improving cognitive function. Feru-guard 100M is a supplement containing FA and AA extract. Using this supplement, we planned to assess the effect of FA and AA on Aβ deposition in the human brain.. This was an open-label, interventional multi-institutional joint study of Kobe University and the Institute of Biomedical Research and Innovation (Kobe, Japan). Seventeen subjects diagnosed with mild cognitive impairment were divided into two groups: the intervention group (n = 10) and the control group (n = 7). The subjects in the intervention group used Feru-guard 100M every day for 48 weeks, whereas the subjects in the control group did not use the supplement. We assessed the differences between the two groups by examining Aβ deposition and brain atrophy at 48 weeks and cognitive function every 24 weeks. We used carbon-11-labelled Pittsburgh compound B (PiB) positron emission tomography to evaluate Aβ deposition.. There were no significant differences in Aβ deposition, brain atrophy, and cognitive function between the two groups. Specifically, differences in Aβ deposition change in seven regions of interest examined with PiB positron emission tomography, brain atrophy change in four indicators of voxel-based morphometry, and cognitive impairment measured by five psychological tests were not significantly between the two groups.. Treatment with Feru-guard 100M, a supplement containing FA and AA extract, for 48 weeks did not reduce cortical PiB retention, which reflects Aβ deposition. It also did not suppress the aggravation of brain atrophy or decline in cognitive function.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Angelica archangelica; Aniline Compounds; Atrophy; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Coumaric Acids; Disease Progression; Female; Humans; Japan; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Impaired physical function (i.e., slowing of gait, muscle weakness, and poor mobility) is common in older adults with cognitive impairment and dementia. Evidence suggests that cerebral small vessel disease, specifically white matter lesions (WMLs), is associated with impaired physical function, but little research has been conducted to understand the specific role of Alzheimer's disease pathology in physical outcomes.. The objective of this study was to examine the association between cerebral amyloid-β (Aβ) deposition and physical function in people with cognitive impairment.. Thirty participants completed an 11C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global Aβ deposition using standardized uptake value ratio (SUVR). We assessed usual gait speed, muscle strength of the lower extremities, balance, and functional mobility using the Short Physical Performance Battery (SPPB) and the Timed Up and Go Test (TUGT). Multiple linear regression analyses examined the association between Aβ and each measure of physical function, adjusting for age, body mass index, and WML load.. Global PIB SUVR was significantly associated with usual gait speed (β= -0.52, p = 0.01) and SPPB performance (β= -0.47, p = 0.02), such that increased Aβ deposition was associated with reduced performance on both measures. Global PIB SUVR was not significantly associated with TUGT performance (β= 0.32, p = 0.08).. Cerebral Aβ deposition is associated with reduced gait speed, muscle strength, and balance in older adults with cognitive impairment independent of WML load. However, Aβ deposition was not associated with functional mobility.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Lower Extremity; Male; Movement Disorders; Muscle Strength; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Walking Speed

To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.. Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.. At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores.. The prevalence of β-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia.

Topics: Aged, 80 and over; Amyloid; Aniline Compounds; Brain; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Dementia; Disease Progression; Double-Blind Method; Female; Geriatric Assessment; Ginkgo biloba; Humans; Longitudinal Studies; Male; Neurodegenerative Diseases; Phytotherapy; Plant Extracts; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

This study examined amyloid-β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment.. Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study.. A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.. The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Double-Blind Method; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Prevalence; Thiazoles

[(11)C]PIB and [(18)F]FDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer's disease (AD). [(18)F]FDG is a glucose analogue and its uptake reflects metabolic activity. The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment (MCI) and in healthy controls.. Longitudinal, paired, dynamic [(11)C]PIB and [(18)F]FDDNP (90 min each) and static [(18)F]FDG (15 min) PET scans were obtained in 11 controls, 12 MCI patients and 8 AD patients. The mean interval between baseline and follow-up was 2.5 years (range 2.0-4.0 years). Parametric [(11)C]PIB and [(18)F]FDDNP images of binding potential (BP(ND)) and [(18)F]FDG standardized uptake value ratio (SUVr) images were generated.. A significant increase in global cortical [(11)C]PIB BP(ND) was found in MCI patients, but no changes were observed in AD patients or controls. Subsequent regional analysis revealed that this increase in [(11)C]PIB BP(ND) in MCI patients was most prominent in the lateral temporal lobe (p < 0.05). For [(18)F]FDDNP, no changes in global BP(ND) were found. [(18)F]FDG uptake was reduced at follow-up in the AD group only, especially in frontal, parietal and lateral temporal lobes (all p < 0.01). Changes in global [(11)C]PIB binding (ρ = -0.42, p < 0.05) and posterior cingulate [(18)F]FDG uptake (ρ = 0.54, p < 0.01) were correlated with changes in Mini-Mental-State Examination score over time across groups, whilst changes in [(18)F]FDDNP binding (ρ = -0.18, p = 0.35) were not.. [(11)C]PIB and [(18)F]FDG track molecular changes in different stages of AD. We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients. [(18)F]FDDNP seems to be less useful for examining disease progression.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Positron-Emission Tomography; Stilbenes; Thiazoles; Time Factors

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Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Brain; Carbolines; Cognitive Dysfunction; Female; Humans; Male; Positron-Emission Tomography; Skull; tau Proteins

Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases.. Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET.. We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage.. On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment.. The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Topics: Aged; Alzheimer Disease; Aminopyridines; Amnesia; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Quinolines; Radiopharmaceuticals; Severity of Illness Index; tau Proteins; Thiazoles

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alz

Topics: Alzheimer Disease; Amyloid; Amyloidogenic Proteins; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Male; Positron-Emission Tomography; tau Proteins

A significant proportion of patients with clinically diagnosed Alzheimer's Disease (AD) and an even higher proportion of patients with amnestic mild cognitive impairment (aMCI) do not show evidence of amyloid deposition on Positron Emission Tomography (PET) with amyloid-binding tracers such as. This study aimed to identify clinical, neuropsychological and neuroimaging factors that might suggest amyloid neuropathology in patients with clinically suspected AD or aMCI.. Forty patients with mild to moderate AD and 23 patients with aMCI who were clinically diagnosed in our memory clinic and had PiB PET scans were included. Clinical, neuropsychological, and imaging characteristics, such as Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMH) on MRI and metabolic pattern on. Compared with PiB positive patients, PiB negative patients had a higher prevalence of hypertension history, better performance on the Mini-Mental State Examination, the Rey Auditory Verbal Learning Test, and the Judgement of Line Orientation, lower score of MTA, and were less likely to have temporoparietal-predominant hypometabolism on FDG PET. Affective symptoms were less common in PiB negative patients diagnosed with AD, and the Animal Fluency Test score was higher in PiB negative patients diagnosed with aMCI.. In patients with clinically diagnosed AD or aMCI, absence of a history of hypertension, deficits in verbal learning and memory, visuospatial function, semantic verbal fluency, presence of affective symptoms, MTA on MRI, and temporoparietal hypometabolism on FDG PET suggested amyloid deposition in the brain.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Atrophy; Brain; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear.. To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition.. Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive group. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition.. PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake.. Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of neurovascular unit are useful for identifying elderly individuals at risk of developing Alzheimer's disease.

Topics: Adenosine Triphosphate; Aged; Alzheimer Disease; Aniline Compounds; Biological Transport; Biomarkers; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles

This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent

Topics: Aged; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Matrix Metalloproteinases; Regression Analysis; Thiazoles; Tissue Inhibitor of Metalloproteinases; White Matter

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Althoug

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Basal Ganglia; Brain; Brain Mapping; Carbolines; Cerebral Cortex; Cognitive Dysfunction; Female; Globus Pallidus; Gray Matter; Humans; Iron; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Positron-Emission Tomography; Putamen; Radiopharmaceuticals; Substantia Nigra; Subthalamic Nucleus; tau Proteins; Thiazoles

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Biomarkers; Carbon Radioisotopes; Cognitive Dysfunction; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Organ Size; Positron-Emission Tomography; Protein Aggregates; Radiopharmaceuticals; Thiazoles; White Matter

This study aimed to evaluated the clinical impact of adding [11C] Pittsburgh compound-B (11C-PiB) PET for clinical diagnosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia.Twenty six (mean age 78.5 ± 5.18 years, 21 females) AD (n = 7), amnestic MCI (n = 12), non-amnestic MCI (n = 3), vascular dementia, progressive supranuclear palsy (PSP) with frontotemporal dementia (FTD), FTD (n = 1 each), and normal (n = 1) patients underwent 11C-PiB-PET, MRI, and SPECT scanning. 11C-PiB-PET was compared with MRI and SPECT for clinical impact.11C-PiB-PET showed positivity in 6, 9, and 0 of the AD, amnestic MCI, and non-amnestic MCI patients, respectively, and 0 of those with another disease. Parahippocampal atrophy at VSASD was observed in 5 AD patients, 6 amnestic and PiB-positive MCI patients, 1 amnestic and PiB-negative MCI patient, and 1 vascular dementia patient. Parietal lobe hypoperfusion in SPECT findings was observed in 6, 4, and 2 of those, respectively, as well as 1 each of non-amnestic MCI, vascular dementia, and normal cases. Sensitivity/specificity/accuracy for selecting PiB-positive patients among the 15 MCI patients for 11C-PiB-PET were 100% (9/9)/100% (6/6)/100% (15/15), for VSRAD were 66.7% (6/9)/83.3% (5/6)/73.3% (11/15), and for SPECT were 44.4% (4/9)/50.0% (3/6)/46.7% (7/15), while those were 88.9% (8/9)/33.3% (2/6)/66.7% (10/15)/for combined VSRAD and SPECT. 11C-PiB-PET accuracy was significantly higher than that of SPECT.11PiB-PET alone may be useful for selecting patients who will progress from MCI to AD in the future, although follow-up study is necessary to clarify the outcome of MCI patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Thiazoles; Tomography, Emission-Computed, Single-Photon

Moderate-to-high correlations have been reported between the [. Test-retest data belonging to twelve participants, who underwent two 90 min [. Test-retest variability was low across regions (max. 5.8 %), and test and retest measures showed high, significant correlations (R. In conclusion, the high precision of [

Topics: Adult; Aged; Alzheimer Disease; Aniline Compounds; Cerebrovascular Circulation; Cognitive Dysfunction; Female; Gray Matter; Humans; Image Processing, Computer-Assisted; Linear Models; Male; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Thiazoles; Water

The objectives of the present study were to investigate (1) whether trinary visual interpretation of amyloid positron emission tomography (PET) imaging (negative/equivocal/positive) reflects quantitative amyloid measurements and the time course of. Trinary visual interpretation (negative/equivocal/positive) of amyloid PET imaging reflects quantitative amyloid measurements evaluated with PET and the CSF amyloid test as well as the amyloid accumulation over time evaluated with PET over 3 years. Subjects in the early stage of the AD continuum could be identified with an equivocal scan, because they showed intermediate quantitative amyloid PET, CSF measurements, and the amyloid accumulation over time.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Cross-Sectional Studies; Databases, Factual; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Thiazoles; Time Factors

Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established.. We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology.. With only 1.5μl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains.. Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains.. The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Peptides; Positron-Emission Tomography; Predictive Value of Tests; Reference Values; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; tau Proteins; Thiazoles

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Humans; Isoquinolines; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neurofibrillary Tangles; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Prodromal Symptoms; tau Proteins; Thiazoles

It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD-related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid-beta (Aβ) burden, AD-signature regional neurodegeneration, and white matter hyperintensities (WMH) in non-demented middle- and old-aged adults.. A total of 397 non-demented participants underwent comprehensive clinical and neuropsychological assessments,. Neither neuroticism nor conscientiousness was associated with cerebral Aβ deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD-signature region cortical thickness. In regards to the direct and indirect effect of each personality on AD-signature region cortical thickness, only the direct effects were found, whereas indirect effects via Aβ deposition or WMH were not.. The present findings suggest that amyloid-independent regional neurodegeneration might underlie relations of neuroticism and conscientiousness with AD.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroticism; Personality; Personality Inventory; Positron-Emission Tomography; Risk Factors; Thiazoles; White Matter

An emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain.. The present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1-13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1-13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163-0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history.. In this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.

Topics: Aged; Aged, 80 and over; Alcohol Drinking; Amyloid beta-Peptides; Aniline Compounds; Brain; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Protective Factors; Republic of Korea; Thiazoles

The pathological cascades associated with the development of Alzheimer's disease (AD) have a common element: acidosis. T. Twenty-seven participants (men, N=13, women, N=14; ages 55-90) across the cognitive spectrum (healthy control subjects [HCs] with normal cognition, N=17; participants with mild cognitive impairment [MCI], N=7; participants with mild AD, N=3) underwent neuropsychological testing, MRI (T. Global mean and median T. Higher T

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Pilot Projects; Positron-Emission Tomography; Thiazoles

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Carbon Radioisotopes; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Positron Emission Tomography Computed Tomography; Pyridines; Radioactive Tracers; Thiazoles

To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition.. A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent. HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas.. Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.

Topics: Aged; AIDS Dementia Complex; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Cohort Studies; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

To determine whether vascular and neurodegenerative factors influence cognition before clinically relevant Alzheimer disease pathology, we analyzed MRI measures and amyloid imaging in an ethnoracially diverse cohort of cognitively normal individuals older than 60 years.. Participants (n = 154; mean age 74.15 ± 6.94; 50% female; 54% Caucasian, 22.1% Hispanic, 14.9% African American) were recruited from the University of California, Davis Alzheimer's Disease Research Center, who were cognitively normal at baseline, time of PET, and MRI, and received yearly cognitive assessment for 6.23 ± 4.16 years. Mixed model regression with random slope and intercept was calculated for episodic memory and executive function, adjusting for age, sex, education, and ethnicity.. Vascular burden score was associated with total white matter hyperintensity (WMH) volume (β, 0.171; 95% confidence interval [CI], 0.024-0.318). WMH volume was associated with low baseline executive function (-0.115; -0.226 to -0.003) and rate of change in memory (-0.029; -0.045 to -0.012). Hippocampal volume was associated with the rate of change in memory (0.040; 0.021-0.059) and executive function (0.024; 0.008-0.039). Continuous measures of amyloid status influenced change in memory (-0.026; -0.044 to -0.008) and executive function (-0.033; -0.046 to -0.021) independently of MRI measures.. Vascular brain injury and neurodegeneration are associated with baseline cognitive performance and the rate of longitudinal change independent of amyloid status among community-dwelling, ethnicity diverse cognitively normal individuals, supporting the role of vascular diseases as risk factors for later-life dementia.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cerebrovascular Disorders; Cognition; Cognitive Dysfunction; Disease Progression; Executive Function; Female; Hippocampus; Humans; Independent Living; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Neuropsychological Tests; Organ Size; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles; White Matter

To assess and compare the involvement of choroidal thickness (CT) in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) defined by amyloid PET and healthy controls (HC).. Sixty-three eyes from 34 AD patients [12 eyes (19.0%) with dementia and 51 eyes (80.9%) with MCI], positive to 11C-labelled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired HC were recruited. All participants underwent enhanced depth imaging optical coherence tomography (EDI-OCT) assessing CT at 14 measurements from 2 B-scans. Paired Student t-test was used to compare CT measurements between MCI, dementia and sex- and age-paired HC. A univariate generalized estimating equations model (GEE) test was performed to compare MCI and dementia individually with all HC included.. Compared with HC, eyes from patients with positive 11C-PiB PET/CT showed a significant CT thinning in 5 selected locations (in foveal thickness in vertical scan, in temporal scan at 1500μm, in superior scan at 500μm and in inferior scan at 1000μm and 1500μm, p = 0.020-0.045) whilst few significant CT reduction data was reported in MCI or dementia individually versus HC. However, the GEE test identified significant CT thinning in AD compared with all HC included (p = 0.015-0.046).. To our knowledge, the present study is the first measuring CT in eyes from MCI and dementia eyes positive to 11C-PiB PET/CT reporting a significant trend towards CT thinning in MCI patients which became more pronounced in dementia stage. We support further investigation involving larger and prospective OCT studies in AD population characterized with available biomarkers to describe whether choroidal vascular damage occurs specifically in prodromal stages of AD.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Anthropometry; Area Under Curve; Carbon Radioisotopes; Case-Control Studies; Choroid; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Early Diagnosis; Female; Humans; Male; Neuroimaging; Observer Variation; Positron Emission Tomography Computed Tomography; Prodromal Symptoms; Radiopharmaceuticals; Reproducibility of Results; Thiazoles; Tomography, Optical Coherence

Studies of elderly subjects using biomarkers that are proxies for Alzheimer's disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum.. To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration.. Patients with mild dementia compatible with AD (n = 38) or amnestic mild cognitive impairment (aMCI; n = 43) and a cognitively unimpaired group (n = 27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18F]FDG-PET assessing neurodegeneration ((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination.. The A+(N)+ subgroup (n = 32) showed decreased (p < 0.001) cognitive test scores compared to both A+(N)-(n = 18) and A-(N)-(n = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n = 9), the A-(N)+ subgroup showed lower (p < 0.043) verbal memory scores relative to A-(N)-subjects, and trend lower (p = 0.096) scores relative to A+(N)-subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)-groups.. These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)-and A-(N)-subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognition; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Male; Memory, Episodic; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer's disease (AD).. To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum.. We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity.. In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP.. The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Aniline Compounds; Brain; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Ethylene Glycols; Female; Glial Fibrillary Acidic Protein; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Adiponectin has been implicated in the pathophysiology of dementia, especially Alzheimer's disease. However, the association between cerebrospinal fluid (CSF) adiponectin levels and positron emission tomography (PET) imaging remains unclear.. To explore whether CSF adiponectin levels are associated with. Thirty-four amnestic MCI subjects underwent PiB-PET, FDG-PET, and CSF analysis. The CSF adiponectin levels were measured using the Bio-Plex 200 suspension array system. PET uptake was assessed for the frontal and temporoparietal lobes and posterior cingulate gyrus, referenced against the cerebellar cortex. The increased brain amyloid burden was defined as a mean uptake value ratio greater than 1.4. Spearman's rank correlation analysis and a multiple regression model were used to examine the association between CSF adiponectin levels and PiB or FDG uptake.. The mean age was 76.3 years; 38.2% were men, and 61.8% were women. A high amyloid burden was identified in 18 (52.9%) subjects. CSF adiponectin levels positively correlated with global FDG uptake (β = 0.45; 95% confidence interval (CI), 0.13 to 0.76, p < 0.01), especially in the parietotemporal lobe and posterior cingulate gyrus (β = 0.70; 95% CI, 0.41 to 0.99, p<0.01, β = 0.33; 95% CI, 0.03 to 0.63, p = 0.03, respectively) after adjusting for covariates, including age, sex, education years, body mass index, vascular risk factors, ApoEε4 status, and PiB status in all amnestic MCI subjects.. CSF adiponectin levels were associated with cortical glucose metabolism, particularly in the specific regions that connect with the medial temporal, but not brain amyloid burden in amnestic MCI subjects.

Topics: Adiponectin; Aged; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Pilot Projects; Positron-Emission Tomography; Thiazoles

Alzheimer's disease (AD) is the most common age-associated dementia. Many studies have sought to predict cerebral amyloid deposition, the major pathological hallmark of AD, using body fluids such as blood or cerebral spinal fluid (CSF). The use of blood in diagnostic procedures is widespread in medicine; however, existing blood biomarkers for AD remain unreliable. We sought to discover blood biomarkers that discriminate Aβ deposition status in the brain. This study used 107 individuals who were cognitively normal (CN), 107 patients with mild cognitive impairment (MCI), and 40 AD patients with Pittsburg compound B positron emission tomography (PiB-PET) amyloid imaging data available. We found five plasma biomarker candidates via mass spectrometry (MS) based-proteomic analysis and validated these proteins using enzyme-linked immunosorbent assay (ELISA). Our integrated models were highly predictive of brain amyloid deposition, exhibiting 0.871 accuracy with 79% sensitivity and 84% specificity overall, and 0.836 accuracy with 68% sensitivity and 90% specificity in patients with MCI. These results indicated that a combination of proteomic-based blood proteins might be a possible biomarker set for predicting cerebral amyloid deposition.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Blood Chemical Analysis; Blood Proteins; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Positron-Emission Tomography; Predictive Value of Tests; Prognosis; Proteomics; Sensitivity and Specificity; Thiazoles

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.

Topics: Adult; Age of Onset; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Male; Mental Recall; Positron-Emission Tomography; Thiazoles; Young Adult

Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer's disease (AD) in large population screening strategies.. This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years.. Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern.. Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF).. TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Early Diagnosis; Female; Fluorodeoxyglucose F18; Genotype; Humans; Male; Neuroimaging; Peptide Fragments; Phosphorylation; Plaque, Amyloid; Positron-Emission Tomography; Prodromal Symptoms; tau Proteins; Thiazoles

Amyloid-β (Aβ) and [18F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aβ PET images have the potential to replace [18F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18F]FDG PET data, a correlation with cognitive performance is known.. The aim of this study was to investigate whether early after administration [11C]PiB PET data also correlate with cognitive performance.. The early after administration [11C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aβ-positive versus Aβ-negative subjects) were performed.. Significant correlations between cognitive performance and early after administration [11C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did.. Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11C]PiB PET data similar to those known from [18F]FDG PET studies. Thus, our data support the assumption that early [11C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption.

Topics: Aged; Aniline Compounds; Carbon Radioisotopes; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles; Time Factors

In Alzheimer's Disease (AD) dual-tracer positron emission tomography (PET) studies with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and 11C-labelled Pittsburgh Compound B (PIB) are used to assess metabolism and cerebral amyloid-β deposition, respectively. Regional cerebral metabolism and blood flow (rCBF) are closely coupled, both providing an index for neuronal function. The present study compared PIB-derived rCBF, estimated by the ratio of tracer influx in target regions relative to reference region (R1) and early-stage PIB uptake (ePIB), to FDG scans. Fifteen PIB positive (+) patients and fifteen PIB negative (-) subjects underwent both FDG and PIB PET scans to assess the use of R1 and ePIB as a surrogate for FDG. First, subjects were classified based on visual inspection of the PIB PET images. Then, discriminative performance (PIB+ versus PIB-) of rCBF methods were compared to normalized regional FDG uptake. Strong positive correlations were found between analyses, suggesting that PIB-derived rCBF provides information that is closely related to what can be seen on FDG scans. Yet group related differences between method's distributions were seen as well. Also, a better correlation with FDG was found for R1 than for ePIB. Further studies are needed to validate the use of R1 as an alternative for FDG studies in clinical applications.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Carbon Radioisotopes; Case-Control Studies; Cerebrovascular Circulation; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer's disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy.. To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia.. Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction.. Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid.. This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apathy; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Surveys and Questionnaires; tau Proteins; Thiazoles

Cerebrospinal fluid (CSF) plays an important role in solute clearance and maintenance of brain homeostasis.

Topics: Adult; Aged; Algorithms; Alzheimer Disease; Aniline Compounds; Area Under Curve; Brain; Case-Control Studies; Cerebrospinal Fluid; Cognitive Dysfunction; Databases, Factual; Female; Homeostasis; Humans; Kinetics; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Thiazoles

The aim of this study was to evaluate the cerebral amyloid distribution in patients with mild cognitive impairment (MCI), assessed by carbon-11-Pittsburgh compound B (C-PIB) PET/CT, after 5 years of follow-up.. Ten amnestic MCI (A-MCI) and four nonamnestic (NA-MCI) patients were studied by C-PIB PET/CT and re-evaluated 5 years later by a new C-PIB PET/CT. PET/CT scans were acquired 60-90 min after the administration of 555 MBq C-PIB and analyzed visually, to obtain a score of the cerebral cortical C-PIB retention in the frontal, basal ganglia (BG), temporoparietal (TP), occipital, posterior cingulate, and cerebellum areas. Initial and 5-year follow-up C-PIB retentions were compared.. Initially, 9/10 A-MCI patients were C-PIB positive and one was C-PIB negative. All four NA-MCI patients were C-PIB negative. Of the C-PIB-positive A-MCI patients, seven progressed to Alzheimer's disease dementia (AD-D), one to mixed dementia and one remained as A-MCI. The C-PIB-negative A-MCI patient remained as A-MCI. Of the four C-PIB-negative NA-MCI, one progressed to semantic dementia. All changes in C-PIB retention were of low intensity. The A-MCI patients who progressed to AD-D (n=7) showed an increase in C-PIB retention in the frontal (5/7), BG (3/7), TP (3/7), occipital (1/7), and posterior cingulate (1/7) regions. The A-MCI patient who progressed to mix dementia showed an increase in C-PIB retention in the frontal region. The C-PIB-positive A-MCI patient who remained as A-MCI showed an increase in C-PIB retention in the frontal, BG, and TP areas. The amyloid deposition in the anterior part of the brain (frontal, TP, and BG) increased more than that in the posterior part (occipital and precuneus) (7/9 vs. 2/9; P<0.05).. PIB retention increased predominantly in the frontal, BG, and TP areas. C-PIB-positive A-MCI patients mostly progressed to AD-D, showing similar topographic changes in their cerebral C-PIB pattern than the patient who remained as A-MCI.

Topics: Aged; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Female; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Thiazoles

To identify potential predictors for outcome in individuals with mild cognitive impairment (MCI) who have reverted to normal cognition (NC).. We selected individuals with MCI, who reverted at follow-up to NC, with follow-up after reversion from Alzheimer's Disease Neuroimaging Initiative. Common clinical markers, Alzheimer disease (AD) biomarkers, and neurodegeneration imaging markers were used to compare MCI reverters based on subsequent clinical outcome (i.e., subsequent decline or stable reversion). For independent comparison, findings of the clinical Amsterdam Dementia Cohort are presented.. Seventy-seven (10%) out of 757 individuals with MCI reverted to NC and 61 of these individuals had follow-up data available. After 3.2 ± 2.2 years, 16 (24%) progressed to MCI, and 3 (5%) to dementia. Those who declined were older and had a higher amyloid PET burden and higher CSF tau levels.. In MCI reverters, abnormal biomarkers for AD pathology are associated with subsequent decline. AD biomarkers may aid in the prognosis of reverting MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Dementia; Disease Progression; Ethylene Glycols; Female; Humans; Male; Middle Aged; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Prognosis; Recurrence; Remission, Spontaneous; Risk Assessment; tau Proteins; Thiazoles

Amyloid imaging with positron emission tomography (PET) often comes with glucose metabolic imaging in diagnosis of Alzheimer's disease (AD).. The present purpose was to explore the clinical valence of early amyloid-β (Aβ) PET scans to determine whether they could substitute for other imaging biomarkers (early and delayed Aβ images of 11C-Pittsburgh compound B (PIB) and 18F-fluorodeoxyglucose (FDG) images) in the AD spectrum.. Thirty healthy control subjects, 20 patients with mild cognitive impairment, and 45 patients with AD underwent 11C-PIB and 18F- FDG PET. Image analyses were performed with three-dimensional stereotactic surface projection and Brodmann's area regions-of-interest methods. Since early accumulation of PIB (ePIB) reflects blood flow, we classified all subjects according to the level of ePIB in the posterior cingulate gyrus, precuneus, and lateral parietal cortex. We compared the PET parameters (ePIB, delayed-phase PIB accumulation or dPIB, FDG) to determine whether ePIB-based categorization reflected Aβ deposition in a Braak stage-related fashion.. We found that ePIB images were similar to 18F-FDG images and that the progress of Aβ deposition deduced from the reduction in ePIB index was similar to the pathological progress of Braak staging. A decrease in the ePIB level in the posterior cingulate gyrus, precuneus, and parietal cortex was shown to correspond to greater and wider Aβ deposition in the medial frontal, anterior, and posterior cingulate gyri.. The early-phase 11C-PIB index can be an alternative to the neurogenerative markers of glucose hypometabolism and reflects the Braak stage of Aβ deposition in the living AD brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Carbon Radioisotopes; Cognitive Dysfunction; Cross-Sectional Studies; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

We aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes.. Seventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression.. There were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET.. Elevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change.

Topics: Aged; Aniline Compounds; Attention; Brain; Cognition; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neurofilament Proteins; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum.. We selected 839 β-amyloid (Aβ)-positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale-cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF).. The median follow-up period was 24 months (interquartile range 6-42). Corrected for age, sex,. Among Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Case-Control Studies; Cognitive Dysfunction; Cognitive Reserve; Contrast Media; Disease Progression; Ethylene Glycols; Executive Function; Female; Gray Matter; Humans; Male; Memory; Middle Aged; Organ Size; Peptide Fragments; Thiazoles; White Matter

Amyloid deposition, tau neurofibrillary tangles, and cerebrovascular dysfunction are important pathophysiologic features in Alzheimer's disease. Pittsburgh compound B ([. We obtained [. Both of the partial-volume corrected PET parameters were correlated with white matter hyperintensities and fractional anisotropy.. Future studies are warranted to explore whether [

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Cerebrovascular Circulation; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles; White Matter

To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline.. In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect.. Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures.. A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Asymptomatic Diseases; Benzothiazoles; Brain; Cognitive Dysfunction; Contrast Media; Disease Progression; Ethylene Glycols; Female; Humans; Male; Mental Recall; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; Time Factors; Trail Making Test

Alzheimer's disease is increasingly considered a large-scale network disconnection syndrome, associated with progressive aggregation of pathological proteins, cortical atrophy, and functional disconnections between brain regions. These pathological changes are posited to arise in a stereotypical spatiotemporal manner, targeting intrinsic networks in the brain, most notably the default mode network. While this network-specific disruption has been thoroughly studied with functional neuroimaging, changes to specific white matter fibre pathways within the brain's structural networks have not been closely investigated, largely due to the challenges of modelling complex white matter structure. Here, we applied a novel technique known as 'fixel-based analysis' to comprehensively investigate fibre tract-specific differences at a within-voxel level (called 'fixels') to assess potential axonal loss in subjects with Alzheimer's disease and mild cognitive impairment. We hypothesized that patients with Alzheimer's disease would exhibit extensive degeneration across key fibre pathways connecting default network nodes, while patients with mild cognitive impairment would exhibit selective degeneration within fibre pathways connecting regions previously identified as functionally implicated early in Alzheimer's disease. Diffusion MRI data from Alzheimer's disease (n = 49), mild cognitive impairment (n = 33), and healthy elderly control subjects (n = 95) were obtained from the Australian Imaging, Biomarkers and Lifestyle study of ageing. We assessed microstructural differences in fibre density, and macrostructural differences in fibre bundle morphology using fixel-based analysis. Whole-brain analysis was performed to compare groups across all white matter fixels. Subsequently, we performed a tract of interest analysis comparing fibre density and cross-section across 11 selected white matter tracts, to investigate potentially subtle degeneration within fibre pathways in mild cognitive impairment, initially by clinical diagnosis alone, and then by including amyloid status (i.e. a positive or negative amyloid PET scan). Our whole-brain analysis revealed significant white matter loss manifesting both microstructurally and macrostructurally in Alzheimer's disease patients, evident in specific fibre pathways associated with default mode network nodes. Reductions in fibre density and cross-section in mild cognitive impairment patients were only exhibited within the posterior cing

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Imaging, Three-Dimensional; Male; Mental Status Schedule; Nerve Fibers; Positron-Emission Tomography; Thiazoles; White Matter

Recent evidence indicates that measures from cerebrospinal fluid, MRI scans and cognitive testing obtained from cognitively normal individuals can be used to predict likelihood of progression to mild cognitive impairment several years later, for groups of individuals. However, it remains unclear whether these measures are useful for predicting likelihood of progression for an individual. The increasing focus on early intervention in clinical trials for Alzheimer's disease emphasizes the importance of improving the ability to identify which cognitively normal individuals are more likely to progress over time, thus allowing researchers to efficiently screen participants, as well as determine the efficacy of any treatment intervention. The goal of this study was to determine which measures, obtained when individuals were cognitively normal, predict on an individual basis, the onset of clinical symptoms associated with a diagnosis of mild cognitive impairment due to Alzheimer's disease. Cognitively normal participants (n = 224, mean baseline age = 57 years) were evaluated with a range of measures, including: cerebrospinal fluid amyloid-β and phosphorylated-tau, hippocampal and entorhinal cortex volume, cognitive tests scores and APOE genotype. They were then followed to determine which individuals developed mild cognitive impairment over time (mean follow-up = 11 years). The primary outcome was progression from normal cognition to the onset of clinical symptoms of mild cognitive impairment due to Alzheimer's disease at 5 years post-baseline. Time-dependent receiver operating characteristic analyses examined the sensitivity and specificity of individual measures, and combinations of measures, as predictors of the outcome. Six measures, in combination, were the most parsimonious predictors of transition to mild cognitive impairment 5 years after baseline (area under the curve = 0.85; sensitivity = 0.80, specificity = 0.75). The addition of variables from each domain significantly improved the accuracy of prediction. The incremental accuracy of prediction achieved by adding individual measures or sets of measures successively to one another was also examined, as might be done when enrolling individuals in a clinical trial. The results indicate that biomarkers obtained when individuals are cognitively normal can be used to predict which individuals are likely to develop clinical symptoms at 5 years post-baseline. As a number of the measures included in the study

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; ROC Curve; tau Proteins; Thiazoles; Time Factors

To describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.. Eight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.. All participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33).. The participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.

Topics: Aged; Aged, 80 and over; Amnesia; Aniline Compounds; Atrophy; Brain; Carbolines; Cognitive Dysfunction; Dementia; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Organ Size; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-β deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-β-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-β-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-β-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-β-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-β deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-β deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Brain; Brain Mapping; Cognitive Dysfunction; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Magnetoencephalography; Male; Neuropsychological Tests; Positron-Emission Tomography; Prodromal Symptoms; Psychiatric Status Rating Scales; Thiazoles

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder. The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 (HO-1)-an important cellular cytoprotectant in preserving mental acuity-using an aging rat model of dementia. Male and female Wistar rats were segregated into six groups-namely, (i) aged sedentary (control) females (ASF,

Topics: Aging; Amyloid; Aniline Compounds; Animals; Brain; Cerebral Amyloid Angiopathy; Cognitive Dysfunction; Dementia; Disease Models, Animal; Female; Heme Oxygenase-1; Male; Maze Learning; Physical Conditioning, Animal; Positron-Emission Tomography; Rats, Wistar; Spatial Memory; Thiazoles

Brain amyloid deposition is a marker of Alzheimer disease (AD) pathology. The population-based prevalence and outcomes of amyloid positivity in a population without dementia are important for understanding the trajectory of amyloid positivity to clinically significant outcomes and for designing AD prevention trials.. To determine prevalence and outcomes of amyloid positivity in a population without dementia.. In the prospective, population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, participants without dementia were randomly selected from the county population and were clinically and cognitively evaluated at baseline and every 15 months from August 1, 2008, to September 18, 2018. They were also invited to undergo carbon11-Pittburgh compound B positron emission tomography (PET) imaging.. Amyloid positivity (defined as a standardized uptake value ratio >1.42 on PET).. Prevalence of amyloid positivity in the Olmsted County population without dementia and risk of progression from no cognitive impairment (ie, normal cognition for age) to incident amnestic MCI (aMCI) and from MCI or aMCI to incident AD dementia.. Of 3894 participants, 1671 underwent PET imaging and were included in the study; 2198 did not undergo imaging, and 25 were excluded for other reasons. The mean (SD) age of participants was 71.3 (9.8) years; 892 (53.4%) were men, and 179 (10.7%) had prevalent MCI. The prevalence of amyloid positivity without cognitive impairment in the population without dementia increased from 2.7% (95% CI, 0.5% to 4.9%) in persons aged 50 to 59 years to 41.3% (95% CI, 33.4% to 49.2%) in those aged 80 to 89 years at baseline. Prevalence of amyloid-positive MCI in the population without dementia increased from 0% in persons aged 50 to 59 years to 16.4% (95% CI, 10.3% to 22.5%) in those aged 80 to 89 years. The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio [HR], 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia.. Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Asymptomatic Diseases; Brain; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Prevalence; Proportional Hazards Models; Prospective Studies; Thiazoles; United States

In subjects with amyloid deposition, striatal accumulation of. Seventy-three subjects who complained of cognitive disturbance underwent dynamic PiB-PET studies and showed positive PiB accumulation were retrospectively selected. These subjects included 34 AD, 26 mild cognitive impairment, 2 frontotemporal lobar degeneration, 2 Parkinson's disease, 5 dementia with Lewy bodies, and 4 undefined diagnosis patients. Individual BP. There were highly significant correlations between striatal and prefrontal BP. Our study demonstrated positive correlations in amyloid deposits between the striatum and other cortical areas with functional and anatomical links. The amyloid distribution in the brain is not random, but spreads following the functional and anatomical connections.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Corpus Striatum; Female; Frontotemporal Lobar Degeneration; Humans; Lewy Body Disease; Male; Parkinson Disease; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Thiazoles

Accurate spatial normalization (SN) of amyloid positron emission tomography (PET) images for Alzheimer's disease assessment without coregistered anatomical magnetic resonance imaging (MRI) of the same individual is technically challenging. In this study, we applied deep neural networks to generate individually adaptive PET templates for robust and accurate SN of amyloid PET without using matched 3D MR images. Using 681 pairs of simultaneously acquired

Topics: Algorithms; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Deep Learning; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Radiopharmaceuticals; Supervised Machine Learning; Thiazoles

There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood.. To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition.. The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake.. Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio.. Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Dementia; Diet, Mediterranean; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Prospective Studies; Psychiatric Status Rating Scales; Surveys and Questionnaires; Thiazoles

Mild cognitive impairment (MCI) can include the transition from a normal state to dementia. To explore biomarkers for the development of dementia, we performed an 18-month follow-up study in 28 patients with amnestic MCI. Amyloid deposition was examined using PiB PET, and cerebral blood flow (CBF) was examined using SPECT. Cognitive function was periodically assessed. The rate of conversion to dementia was higher in the PiB-positive/equivocal group (74%) than in the PiB-negative group (33%) (p = 0.041). Perfusion SPECT was performed in 16 patients. MCI patients with an AD-characteristic pattern of reduced CBF had a higher PiB-positive/equivocal rate (82%) than those with a non-AD pattern (20%) (p = 0.018), and patients with an AD pattern had a higher conversion rate (82%) than those with a non-AD pattern (40%) (p = 0.094). Clinically, all PiB-positive converters were diagnosed as having Alzheimer's disease (AD), whereas PiB-negative converters were thought to have some form of dementia other than AD. Amyloid PET is useful for predicting conversion to AD in MCI patients. A pattern analysis of perfusion SPECT findings might also be helpful for predicting conversion to AD, but with a lower specificity.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Male; Neuropsychological Tests; Perfusion Imaging; Phenanthrolines; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Retrospective Studies; Thiazoles; Tomography, Emission-Computed, Single-Photon

Late life depression is related to pathologic burdens, such as cerebral small vascular disease (CSVD) and amyloid, which are associated with brain network changes and cortical thinning. To examine the associations of various CSVD imaging markers, amyloid, and network changes with depression in cognitively impaired patients, we prospectively recruited 228 cognitively impaired patients having various degrees of amyloid and CSVD who underwent diffuse tensor image and PiB PET. Greater CSVD burden was associated with greater Geriatric Depression Scale (GDS) (white matter hyperintensities, WMH: p = 0.025, lacunes: p < 0.001) but not with amyloid (p = 0.095), and cortical thinning (p = 0.630) was not associated with greater GDS. The changes in white matter networks were related to GDS with decreasing integration (global efficiency: p < 0.001) and increasing segregation (clustering coefficient: p = 0.009). The network changes mediated the relationships of WMH and lacunes with GDS. Our findings provide insight to better understand how CSVD burdens contribute to depression in cognitively impaired patients having varying degrees of amyloid and vascular burdens.

Topics: Aged; Amyloid; Aniline Compounds; Brain; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Depression; Diffusion Tensor Imaging; Female; Humans; Male; Organ Size; Phenanthrolines; Positron-Emission Tomography; Prospective Studies; Psychiatric Status Rating Scales; Radiopharmaceuticals; Thiazoles

Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitu

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Biomarkers; Cognitive Dysfunction; Female; Genotype; Humans; Incidence; Kaplan-Meier Estimate; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Psychometrics; Thiazoles

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloidogenic Proteins; Aniline Compounds; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Occipital Lobe; Positron-Emission Tomography; Thiazoles

Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Apolipoproteins E; Brain; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Peptide Fragments; Positron-Emission Tomography; ROC Curve; Statistics, Nonparametric; tau Proteins; Thiazoles

As a new beta amyloid (Aβ) positron emission tomography (PET) tracer, F-FC119S has shown higher cortical uptake in patients with Alzheimer's disease (AD) than that in healthy control subjects without adverse effects in a previous preliminary study. The aim of this study was to compare F-FC119S PET and C-PiB PET in healthy control (HC) subjects, mild cognitive impairment (MCI) patients, and AD patients.A total of 48 subjects, including 28 HC subjects, 10 MCI patients, and 10 AD patients, underwent static F-FC119S PET (30 minutes after intravenous [i.v.] injection) and C-PiB PET (40 minutes after i.v. injection) on the same day. Both PET images were visually and quantitatively assessed. Standardized uptake value ratios (SUVRs) were calculated for each brain region using the cerebellar cortex as a reference region.None (0%) of the 28 HC subjects and 4 (40%) of 10 MCI patients had positive scans on both PET images. Of the 10 AD patients, 7 (70%) had positive scans on C-PiB PET while 6 (60%) had positive scans on F-FC119S PET. Overall, 47 (98%) of 48 participants showed identical results based on visual analysis. Cortical SUVR of F-FC119S was higher in AD patients (1.38 ± 0.16), followed by that in MCI patients (1.24 ± 0.10) and in HC subjects (1.14 ± 0.05). Compared with C-PiB PET, F-FC119S PET yielded a higher effect size (d = 2.02 vs. 1.67) in AD patients and a slightly lower effect size (d = 1.26 vs. 1.38) in MCI patients. In HC subjects, the nonspecific binding of F-FC119S to white matter (with the frontal cortex-to-white matter SUV ratio of 0.76) was slightly lower than that of C-PiB (ratio of 0.73). There was a significant linear correlation (slope = 0.41, r = 0.78, P < 0.001) between C-PiB and F-FC119S cortical SUVR.We could safely obtain images similar to C-PiB PET imaging Aβ in the brain using F-FC119S PET. Therefore, F-FC119S might be suitable for imaging Aβ deposition.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Healthy Volunteers; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis.. We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology.. MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition.. MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Male; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Thiazoles

The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.. Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.. Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ. Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amino Acids; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Fasting; Female; Humans; Male; Metabolic Diseases; Metabolic Networks and Pathways; Metabolomics; Peptide Fragments; Phosphatidylcholines; Sphingomyelins; tau Proteins; Thiazoles

While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden was estimated from Alzheimer's disease vulnerable regions, including the frontal, lateral parietal and lateral temporal, and retrosplenial cortex. Memory self-awareness was assessed using discrepancy scores between subjective and objective measures of memory function. A set of univariate analysis of variance were performed to assess the relationship between self-awareness of memory and amyloid pathology. Whereas CN individuals harboring amyloid pathology demonstrated hypernosognosia, MCI patients with increased amyloid pathology demonstrated anosognosia. In contrast, MCI patients with low amounts of amyloid were observed to have normal insight into their memory functions. Altered self-awareness of memory tracks with amyloid pathology. The findings of variability of awareness may have important implications for the reliability of self-report of dysfunction across the spectrum of preclinical and prodromal Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Awareness; Brain; Cognitive Dysfunction; Cost of Illness; Cross-Sectional Studies; Diagnostic Self Evaluation; Disease Progression; Female; Humans; Male; Memory; Mental Status and Dementia Tests; Middle Aged; Positron-Emission Tomography; Prodromal Symptoms; Radiopharmaceuticals; Thiazoles

We investigated the amyloid and vascular burden in Pittsburgh compound B (PiB)-negative subcortical vascular mild cognitive impairment (svMCI) and PiB-negative subcortical ischemic vascular dementia (SIVD) to elucidate the potential roles of amyloid deposition and small vessel disease (SVD). Thirty-eight svMCI patients and 42 SIVD patients were enrolled. The regional PiB uptake values and SVD markers were obtained and compared between groups. Additionally, correlations among amyloid burden, SVD, and cognition were made. Patients with PiB-negative SIVD showed more amyloid deposition than those with PiB-negative svMCI, particularly in the cuneus, lingual gyrus, supramarginal, and angular gyri. Despite subthreshold levels for amyloid deposition, our findings showed a marked regional difference in amyloid uptake between svMCI and SIVD, particularly in posteriorly located brain areas. However, lacune, a proxy for vascular burden, showed a broader association with cognition and had more impacts on developing dementia than amyloid burden. The topographical pattern of amyloid deposition and its impact on clinical status in pure subcortical vascular cognitive impairment were different from those in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Amyloidogenic Proteins; Aniline Compounds; Brain; Brain Mapping; Cerebral Small Vessel Diseases; Cognition; Cognitive Dysfunction; Dementia, Vascular; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Thiazoles; Tomography, X-Ray Computed

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Case-Control Studies; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Encephalitis; Female; Humans; Isoquinolines; Male; Microglia; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD).. A total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years.. Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance.. In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Connectome; Disease Progression; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Positron-Emission Tomography; Prodromal Symptoms; Prognosis; Thiazoles

Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Dementia; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; ROC Curve; Thiazoles

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB-, and 6 (11.7%) converted from PiB- at cycle 1 to PiB+ at cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB- evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Down Syndrome; Executive Function; Female; Humans; Male; Memory, Episodic; Middle Aged; Phenanthrolines; Positron-Emission Tomography; Thiazoles; Time Factors

The analysis of. Twenty-three subjects with MCI (10 men and 13 women, mean age; 74.2 years) underwent brain perfusion SPECT and. Five of 12 (41.7%) subjects in the PiB-positive subgroup and three of 11 (27.3%) subjects in the PiB-negative subgroup showed the abnormal value for each indicator. The frequency of subjects with abnormal ratio values was significantly higher in the PiB-positive subgroup compared to the PiB-negative subgroup (p=0.02), whereas that of subjects with abnormal values in severity and extent did not differ among the two subgroups. In particular, all subjects in the PiB-negative subgroup showed normal ratio values. Moreover, the subjects with abnormal values on two indicators, including ratio, or on all three indicators, showed PiB-positive.. The analysis of brain perfusion SPECT using an eZIS program cannot identify the amnestic MCI subjects with brain amyloid-β deposition. However, abnormal three indicators or normal ratio values may be helpful SPECT findings for predicting the results of PiB-PET in the amnestic MCI subjects.

Topics: Aged; Aged, 80 and over; Amnesia; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Organotechnetium Compounds; Perfusion Imaging; Positron-Emission Tomography; Sensitivity and Specificity; Thiazoles; Tomography, Emission-Computed, Single-Photon

Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer's disease (AD).. In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-β (Aβ) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI).. Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aβ deposition was measured with [11C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively.. Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aβ positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aβ positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aβ positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aβ negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI.. Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aβ deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Area Under Curve; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Tissue Proteins; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Psychiatric Status Rating Scales; Radioisotopes; Thiazoles

Dynamic

Topics: Aged; Aged, 80 and over; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Case-Control Studies; Cognitive Dysfunction; Exercise; Humans; Image Processing, Computer-Assisted; Kinetics; Middle Aged; Phantoms, Imaging; Positron-Emission Tomography; Thiazoles; Tissue Distribution; Whole Body Imaging

The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical β-amyloid [Aβ] and tau) provides an important opportunity to understand the basis of SCD and AD risk.. To examine associations between SCD and global Aβ and tau burdens in regions of interest in clinically healthy older adults.. This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11-labeled PET (PiB-PET) imaging for Aβ. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016.. Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The Aβ level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of Aβ, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score.. Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high Aβ burden. Greater SCD was associated with increasing entorhinal cortical tau burden (β = 0.35; 95% CI, 0.19-.52; P < .001) and Aβ burden (β = 0.24; 95% CI, 0.08-.40; P = .005), but not inferior temporal tau burden (β = 0.10; 95% CI, -0.08 to 0.28; P = .27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for Aβ burden (β = 0.36; 95% CI, 0.15-.58; P = .001), and no interaction influenced SCD (β = -0.36; 95% CI, -0.34 to 0.09; P = .25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex.. Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of Aβ. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Carbolines; Cognitive Dysfunction; Cross-Sectional Studies; Diagnostic Self Evaluation; Entorhinal Cortex; Female; Frontal Lobe; Humans; Male; Middle Aged; Neocortex; Parietal Lobe; Phenanthrolines; Positron-Emission Tomography; Radiopharmaceuticals; Surveys and Questionnaires; tau Proteins; Tauopathies; Temporal Lobe; Thiazoles

This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Apolipoproteins E; Benzothiazoles; Brain; Cognitive Dysfunction; Dementia; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Positron-Emission Tomography; Prognosis; Proportional Hazards Models; Radiopharmaceuticals; Thiazoles

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pat

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Aphasia, Primary Progressive; Benzothiazoles; Brain; Carbolines; Carbon Radioisotopes; Case-Control Studies; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Regression Analysis; tau Proteins; Thiazoles

Alzheimer's Disease (AD) is one of the leading causes of death and dementia worldwide. Early diagnosis confers many benefits, including improved care and access to effective treatment. However, it is still a medical challenge due to the lack of an efficient and inexpensive way to assess cognitive function [1]. Although research on data from Neuroimaging and Brain Initiative and the advancement in data analytics has greatly enhanced our understanding of the underlying disease process, there is still a lack of complete knowledge regarding the indicative biomarkers of Alzheimer's Disease. Recently, computer aided diagnosis of mild cognitive impairment and AD with functional brain images using machine learning methods has become popular. However, the prediction accuracy remains unoptimistic, with prediction accuracy ranging from 60% to 88% [2,3,6]. Among them, support vector machine is the most popular classifier. However, because of the relatively small sample size and the amount of noise in functional brain imaging data, a single classifier cannot achieve high classification performance. Instead of using a global classifier, in this work, we aim to improve AD prediction accuracy by combining three different classifiers using weighted and unweighted schemes. We rank image-derived features according to their importance to the classification performance and show that the top ranked features are localized in the brain areas which have been found to associate with the progression of AD. We test the proposed approach on 11C-PIB PET scans from The Alzheimer's Disease Neuroimaging Initiative (ADNI) database and demonstrated that the weighted ensemble models outperformed individual models of K-Nearest Neighbors, Random Forests, Neural Nets with overall cross validation accuracy of 86.1% ± 8.34%, specificity of 90.6% ± 12.9% and test accuracy of 80.9% and specificity 85.76% in classification of AD, mild cognitive impairment and healthy elder adults.

Topics: Alzheimer Disease; Aniline Compounds; Benzothiazoles; Carbon Radioisotopes; Cognitive Dysfunction; Humans; Positron-Emission Tomography; Thiazoles

For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R

Topics: Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Positron-Emission Tomography; Quinolines; Radiopharmaceuticals; Thiazoles

Quantitative measurements of change in β-amyloid load from Positron Emission Tomography (PET) images play a critical role in clinical trials and longitudinal observational studies of Alzheimer's disease. These measurements are strongly affected by methodological differences between implementations, including choice of reference region and use of partial volume correction, but there is a lack of consensus for an optimal method. Previous works have examined some relevant variables under varying criteria, but interactions between them prevent choosing a method via combined meta-analysis. In this work, we present a thorough comparison of methods to measure change in β-amyloid over time using Pittsburgh Compound B (PiB) PET imaging.. We compare 1,024 different automated software pipeline implementations with varying methodological choices according to four quality metrics calculated over three-timepoint longitudinal trajectories of 129 subjects: reliability (straightness/variance); plausibility (lack of negative slopes); ability to predict accumulator/non-accumulator status from baseline value; and correlation between change in β-amyloid and change in Mini Mental State Exam (MMSE) scores.. From this analysis, we show that an optimal longitudinal measure of β-amyloid from PiB should use a reference region that includes a combination of voxels in the supratentorial white matter and those in the whole cerebellum, measured using two-class partial volume correction in the voxel space of each subject's corresponding anatomical MR image.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Dementia; Female; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography; Reproducibility of Results; Thiazoles

Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials.. We examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort.. Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression.. This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Asymptomatic Diseases; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), and this pathology may be associated with alterations in PreC synapses and cognitive impairment. We quantified the spinophilin-immunoreactive (ir) dendritic spine density and the intensity of spinophilin immunofluorescence, the latter as a measure of relative protein levels of spinophilin, in PreC lamina III from 33 subjects with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or severe AD (sAD). Both measures of spinophilin were lower in mAD and sAD compared with NCI. The MCI group had higher protein levels of spinophilin compared with mAD and sAD, and higher spinophilin-ir dendritic spine density compared with sAD. Lower spinophilin-ir dendritic spine density and relative protein levels of spinophilin were associated with greater amyloid beta (Aβ) plaque burden, detected with a derivative of Pittsburgh compound-B (6-CN-PiB), and worse cognitive performance. Clinical onset of AD is marked by the loss of PreC spinophilin-ir dendritic spines that is related to Aβ pathology and may contribute to cognitive symptoms early in the disease.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Dendritic Spines; Female; Humans; Male; Microfilament Proteins; Nerve Tissue Proteins; Parietal Lobe; Plaque, Amyloid; Thiazoles

In the present study, we examined the relationship between cytokine levels in the cerebrospinal fluid (CSF) and. A total of 33 participants (12 men and 21 women; mean age 76.5 years) with mild cognitive impairment underwent neuropsychological assessments, PiB positron emission tomography and analysis of cytokine levels in the CSF. The CSF levels of 48 cytokines and growth factors were measured using multiplex immunoassays. PiB retention was assessed based on a standardized uptake value ratio. Mild cognitive impairment participants were classified as PiB-positive and PiB-negative, with a cut-off level of 1.4. We compared the CSF cytokine levels and Alzheimer's disease biomarkers, including β-amyloid 1-42, total tau and tau phosphorylated at threonine 181, between the two subgroups, and evaluated the correlation between PiB retention or CSF Alzheimer's disease biomarkers and CSF cytokine levels.. Cytokine levels in the CSF did not differ between the two subgroups. Macrophage inflammatory protein-1β levels in the CSF significantly correlated with PiB retention only in the PiB-positive subgroup, whereas stem cell growth factor-β levels significantly correlated with PiB retention in the PiB-negative subgroup. Furthermore, stem cell growth factor-β levels significantly correlated with total tau and tau phosphorylated at threonine 181 levels in only the PiB-negative subgroup.. The present findings suggest that macrophage inflammatory protein-1β and stem cell growth factor-β are associated with chronic inflammatory processes accompanied by amyloid deposition or AD pathophysiology. Geriatr Gerontol Int 2017; 17: 1907-1913.

Topics: Aged; Aniline Compounds; Cognitive Dysfunction; Cytokines; Female; Humans; Male; Thiazoles

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Mental Recall; Neuroimaging; Neuropsychological Tests; Organ Size; Positron-Emission Tomography; Prodromal Symptoms; Radiopharmaceuticals; Survival Analysis; Thiazoles

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Thiazoles

The present study investigated the characteristics of amnestic mild cognitive impairment (aMCI) in subjects with low brain amyloid-beta (Aβ) burden. Furthermore, the relationships between amyloid-independent cognitive decline and serum lipid profiles, particularly apolipoprotein A1 (APOA1), were evaluated.. Cross-sectional and longitudinal follow-up study.. University hospital dementia clinic.. 28 aMCI and 35 cognitive normal (CN) elderly.. The study measures included baseline assessments of the subjects' clinical characteristics, lipid profiles, and magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B (PiB) positron emission tomography scans. Based on PiB retention at baseline, the aMCI subjects were divided into low Aβ (aMCI-) and high Aβ (aMCI+) subgroups. All aMCI subjects were followed up over a 1-year period.. The aMCI- group had a longer duration of illness than did the aMCI+ group. None of the aMCI- subjects were diagnosed with Alzheimer disease (AD) dementia during the 1-year follow-up period, whereas 26.7% of aMCI+ subjects developed AD dementia. The aMCI- group also exhibited lower serum APOA1 levels compared with both the aMCI+ and CN groups. Additionally, lower serum APOA1 levels were associated with cognitive decline and brain atrophy independent of Aβ deposition and vascular burden.. Patients with aMCI- likely exhibit different clinical and pathophysiological characteristics than patients with aMCI+. Additionally, APOA1 may be an important contributor underlying amyloid-independent neurodegeneration.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid; Aniline Compounds; Apolipoprotein A-I; Atrophy; Brain; Brain Mapping; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Female; Follow-Up Studies; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The aim of this study was to evaluate amyloid imaging with 11C-PIB PET/CT in the study of cognitive impairment in a clinical setting.. The study included 64 patients, with a mean age of 65 years, classified as subjective memory complaints (SMCs; n = 8), nonamnestic mild cognitive impairment (NA-MCI; n = 10), amnestic MCI (A-MCI; n = 19), prodromal Alzheimer disease (AD; n = 12), suspicion of frontotemporal dementia (n = 8), Lewy bodies dementia (DLB; n = 2), and cortical degeneration (CD; n = 5). Ten healthy controls (HCs), with a mean age of 59 years, were also included. 11C-PIB was acquired 60 minutes after IV injection of 555 MBq 11C-PIB. A visual and semiquantitative analysis was performed.. In HC, 11C-PIB was negative in 9 and positive in 1. Of the 64 patients, 11C-PIB was negative in 27 (42%) and positive in 37 (58%). 11C-PIB was positive in 3 of 8 SMC, in none of 10 NA-MCI, in 14 of 19 A-MCI, in 10 of 12 prodromal AD, in 3 of 8 frontotemporal dementia, and in the 2 and 5 DLB and CD patients. The semiquantitative results in terms of mean global SUV ratio were 1.13 for HC, 1.36 for SMC, 1.07 for NA-MCI, 2.01 for A-MCI, 2.37 for prodromal AD, 2.75 for DLB, and 2.44 for CD.. In a clinical setting, 11C-PIB scan had a relevant contribution on patients with cognitive impairment, excluding AD in a high proportion of MCI patients and differentiating AD from other dementias. In A-MCI, 11C-PIB revealed β-amyloid deposit in 74%, whereas it was negative in all NA-MCI patients.

Topics: Aged; Amyloid; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Thiazoles; Tomography, X-Ray Computed

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies.. We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-β PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia.. We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18)F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18)F T807 than with mean cortical (11)C PIB. Regional (18)F T807 was correlated with mean cortical (11)C PiB among both impaired and control subjects.. These findings suggest that (18)F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Carbolines; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; tau Proteins; Temporal Lobe; Thiazoles

Biomarkers of Alzheimer disease (AD) can be imaged in vivo and can be used for diagnostic and prognostic purposes in people with cognitive decline and dementia. Indicators of amyloid deposition such as (11)C-Pittsburgh compound B ((11)C-PiB) PET are primarily used to identify or rule out brain diseases that are associated with amyloid pathology but have also been deployed to forecast the clinical course. Indicators of neuronal metabolism including (18)F-FDG PET demonstrate the localization and severity of neuronal dysfunction and are valuable for differential diagnosis and for predicting the progression from mild cognitive impairment (MCI) to dementia. It is a matter of debate whether to analyze these images visually or using automated techniques. Therefore, we compared the usefulness of both imaging methods and both analyzing strategies to predict dementia due to AD.. In MCI participants, a baseline examination, including clinical and imaging assessments, and a clinical follow-up examination after a planned interval of 24 mo were performed.. Of 28 MCI patients, 9 developed dementia due to AD, 2 developed frontotemporal dementia, and 1 developed moderate dementia of unknown etiology. The positive and negative predictive values and the accuracy of visual and fully automated analyses of (11)C-PiB for the prediction of progression to dementia due to AD were 0.50, 1.00, and 0.68, respectively, for the visual and 0.53, 1.00, and 0.71, respectively, for the automated analyses. Positive predictive value, negative predictive value, and accuracy of fully automated analyses of (18)F-FDG PET were 0.37, 0.78, and 0.50, respectively. Results of visual analyses were highly variable between raters but were superior to automated analyses.. Both (18)F-FDG and (11)C-PiB imaging appear to be of limited use for predicting the progression from MCI to dementia due to AD in short-term follow-up, irrespective of the strategy of analysis. On the other hand, amyloid PET is extremely useful to rule out underlying AD. The findings of the present study favor a fully automated method of analysis for (11)C-PiB assessments and a visual analysis by experts for (18)F-FDG assessments.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Dementia; Disease Progression; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Observer Variation; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Thiazoles

Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD.. We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies.. Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.

Topics: Alzheimer Disease; Aniline Compounds; Brain; Carbolines; Cocaine; Cognitive Dysfunction; Cross-Sectional Studies; Diagnosis, Differential; Lewy Body Disease; Magnetic Resonance Imaging; Neuropsychological Tests; Parkinson Disease; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Survival Analysis; Thiazoles

The PET tracer (11)C-deuterium-L-deprenyl ((11)C-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase (11)C-DED and (11)C-Pittsburgh compound B ((11)C-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which (11)C-DED binding is influenced by brain perfusion was investigated.. (11)C-DED, (11)C-PiB, and (18)F-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify (11)C-DED binding. A simplified reference tissue model was applied to both (11)C-DED and (11)C-PiB to measure brain perfusion relative to the cerebellar gray matter (R1) and binding potentials. (11)C-PiB retention and (18)F-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs).. The strongest within-subject correlations with the corresponding R1 values (R1,DED and R1,PiB, respectively) and with (18)F-FDG uptake were obtained when the eDED and ePiB PET data were measured 1-4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R1,DED/R1,PiB and with (18)F-FDG uptake, whereas (11)C-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal (18)F-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls.. The 1- to 4-min early-frame intervals of (11)C-DED or (11)C-PiB are suitable surrogate measures for brain perfusion. (11)C-DED binding is independent of brain perfusion, and thus (11)C-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase (11)C-DED and (11)C-PiB perfusion appear to provide complementary rather than redundant information.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Cerebellum; Cerebrovascular Circulation; Cognitive Dysfunction; Deuterium; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Gliosis; Gray Matter; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Perfusion; Pons; Positron-Emission Tomography; Radiopharmaceuticals; Selegiline; Thiazoles

SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse perfo

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoproteins E; Benzothiazoles; Brain; Carbolines; Case-Control Studies; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Positron-Emission Tomography; tau Proteins; Thiazoles

SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β =

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Executive Function; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Positron-Emission Tomography; Stroke, Lacunar; Thiazoles

Amyloid imaging clinically is usually reported as positive or negative, and the role of amyloid topography has not been studied before. To evaluate in a clinical setting the regional distribution patterns of C-Pittsburgh compound B (C-PIB) and the fluorine-18-fluorodeoxyglucose (F-FDG) uptake in patients with mild cognitive impairment (MCI), we designed this study.. We studied 81 consecutive MCI patients, 64 amnestic (A-MCI) and 17 nonamnestic (NA-MCI) by C-PIB and F-FDG PET/computed tomography, by visual analysis. PIB retention was classified according to the regional distribution into the following patterns: A (frontal, lateral temporal, basal ganglia and anterior cingulate) and B (global retention). F-FDG images were considered positive only if temporoparietal hypometabolism consistent with Alzheimer's disease was observed.. In 42 of the 64 A-MCI, C-PIB was positive. Twelve of the 42 positive A-MCI showed an A-pattern, all F-FDG negative, and 30 a B-pattern, 10 F-FDG positive and 20 F-FDG negative. Of the 17 NA-MCI, C-PIB was positive in three and F-FDG was positive in one. The different proportion of C-PIB positivity in A-MCI and NA-MCI was highly significant (P<0.001).. Two different C-PIB patterns were observed in MCI patients and for the A-pattern, glucose hypometabolism consistent with Alzheimer's disease is highly unlikely. These findings may contribute towards a better selection of patients for future potential treatments and also to optimize the use of F-FDG-PET/CT.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Aniline Compounds; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Thiazoles

Development of a simple, non-invasive early diagnosis platform of Alzheimer's disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Blood Proteins; Chromatography, Liquid; Cognitive Dysfunction; Disease Progression; Enzyme-Linked Immunosorbent Assay; Factor XIII; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Peptides; Positron-Emission Tomography; Proprotein Convertase 9; Tandem Mass Spectrometry; Thiazoles

The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-β42/40 Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Dementia; Enzyme-Linked Immunosorbent Assay; Europe; Female; Humans; Male; Mass Spectrometry; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Thiazoles

Hippocampal volume (HV), cortical metabolism, and thickness are decreased in mild cognitive impairment (MCI). Hippocampal metabolism (HM) studies comparing MCI and clinically normal (CN) elderly gave inconsistent results. As hippocampus is a key region in Alzheimer's disease, we hypothesized that HM is specifically decreased in high-amyloid MCI.. Overall, 250 CN and 45 MCI underwent three-dimensional magnetic resonance imaging, fludeoxyglucose-positron emission tomography, and fluorodeoxyglucose-positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET. We investigated the interaction between clinical and amyloid status on HM, HV, cortical metabolism, and thickness using linear models, covarying age, gender, and education. Analyses were conducted with and without correction for multiple comparisons and for partial volume effects.. Volume-adjusted HM was decreased in high-amyloid MCI but close to normal in low-amyloid MCI and in high-amyloid CN. Both MCI groups had hippocampal atrophy, although less severe in low-amyloid MCI. High-amyloid CN and high-amyloid MCI had cortical hypometabolism.. HM is decreased when both cognitive impairment and amyloid are present.

Topics: Aged; Amyloid; Aniline Compounds; Atrophy; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Image Processing, Computer-Assisted; Male; Positron-Emission Tomography; Thiazoles

A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear.. To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline).. This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016.. Evidence of amyloid-independent tau deposition and/or cognitive decline.. Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03).. In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Male; Middle Aged; tau Proteins; Tauopathies; Thiazoles

The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.. To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.. This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET).. Imaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.. Main outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.. In patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.. Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Carbolines; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Parkinson Disease; Positron-Emission Tomography; tau Proteins; Thiazoles

Reduction of precuneus choline acetyltransferase activity co-occurs with greater beta-amyloid (Aβ) in Alzheimer's disease (AD). Whether this cholinergic deficit is associated with alteration in nerve growth factor (NGF) signaling and its relation to Aβ plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown.. Precuneus NGF upstream and downstream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and histochemistry in 62 subjects with a premortem diagnosis of non-cognitively impaired (NCI; n = 23), mild cognitive impairment (MCI; n = 21), and mild to moderate AD (n = 18).. Immunoblots revealed increased levels of proNGF in AD subjects but not MCI subjects, whereas cognate receptors were unchanged. There were no significant differences in protein level for the downstream survival kinase-signaling proteins Erk and phospho-Erk among groups. Apoptotic phospho-JNK, phospho-JNK/JNK ratio, and Bcl-2 were significantly elevated in AD subjects. Soluble Aβ1-42 and fibrillar Aβ measured by [(3)H] Pittsburgh compound-B ([(3)H]PiB) binding were significantly higher in AD subjects compared with MCI and NCI subjects. The density of plaques showed a trend to increase, but only 6-CN-PiB-positive plaques reached significance in AD subjects. AT8-positive, TOC-1-positive, and Tau C3-positive NFT densities were unchanged, whereas only AT8-positive neuropil thread density was statistically higher in AD subjects. A negative correlation was found between proNGF, phospho-JNK, and Bcl-2 levels and phospho-JNK/JNK ratio and cognition, whereas proNGF correlated positively with 6-CN-PiB-positive plaques during disease progression.. Data indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Choline O-Acetyltransferase; Cognitive Dysfunction; Female; Humans; In Vitro Techniques; Male; Mental Status Schedule; Nerve Growth Factor; Neuropil Threads; Parietal Lobe; Prodromal Symptoms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Statistics, Nonparametric; Thiazoles; Tritium

Amyloid-β pathology (Aβ) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aβ-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aβ-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest- and cognitive task-states, might link Aβ-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aβ-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aβ-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aβ-pathology with cognitive impairment in early AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Attention; Brain Mapping; Cognition; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Alzheimer's disease (AD) is associated with amyloid accumulation that takes place decades before symptoms appear. Cognitive impairment in AD is associated with reduced glucose metabolism. However, neuronal plasticity/compensatory mechanisms might come into play before the onset of dementia. The aim of this study was to determine whether there is evidence of cortical hypermetabolism as a compensatory mechanism before amyloid deposition takes place in subjects with amnestic mild cognitive impairment (aMCI).. Nine AD subjects and ten aMCI subjects had both [(11)C]PIB and [(18)F]FDG PET scans with arterial input in order to quantify the amyloid deposition and glucose metabolism in vivo in comparison with healthy control subjects who underwent either [(11)C]PIB or [(18)F]FDG PET scans. The [(11)C]PIB PET scans were quantified using [(11)C]PIB target region to cerebellum uptake ratio images created by integrating the activity collected from 60 to 90 min, and regional cerebral glucose metabolism was quantified using spectral analysis.. In MCI subjects, cortical hypermetabolism was observed in four amyloid-negative subjects and one amyloid-positive subject, while hypometabolism was seen in five other MCI subjects with high amyloid load. Subjects with hypermetabolism and low amyloid did not convert to AD during clinical follow-up for 18 months in contrast to four amyloid-positive hypometabolic subjects who did convert to AD.. This preliminary study suggests that compensatory hypermetabolism can occur in aMCI subjects, particularly in those who are amyloid-negative. The increase in metabolic rate in different cortical regions with predominance in the occipital cortex may be a compensatory response to the neuronal damage occurring early in the disease process. It may also reflect recruitment of relatively minimally affected cortical regions to compensate for reduced function in the temporoparietal cortical association areas.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Blood Glucose; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

We investigated the extent to which decline in memory and working memory in beta-amyloid (Aβ) positive non-demented individuals was related to hippocampal atrophy and Aβ accumulation over 36 months. Cognitively normal older adults (CN) (n = 178) and adults with mild cognitive impairment (MCI) (n = 49) underwent positron emission tomography neuroimaging, magnetic resonance imaging, and cognitive assessments at baseline, 18- and 36-months. Relative to Aβ- CNs, Aβ+ CNs and Aβ+ MCIs showed greater rates of cognitive decline, Aβ accumulation, and hippocampal atrophy. Analysis of interrelationships between these Alzheimer's disease markers in Aβ+ CNs and MCIs indicated that rate of Aβ accumulation was associated with rate of hippocampal atrophy (β = -0.05, p = .037), which was in turn associated independently with rate of decline in memory (β = -0.03, p = .032). This suggests that Aβ accumulation precedes any neurodegeneration or clinical symptoms, and that the relationship between Aβ and cognitive decline is mediated by hippocampal atrophy.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Atrophy; Carbon Isotopes; Cognitive Dysfunction; Female; Hippocampus; Humans; Linear Models; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Middle Aged; Nerve Degeneration; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; Time Factors

The goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.. We developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.. The CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.. Automated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.. This study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

Topics: Aged; Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Cohort Studies; Databases, Factual; Disease Progression; Female; Humans; Male; Neuropsychological Tests; Pattern Recognition, Automated; Peptide Fragments; Positron-Emission Tomography; Sensitivity and Specificity; Thiazoles

Alzheimer's disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-β1-42 (Aβ1-42), total-tau (t-tau), and phosphorylated tau (p-tau181p), as well as with positron emission tomography (PET) using [(11)C]Pittsburgh compound-B ([(11)C]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [(11)C]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD.. To determine concordance and classification accuracy of CSF biomarkers and [(11)C]PIB PET in a cohort of patients with MCI and AD.. 68 patients (MCI, n = 33; AD, n = 35) underwent [(11)C]PIB PET and CSF sampling. Cutoffs of >1.41 ([(11)C]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(Aβ1-42), <6.5 (Aβ1-42/p-tau181p), and 1.14 (Aβ1-42/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI).. Concordance between [(11)C]PIB and Aβ1-42 was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using Aβ1-42 <550 pg/mL, or Aβ1-42 to tau ratios. Logistic regression showed that classification accuracy of [(11)C]PIB, between sMCI and pMCI, was superior to Aβ1-42 (73% versus 58%), Aβ1-42/t-tau (63%), and Aβ1-42/p-tau181p (65%).. In the present study, [(11)C]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of Aβ1-42 or Aβ1-42/tau. Discordance between PET and CSF markers for Aβ1-42 suggests they cannot be used interchangeably, as is currently the case.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Cognitive Dysfunction; Cohort Studies; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Phosphorylation; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

Topics: Aged; Aged, 80 and over; Aging; Alleles; Amyloidogenic Proteins; Aniline Compounds; Apolipoprotein E4; Brain; Cognition; Cognitive Dysfunction; Female; Genotype; Humans; Male; Middle Aged; Regional Blood Flow; Thiazoles

Today, ligands that bind to fibrillar β-amyloid are detectable by Positron Emission Tomography (PET) allowing for in vivo visualization for Abeta burden. However, amyloid plaques detection per se does not establish Alzheimer's Disease diagnosis. In this sense, the utility of amyloid imaging to improve clinical diagnosis was settled only for specific clinical scenarios and few studies have assessed amyloid molecular neuroimaging in a broader clinical setting. The aim of this study is to determine the frequency of PiB amyloid findings in different diagnostic syndromes grouped into high and low probability pre- test categories, taking into account pre-test clinical assumption of the presence of AD related pathology.. 144 patients were assigned into categories of high or low pretest probability according to clinical suspicion of AD pathology. The high probability group included: amnestic Mild Cognitive Impairment (MCI), amnestic and other domains MCI, Dementia of Alzheimer's Type (DAT), Posterior Cortical Atrophy (PCA), logopenic Primary Progressive Aphasia (PPA), Cerebral Amyloid Angiopathy and mixed dementia. The low assumption group included: normal controls, non-amnestic MCI, non-logopenic PPA and Frontotemporal Dementia (FTD).. Only normal controls and DAT patients (typical and atypical presentation) were the most consistent across clinical and molecular diagnostics. MCI, non-logopenic PPA and FTD were the syndromic diagnoses that most discrepancies were found.. This study demonstrates that detecting in vivo amyloid plaques by molecular imaging is considerably frequent in most of the dementia syndromes and shows that there are frequent discordance between molecular diagnosis and clinical assumption.

Topics: Aged; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Aniline Compounds; Aphasia, Primary Progressive; Atrophy; Benzothiazoles; Cerebral Amyloid Angiopathy; Cerebral Cortex; Cognitive Dysfunction; Dementia; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged; Positron-Emission Tomography; Retrospective Studies; Thiazoles

Connectivity analysis allows researchers to explore interregional correlations, and thus is well suited for analysis of complex networks such as the brain. We applied whole brain connectivity analysis to assess the progression of Alzheimer's disease (AD). To detect early AD progression, we focused on distinguishing between normal control (NC) subjects and subjects with mild cognitive impairment (MCI). Fludeoxyglucose (FDG) and Pittsburgh compound B (PiB)-positron emission tomography (PET) were acquired for 75 participants. A graph network was implemented using correlation matrices. Correlation matrices of FDG and PiB-PET were combined into one matrix using a novel method. Group-wise differences between NC and MCI patients were assessed using clustering coefficients, characteristic path lengths, and betweenness centrality using various correlation matrices. Using connectivity analysis, this study identified important regions differentially affected by AD progression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Case-Control Studies; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Alzheimer's disease (AD) is the most common neurodegenerative disorder pathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The aggregation of Aβ precedes tau pathologies in AD; however, the causal relation between the two pathologies and the mechanisms by which aggregated forms of Aβ contribute to cortical thinning are not fully understood. We proposed quantitative Aβ-weighted cortical thickness analysis to investigate the regional relationship between cortical thinning and amyloid plaque deposition using magnetic resonance (MR) and Pittsburg Compound B (PiB) positron emission tomography (PET) images in patients with AD, mild cognitive impairment (MCI), and subjects with normal cognition. We hypothesized that there are cortical areas that have prominent changes associated with Aβ deposition and there are areas that are relatively independent from Aβ deposition where pathologies other than Aβ (such as tau) are predominant. The study was performed using MRI and PiB PET data from the Alzheimer's Disease Neuroimaging Initiative. We measured accuracy of classification models in three different pairs of groups comparing AD, MCI, and normal cognition. Classification models that used Aβ-weighted cortical thickness were not inferior to classification models that used only cortical thickness or amyloid deposition. In addition, based on timing of changes in cortical thinning and Aβ deposition such as Aβ deposition after cortical thinning; cortical thinning after Aβ deposition, or concurrent Aβ deposition and cortical thinning, we identified three types of relationships between cortical thinning and Aβ deposition: (1) Aβ-associated cortical thinning; (2) Aβ-independent cortical thinning; and (3) Aβ deposition only without cortical thinning. Taken together, these findings suggest that Aβ-weighted cortical thickness values can be used as an objective biomarker of structural changes caused by amyloid pathology in the brain.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain Mapping; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neurofibrillary Tangles; Positron-Emission Tomography; Thiazoles

The purpose of this study was to evaluate the clinical impact of addition of [(11)C]Pittsburgh compound-B positron emission tomography ((11)C-PiB PET) on routine clinical diagnosis of Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), and to assess diagnostic agreement between clinical criteria and research criteria of the National Institute on Aging-Alzheimer's Association.. The diagnosis in 85 patients was made according to clinical criteria. Imaging examinations, including both magnetic resonance imaging and single-photon emission computed tomography/computed tomography to identify neuronal injury (NI), and (11)C-PiB PET to identify amyloid were performed, and all subjects were re-categorized according to the research criteria.. Among 40 patients with probable AD dementia (ProAD), 37 were NI-positive, 29 were (11)C-PiB-positive, and 27 who were both NI- and (11C-PiB-positive were categorized as having 'ProAD dementia with a high level of evidence of the AD pathophysiological process'. Among 20 patients with possible AD dementia (PosAD), 17 were NI-positive, and six who were both NI- and (11)C-PiB-positive were categorized as having 'PosAD with evidence of the AD pathophysiological process'. Among 25 patients with MCI, 18 were NI-positive, 13 were (11)C-PiB-positive, and 10 who were both NI- and (11)C-PiB-positive were categorized as having 'MCI due to AD-high likelihood'.. Diagnostic concordance between clinical criteria and research criteria may not be high in this study. (11)C-PiB PET may be of value in making the diagnosis of dementia and MCI in cases with high diagnostic uncertainty.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Dementia; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Thiazoles; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Structural magnetic resonance imaging (sMRI) is an established technique for measuring brain atrophy, and dynamic positron emission tomography with (11)C-Pittsburgh compound B ((11)C-PIB PET) has the potential to provide both perfusion and amyloid deposition information. It remains unclear, however, how to better combine perfusion, amyloid deposition and morphological information extracted from dynamic (11)C-PIB PET and sMRI with the goal of improving the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). We adopted a linear sparse support vector machine to build classifiers for distinguishing AD and MCI subjects from cognitively normal (CN) subjects based on different combinations of regional measures extracted from imaging data, including perfusion and amyloid deposition information extracted from early and late frames of (11)C-PIB separately, and gray matter volumetric information extracted from sMRI data. The experimental results demonstrated that the classifier built upon the combination of imaging measures extracted from early and late frames of (11)C-PIB as well as sMRI achieved the highest classification accuracy in both classification studies of AD (100%) and MCI (85%), indicating that multimodality information could aid in the diagnosis of AD and MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Atrophy; Cognitive Dysfunction; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Thiazoles

Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging.. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake.. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively).. These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Cohort Studies; Ethylene Glycols; Europe; Female; Humans; Male; Middle Aged; Molecular Imaging; North America; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Sex Characteristics; Thiazoles

The goal of this study was to clarify whether binding potential (BP) images using (11)C-Pittsburgh compound B ((11)C-PiB) and dynamic PET can reliably detect cortical amyloid deposits for patients whose (11)C-PiB PET static images are ambiguous and whether visual ratings are affected by white matter retention.. Static and BP images were constructed for 85 consecutive patients with cognitive impairment after (11)C-PiB dynamic PET. Cortical uptake was visually assessed as positive, negative, or equivocal for both types of images. Quantitatively, the standardized uptake value ratio (SUVR) from the static image, the nondisplaceable BP from the dynamic image for mean gray matter uptake, and the ratio of gray matter uptake to white matter retention were compared among (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups.. Forty-three scans were visually assessed as (11)C-PiB-positive in both the static and the BP images. Ten scans were (11)C-PiB-equivocal in the static images. In 8 of them, the BP images were (11)C-PiB-positive, whereas the other 2 were (11)C-PiB-equivocal. Thirty-two scans were assessed as (11)C-PiB-negative in the static images. In the BP images, 4 were (11)C-PiB-positive and 2 were (11)C-PiB-equivocal. The mean gray matter uptake of (11)C-PiB in SUVR and nondisplaceable BP, respectively, showed statistically significant differences among the (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. The ratio of gray matter uptake to white matter retention was lower in the BP images than static images from the (11)C-PiB-negative and (11)C-PiB-equivocal groups, whereas it was higher in the (11)C-PiB-positive group.. (11)C-PiB PET BP images can clarify visual interpretation of clinical static (11)C-PiB-equivocal images by reducing the interference of nonspecific white matter retention. We conclude that (11)C-PiB-equivocal PET findings on static images reflect cortical amyloid deposits, which can be verified using BP images. Furthermore, quantitative assessments, such as SUVR and nondisplaceable BP, are of no use for correctly rating equivocal visual findings.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Cerebral Cortex; Cognition Disorders; Cognitive Dysfunction; Female; Gray Matter; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; White Matter

The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.

Topics: Aged; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Thiazoles

To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).. To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.. Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography.. Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions.. In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups.. Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloidosis; Aniline Compounds; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Fluorodeoxyglucose F18; Gray Matter; Humans; Male; Neurodegenerative Diseases; Positron-Emission Tomography; Thiazoles

Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([(11)C]PiB PET) has not been assessed.. Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [(11)C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [(11)C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [(11)C]PiB uptake.. In APOE ε4- but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [(11)C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [(11)C]PiB binding compared with using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.. The results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain; Cerebral Cortex; Cognitive Dysfunction; Female; Humans; Male; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimer's dementia using data from the Alzheimer's Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimer's Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimer's dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoproteins E; Brain; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Forecasting; Genotype; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Temporal Lobe; Thiazoles

The aim of this study was to evaluate the longitudinal changes in [(11)C]PIB uptake in mild cognitive impairment (MCI) and Alzheimer's disease (AD) over a long-term follow-up.. Six AD patients, ten MCI patients and eight healthy subjects underwent a [(11)C]PIB PET scan at baseline and at 2 and 5 years. The clinical status of the MCI patients was evaluated every 6 months.. The MCI group showed a significant increase in [(11)C]PIB uptake over time (p < 0.001), with a similar increase from baseline to 2 years (4.7% per year) and from 2 to 5 years (5.0% per year). Eight MCI patients (80%) converted to AD, and two of these patients showed a normal [(11)C]PIB scan at baseline but increased uptake later. There was an increase in [(11)C]PIB uptake with time in the AD group (p = 0.02), but this did not significantly differ from the change in the control group.. Our results revealed a significant increase in amyloid load even at the time of AD diagnosis in some of the MCI patients who converted. A positive [(11)C]PIB scan at baseline in MCI patients strongly predicted future conversion to AD but a negative PIB scan in MCI patients did not exclude future conversion. The results suggest that there is wide individual variation in the brain amyloid load in MCI, and in the course of amyloid accumulation in relation to the clinical diagnosis of AD.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognitive Dysfunction; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Although patients with amnestic mild cognitive impairment (aMCI) are at higher risk of developing Alzheimer's disease (AD), their pathologies could be heterogeneous. We aimed to evaluate structural changes in amyloid-negative and amyloid-positive aMCI patients. Forty-eight aMCI patients who underwent Pittsburgh compound B (PiB) positron emission tomography were recruited. They were classified as PiB (-) aMCI (N = 16) and PiB (+) (N = 32). Hippocampal shape and regional cortical thickness were compared with 41 subjects with normal cognition (NC). Relative to NC, PiB(-) aMCI exhibited hippocampal deformity in the right cornu ammonis 1, whereas PiB(+) aMCI exhibited hippocampal deformity in bilateral subiculum and cornu ammonis 1 subregions. Relative to NC, PiB(-) aMCI showed cortical thinning in the left medial prefrontal and right anterior temporal regions, whereas PiB(+) aMCI exhibited cortical thinning in bilateral medial temporal regions, temporoparietal junctions and precuneus, and prefrontal cortices. Our findings suggest that structural changes in PiB(-) aMCI might be due to several possible pathologic changes, whereas structural changes in PiB(+) aMCI reflect AD-like structural changes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Atrophy; Cerebral Cortex; Cognitive Dysfunction; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Risk; Thiazoles

The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The (18)F-labeled amyloid tracer, [(18)F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [(11)C]Pittsburgh compound B (PIB) and [(18)F]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.. Two PET scans, one of each with [(11)C]PIB and [(18)F]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [(18)F]FACT studies without partial volume correction, while significant differences were observed in [(11)C]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [(18)F]FACT studies as well as [(11)C]PIB. Relatively lower uptakes of [(11)C]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [(18)F]FACT. Relatively higher uptake of [(11)C]PIB in distribution was observed in the frontal and parietal cortices.. Since [(18)F]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [(11)C]PIB and [(18)F]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Benzoxazoles; Brain; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Tissue Distribution

The progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized.. Forty-five patients with svMCI and 46 patients with SVaD who were negative on Pittsburgh compound B (PiB) positron emission tomography imaging and 75 individuals with normal cognition (NC) were recruited.. Compared with NC, patients with PiB(-) svMCI exhibited frontal, language and retrieval type memory dysfunctions, which in patients with PiB(-) SVaD were further impaired and accompanied by visuospatial and recognition memory dysfunctions. Compared with NC, patients with PiB(-) svMCI exhibited cortical thinning in the frontal, perisylvian, basal temporal and posterior cingulate regions. This atrophy was more prominent and extended further toward the lateral parietal and medial temporal regions in patients with PiB(-) SVaD. Compared with NC subjects, patients with PiB(-) svMCI exhibited hippocampal shape deformities in the lateral body, whilst patients with PiB(-) SVaD exhibited additional deformities within the lateral head and inferior body.. Our findings suggest that patients with CVD in the absence of Alzheimer's disease pathology can be demented, showing cognitive impairment in multiple domains, which is consistent with the topography of cortical thinning and hippocampal shape deformity.

Topics: Aged; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Dementia; Dementia, Vascular; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Increased plasma glucose levels can cause the regional reduction of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) uptake in the posterior cingulate, precuneus, and/or temporoparietal cortices as an Alzheimer's disease (AD)-like pattern. However, the association of such an AD-like pattern of cerebral 18F-FDG uptake with AD pathophysiology is unknown. We report a case of a 70-year-old patient with mild cognitive impairment, and show that the AD-like pattern of cerebral 18F-FDG uptake during a hyperglycemic state could be reversible and is not associated with amyloid-β accumulation. Our case concludes that the AD-like pattern is dependent on the plasma glucose level and independent of AD pathophysiology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Hyperglycemia; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Cognitive Dysfunction; Disease Progression; Humans; Positron-Emission Tomography; Thiazoles

Recent advances in biomarkers provide the possibility of early or preclinical diagnosis of Alzheimer's pathology. Currently, decreased levels of Aβ-42 and increased levels of tau proteins in cerebral spinal fluid are considered reliable biomarkers of Alzheimer's disease (AD); however, little evidence exists for the use of amyloid and tau protein levels in the plasma as useful biomarkers. We investigated the potential use of plasma biomarkers to diagnose AD and explored their relationships with brain Aβ deposition in amyloid imaging. We used an immunomagnetic reduction assay to measure the plasma levels of Aβ40, Aβ42, and tau proteins in 20 older control participants and 25 participants who had either mild cognitive impairment due to AD or early AD dementia. All participants received (11)C-labeled Pittsburgh compound B PET scans. The sensitivity of the plasma tau level at the cutoff value of 28.27 pg/mL was 92%, and the specificity was 100%; the sensitivity of the Aβ42/40 ratio at the cutoff value of 0.3693 was 84%, and the specificity was 100%. Regression analyses of the effects of plasma protein levels on brain amyloid retention, as determined by standard uptake value ratios in either side of the frontal, parietal, and temporal lobes and the precuneus, are predicted only by ratios of plasma Aβ42/40 (R(2) 0.326-0.449, all p < 0.001) but not by plasma tau levels. Plasma Aβ in terms of Aβ42/40 might provide an indirect estimation of Aβ deposition in the brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Chi-Square Distribution; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Psychiatric Status Rating Scales; Radionuclide Imaging; Regression Analysis; tau Proteins; Thiazoles

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of β amyloid (Aβ) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aβ levels have focused primarily on plasma Aβ(1-40) and not on the more pathogenic Aβ(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aβ levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aβ(1-40) and Aβ(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aβ(1-40); beta=0.208, P=0.017; Aβ(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Cognitive Dysfunction; Cohort Studies; Gonadotropins; Humans; Linear Models; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; Risk Factors; Statistics, Nonparametric; Testosterone; Thiazoles

The purpose of this study was to investigate the association between functional connectivity and β-amyloid depositions in the default mode network (DMN) in Alzheimer's disease (AD), patients with mild cognitive impairment (MCI), and healthy elderly. Twenty-five patients with AD, 12 patients with MCI, and 18 healthy controls were included in the study. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in the DMN. In parallel, amyloid burden was measured in the same subjects using positron emission tomography with carbon-11-labeled Pittsburgh Compound-B as amyloid tracer. Functional connectivity of the DMN and amyloid deposition within the DMN were not associated across all subjects or within diagnostic groups. Longitudinal studies are needed to examine if amyloid depositions precede aberrant functional connectivity in the DMN.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Positron-Emission Tomography; Thiazoles

Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation.. To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography-derived amyloid positivity on the clinical expression of AD.. Baseline PIB-positron-emission tomography values were downloaded from the Alzheimer's Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59).. The Alzheimer's Disease Neuroimaging Initiative public database.. The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Disease's Neuroimaging Initiative database.. Clinical AD diagnosis and WMH volume.. Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD.. White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloidosis; Aniline Compounds; Brain Mapping; Cerebral Cortex; Cognitive Dysfunction; Databases, Factual; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Fibers, Myelinated; Positron-Emission Tomography; Thiazoles

Large prospective studies of Alzheimer's disease (AD) have sought to understand the pathological evolution of AD and factors that may influence the rate of disease progression. Estimates of rates of cognitive change are available for 12 or 24 months, but not for shorter time frames (e.g., 3 or 6 months). Most clinical drug trials seeking to reduce or modify AD symptoms have been conducted over 12- or 24-week periods. As such, we aimed to characterize the performance of a group of healthy older adults, adults with amnestic mild cognitive impairment (aMCI), and adults with AD on the CogState battery of tests over short test-retest intervals. This study recruited 105 healthy older adults, 48 adults with aMCI, and 42 adults with AD from the Australian Imaging, Biomarkers, and Lifestyle study and administered the CogState battery monthly over 3 months. The CogState battery of tests showed high test-retest reliability and stability in all clinical groups when participants were assessed over 3 months. When considered at baseline, the CogState battery of tests was able to detect AD-related cognitive impairment. The data provide important estimates of the reliability, stability, and variability of each cognitive test in healthy older adults, adults with aMCI, and adults with AD. This may potentially be used to inform future estimates of cognitive change in clinical trials.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Aniline Compounds; Association Learning; Australia; Case-Control Studies; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Reaction Time; Reproducibility of Results; Thiazoles; Time Factors

We evaluated PET-based classification of neurodegenerative pathology in mild cognitive impairment (MCI).. Our study was a cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based cognitive disorders clinic. We compared expert clinical consensus classification of MCI at entry and possible dementia at follow-up with molecular imaging-based classification using (11)C-dihydotetrabenazine PET measurement of striatal dopamine terminal integrity and (11)C-Pittsburgh compound B ((11)C-PiB) PET measurement of cerebral amyloid burden.. Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 y, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition or nigrostriatal denervation was a strong predictor of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes.. Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful for identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.

Topics: Aged; Amyloid; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Cohort Studies; Dopamine; Female; Follow-Up Studies; Humans; Male; Positron-Emission Tomography; Prognosis; Tetrabenazine; Thiazoles

In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444(C) risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, P(joint) = 1.3 × 10(-13)) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cohort Studies; Dextrans; Female; Genetic Association Studies; Genotype; HLA-D Antigens; Humans; Male; Microglia; Middle Aged; Monocytes; Peptide Fragments; Plaque, Amyloid; Polymorphism, Genetic; Radionuclide Imaging; Sialic Acid Binding Ig-like Lectin 3; Thiazoles; Young Adult

The aim of this study is to identify mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid imaging of beta amyloid (Aβ) deposition and FDG imaging of reflecting neuronal dysfunction as PET biomarkers. Sixty-eight MCI patients underwent cognitive testing, [11C]-PIB PET and [18F]-FDG PET at baseline and follow-up. Regions of interest were defined on co-registered MRI. PIB distribution volume ratio (DVR) was calculated using Logan graphical analysis, and the standardized uptake value ratio (SUVR) on the same regions was used as quantitative analysis for [18F]-FDG. Thirty (44.1%) of all 68 MCI patients converted to AD over 19.2±7.1 months. The annual rate of MCI conversion was 23.4%. A positive Aβ PET biomarker significantly identified MCI due to AD in individual MCI subjects with a sensitivity (SS) of 96.6% and specificity (SP) of 42.1%. The positive predictive value (PPV) was 56.8%. A positive Aβ biomarker in APOE ε4/4 carriers distinguished with a SS of 100%. In individual MCI subjects who had a prominent impairment in episodic memory and aged older than 75 years, an Aβ biomarker identified MCI due to AD with a greater SS of 100%, SP of 66.6% and PPV of 80%, compared to FDG biomarker alone or both PET biomarkers combined. In contrast, when assessed in precuneus, both Aβ and FDG biomarkers had the greatest level of certainty for MCI due to AD with a PPV of 87.8%. The Aβ PET biomarker primarily defines MCI due to AD in individual MCI subjects. Furthermore, combined FDG biomarker in a cortical region of precuneus provides an added diagnostic value in predicting AD over a short period.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Thiazoles

Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI.. The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years.. During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other.. The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.

Topics: Aged; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Thiazoles

Several methods are in use for analyzing (11)C-Pittsburgh compound-B ((11)C-PiB) data. The objective of this study was to identify the method of choice for measuring longitudinal changes in specific (11)C-PiB binding.. Dynamic 90-min (11)C-PiB baseline and follow-up scans (interval, 30 ± 5 mo) were obtained for 7 Alzheimer disease (AD) patients, 11 patients with mild cognitive impairment (MCI), and 11 healthy controls. Parametric images were generated using reference parametric mapping (RPM2), reference Logan values, and standardized uptake value volume ratios (SUVr), the latter for intervals between 60 and 90 (SUVr(60-90)) and 40 and 60 (SUVr(40-60)) minutes after injection. In all analyses, cerebellar gray matter was used as a reference region. A global cortical volume of interest was defined using a probability map-based template. Percentage change between baseline and follow-up was derived for all analytic methods.. SUVr(60-90) and SUVr(40-60) overestimated binding with 13% and 10%, respectively, compared with RPM2. Reference Logan values were on average 6% lower than RPM2. Both SUVr measures showed high intersubject variability. Over time, R1, the delivery of tracer to the cortex relative to that to the cerebellum, decreased in AD patients (P < 0.05) but not in MCI patients and controls. Simulations showed that SUVr, but not RPM2 and reference Logan values, was highly dependent on uptake period and that changes in SUVr over time were sensitive to changes in flow.. To reliably assess amyloid binding over time--for example, in drug intervention studies--it is essential to use fully quantitative methods for data acquisition and analysis.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Male; Molecular Imaging; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Thiazoles; Tissue Distribution

Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. The authors sought to determine whether apathy is associated with cortical amyloid burden, as measured by Pittsburgh Compound B (PiB) positron emission tomography (PET), and regional hypometabolism, measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. The authors found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age, but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Apathy; Cerebral Cortex; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Functional Neuroimaging; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

(18)F-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as 'normal' versus 'Alzheimer-like', is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how (18)F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed (18)F-flutemetamol scans and volumetric MRI scans from 72 cases from the (18)F-flutemetamol phase 2 study (27 clinically probable Alzheimer's disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the (18)F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The (18)F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the (18)F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the (18)F-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the (18)F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the (18)F-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of (18)F-flutemetamol scans can be replicated using SVM. In this sample the specificity of (18)F-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM.

Topics: Aged; Algorithms; Alzheimer Disease; Aniline Compounds; Artificial Intelligence; Benzothiazoles; Cognitive Dysfunction; Diagnosis, Differential; Female; Fluorine Radioisotopes; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Male; Observer Variation; Pattern Recognition, Automated; Positron-Emission Tomography; Reproducibility of Results; Sensitivity and Specificity; Thiazoles

Mild cognitive impairment (MCI) is a syndrome heterogeneous with regards to etiology and prognosis. Amyloid imaging enables to visualize a hallmark pathology of Alzheimer's disease (AD). Therefore we aimed to assess the usefulness of [(11)C]PiB PET for predicting clinical outcome of MCI patients after an interval of 2 years.. In 28 MCI participants with a global CDR rating at baseline of 0.5 a baseline examination including clinical assessments and [(11)C]PiB PET imaging and a clinical follow-up examination after a planned interval of 24 months were performed. Predictive values and accuracy of amyloid-positive and negative scans for conversion to dementia of any type and to dementia due to AD were calculated and compared to neuropsychological tests and ApoE genotyping.. Of 17 MCI patients who were amyloid-positive at baseline converted 9 to dementia all of the AD type. 3 of the 11 amyloid-negative MCI subjects converted to dementia but none to dementia due to AD. PPV, NPV and accuracy (to dementia: 0.53, 0.73 and 0.61; to AD: 0.53, 1.00 and 0.70) was comparable to neuropsychological tests and superior to ApoE genotyping.. All MCI subjects who converted to dementia due to AD were amyloid-positive. However, only 50% of these MCI due to AD, intermediate likelihood, patients developed manifest dementia due to AD after 24 months limiting the usefulness of [(11)C]PiB PET for individual prediction of clinical outcome.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoprotein E4; Benzothiazoles; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

To determine whether amyloid burden, as indexed by Pittsburgh compound B (PiB) retention, identifies patients with Parkinson disease with mild cognitive impairment (PD-MCI) compared to those with normal cognition (PD-nl). A related aim is to determine whether amyloid burden predicts cognitive decline in a cohort of subjects with PD without dementia.. In this prospective cohort study, we examined 46 subjects with PD without dementia, of whom 35 had normal cognition and 11 met criteria for PD-MCI at study baseline. All subjects underwent standardized neurologic and neuropsychological examinations and PiB PET at baseline, and clinical examinations were conducted annually for up to 5 years.. At baseline, precuneus PiB retention did not distinguish PD-MCI from PD-nl. Subjects with PD-MCI declined more rapidly than PD-nl subjects on cognitive tests of memory, executive function, and activation retrieval. Of the 35 PD-nl subjects, 8 progressed to PD-MCI and 1 to dementia; of the 11 PD-MCI subjects, 5 converted to dementia. Both higher PiB retention and a diagnosis of PD-MCI predicted a greater hazard of conversion to a more severe diagnosis. Baseline PiB retention predicted worsening in executive function over time. The APOE ε4 allele also related to worsening in executive function, as well as visuospatial function, activation retrieval, and performance on the Mini-Mental State Examination. In contrast to its relation to cognitive decline, PiB retention did not affect progression of motor impairment.. At baseline measurements, amyloid burden does not distinguish between cognitively impaired and unimpaired subjects with PD without dementia, but our data suggest that amyloid contributes to cognitive, but not motor, decline over time.

Topics: Aged; Amyloid; Aniline Compounds; Apolipoprotein E4; Biomarkers; Carbon Radioisotopes; Cognitive Dysfunction; Dementia; Disease Progression; Female; Functional Neuroimaging; Humans; Male; Neuropsychological Tests; Parietal Lobe; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Thiazoles

[(11)C]Pittsburgh compound-B (PIB) has been the most widely used positron emission tomography (PET) imaging agent for brain amyloid. Several longitudinal studies evaluating the progression of Alzheimer's disease (AD), and numerous therapeutic intervention studies are underway using [(11)C]PIB PET as an AD biomarker. Quantitative analysis of [(11)C]PIB data requires the definition of regional volumes of interest. This investigation systematically compared two data analysis routes both using a probabilistic brain atlas with 11 bilateral regions. Route 1 used individually segmented structural magnetic resonance images (MRI) for each subject while Route 2 used a standardised [(11)C]PIB PET template.. A total of 54 subjects, 20 with probable Alzheimer's disease (AD), 14 with amnestic Mild Cognitive Impairment (MCI) and 20 age-matched healthy controls, were scanned at two imaging centres either in London (UK) or in Turku (Finland). For all subjects structural volumetric MRI and [(11)C]PIB PET scans were acquired. Target-to-cerebellum ratios 40 min to 60 min post injection were used as outcome measures. Regional read outs for grey matter target regions were generated for both routes. Based on a composite neocortical, frontal, posterior cingulate, combined posterior cingulate and frontal cortical regions, scans were categorised into either 'PIB negative' (PIB-) or 'PIB positive' (PIB+) using previously reported cut-off target-to-cerebellar ratios of 1.41, 1.5 and 1.6, respectively.. Target-to-cerebellum ratios were greater when defined with a [(11)C]PIB PET template than with individual MRIs for all cortical regions regardless of diagnosis. This difference was highly significant for controls (p<0.001, paired samples t-test), less significant for MCIs and borderline for ADs. Assignment of subjects to raised or normal categories was the same with both routes with a 1.6 cut-off while with lower cut off using frontal cortex, and combined frontal cortex and posterior cingulate demonstrated similar results, while posterior cingulate alone demonstrated significantly higher proportion of controls as amyloid positive by Route 2.. Definition of cortical grey matter regions is more accurate when individually segmented MRIs (Route 1) were used rather than a population-based PET template (Route 2). The impact of this difference depends on the grey-to-white matter contrast in the PET images; specifically seen in healthy controls with high white matter and low grey matter uptake. When classifying AD, MCI and control subjects as normal or abnormal using large cortical regions; discordance was found between the MRI and template approach for those few subjects who presented with cortex-to-cerebellum ratios very close to the pre-assigned cut-off. However, posterior cingulate alone demonstrated significant discordance in healthy controls using template based approach. This study, therefore, demonstrates that the use of a [(11)C]PIB PET template (Route 2) is adequate for clinical diagnostic purposes, while MRI based analysis (Route 1) remains more appropriate for clinical research.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Carbon Radioisotopes; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).. To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.. A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.. Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N = 7]) participants.. Magnetic resonance imaging, Aβ (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing.. Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.. Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P < .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.. In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain Infarction; Cognitive Dysfunction; Cross-Sectional Studies; Executive Function; Female; Humans; Magnetic Resonance Imaging; Male; Memory; Mental Status Schedule; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; Vascular System Injuries

In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer's disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Cognition; Cognitive Dysfunction; Disease Progression; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Follow-Up Studies; Glucose; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Time Factors

Beta-amyloid (Aβ) is a histopathological hallmark of Alzheimer's disease dementia, but high levels of Aβ in the brain can also be found in a substantial proportion of nondemented subjects. Here we investigated which 2-year rate of brain and cognitive changes are present in nondemented subjects with high and low Aβ levels, as assessed with cerebrospinal fluid and molecular positron emission tomography (PET)-based biomarkers of Aβ. In subjects with mild cognitive impairment, increased brain Aβ levels were associated with significantly faster cognitive decline, progression of gray matter atrophy within temporal and parietal brain regions, and a trend for a faster decline in parietal Fludeoxyglucose (FDG)-PET metabolism. Changes in gray matter and FDG-PET mediated the association between Aβ and cognitive decline. In contrast, elderly cognitively healthy controls (HC) with high Aβ levels showed only a faster medial temporal lobe and precuneus volume decline compared with HC with low Aβ. In conclusion, the current results suggest not only that both functional and volumetric brain changes are associated with high Aβ years before the onset of dementia but also that HC with substantial Aβ levels show higher Aβ pathology resistance, lack other pathologies that condition neurotoxic effects of Aβ, or accumulated Aβ for a shorter time period.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Early Diagnosis; Humans; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was quantified using the Framingham Coronary Risk Profile (FCRP) score. Cerebral amyloid was measured by [(11)C]Pittsburgh compound B (PIB) positron emission tomography (PET) and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index (p < 0.008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of apolipoprotein E (APOE) genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol, and glycemic status on PIB index were all nonsignificant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Apolipoproteins E; Brain Mapping; Carbon Radioisotopes; Carotid Intima-Media Thickness; Cerebral Cortex; Cognitive Dysfunction; Coronary Disease; Female; Humans; Lipoproteins; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Risk; Thiazoles

Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimer's disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB-). Data of the unidirectional influx K(1) from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K(1) and ePIB (r=0.70; p≤0.001). The ePIB values were significantly lower in the posterior cingulate (p≤0.001) and the parietal cortices (p=0.002) in PIB+ subjects compared to PIB-, although the group difference were stronger for rCMRglc in cortical areas (p≤0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p≤0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Biomarkers; Carbon Radioisotopes; Cognitive Dysfunction; Deoxyglucose; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Parietal Lobe; Positron-Emission Tomography; Regional Blood Flow; Thiazoles

Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar Aβ. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar Aβ deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients.. (11)C-DED PET was performed in MCI patients (n = 8; mean age ± SD, 62.6 ± 7.5 y; mean Mini Mental State Examination, 27.5 ± 2.1), AD patients (n = 7; mean age, 65.1 ± 6.3 y; mean Mini Mental State Examination, 24.4 ± 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 ± 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference.. ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers.. Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Case-Control Studies; Cognitive Dysfunction; Deuterium; Female; Fluorodeoxyglucose F18; Gliosis; Humans; Male; Middle Aged; Monoamine Oxidase; Neuropsychological Tests; Positron-Emission Tomography; Radioactive Tracers; Retrospective Studies; Selegiline; Thiazoles

Given the recent and growing interest in the concepts of prodromal and presymptomatic Alzheimer disease, it is crucial to determine whether the presence of β-amyloid (Aβ) in the brain of asymptomatic elderly individuals is a pathologic condition associated with accelerated neuronal and synaptic loss. The aim of the present study was to assess whether Aβ influences the rate of atrophy in cognitively normal elderly individuals.. Seventy-four healthy elderly individuals underwent an MRI scan and a 11C-Pittsburgh compound B (PiB) PET scan at baseline and a second MRI scan 18 months later. Voxel-wise analyses were performed using maps of annual rate of atrophy generated from the serial MRI scans, including comparison between individuals with high vs low neocortical PiB and correlation with baseline neocortical PiB.. The rate of atrophy was significantly higher in the normal elderly individuals with high PiB compared with those with low PiB and was significantly correlated with baseline neocortical PiB, with the highest significance in the temporal neocortex and the posterior cingulate cortex.. Our findings show that the presence of Aβ in the brain, known to occur in about one-third of asymptomatic elderly individuals, is actually a pathologic state associated with accelerated atrophy. They also suggest that therapy aimed to reduce the neurodegenerative process should be commenced in presymptomatic individuals with high PiB.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Brain Mapping; Cerebellum; Cerebral Cortex; Cognition; Cognitive Dysfunction; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neocortex; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Amyloid-β deposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloid-β deposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloid-β deposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloid-β deposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal distribution of the individual rates of neocortical amyloid-β accumulation observed support the existence of 'Pittsburgh compound B non-accumulators' and 'Pittsburgh compound B accumulators' and different clustering analyses led to a consistent threshold to separate these two subgroups (0.014-0.022 standardized uptake value ratio(pons)/year). The voxelwise three-way analysis of covariance was thus recomputed with the 'Pittsburgh compound B accumulators' only and the results were almost unchanged, with the Pittsbur

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain Mapping; Carbon Radioisotopes; Case-Control Studies; Cognitive Dysfunction; Disease Progression; Female; Humans; Longitudinal Studies; Male; Neocortex; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

A family history of Alzheimer's disease (AD) increases one's risk of developing late-onset AD (LOAD), and a maternal family history of LOAD influences risk more than a paternal family history. Accumulating evidence suggests that a family history of dementia associates with AD-typical biomarker changes. We analyzed cross-sectional data from non-demented, mild cognitive impairment (MCI), and LOAD participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 99) and cerebrospinal fluid (CSF) analysis (n = 403) for amyloid-β peptide (Aβ) and total tau. We assessed the relationship of CSF and PiB biomarkers and family history of dementia, as well as parent gender effects. In the larger analysis of CSF biomarkers, we assessed diagnosis groups individually. In the overall sample, CSF Aβ, tau/Aβ ratio, and global PiB uptake were significantly different between family history positive and negative groups, with markers of increased AD burden associated with a positive maternal family history of dementia. Moreover, a maternal family history of dementia was associated with significantly greater PiB Aβ load in the brain in the parietal cortex, precuneus, and sensorimotor cortex. Individuals with MCI positive for a maternal family history of dementia had significantly more markers of AD pathophysiology than individuals with no family history of dementia. A family history of dementia is associated with AD-typical biomarker changes. These biomarker associations are most robust in individuals with a maternal family history, suggesting that a maternally inherited factor influences AD risk.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Family Health; Female; Humans; Male; Middle Aged; Mothers; Positron-Emission Tomography; Thiazoles

Many patients with PD develop PD with dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account, in part, for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases. Twenty-nine cognitively healthy PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD, and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and Pittsburgh compound B (PiB) imaging with PET. Apolipoprotein E (ApoE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference. PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the ApoE ε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition. DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD, or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Antiparkinson Agents; Apolipoprotein E3; Cognition; Cognitive Dysfunction; Female; Genotype; Humans; Levodopa; Lewy Body Disease; Male; Neurologic Examination; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Thiazoles

The development of imaging reagents is of considerable interest in the Alzheimer's disease (AD) field. Some of these, such as Pittsburgh Compound B (PiB), were designed to bind to the amyloid-β peptide (Aβ), the major component of amyloid deposits in the AD brain. Although these agents were designed for imaging amyloid deposits in vivo, a major avenue of evaluation relies on postmortem cross validation with established indices of AD pathology. In this study, we evaluated changes in the postmortem binding of PiB and its relationship to other aspects of Aβ-related pathology in a series of AD cases and age-matched controls. We also examined cases of preclinical AD (PCAD) and amnestic mild cognitive impairment (MCI), both considered early points in the AD continuum. PiB binding was found to increase with the progression of the disease and paralleled increases in the less soluble forms of Aβ, including SDS-stable Aβ oligomers. Increased PiB binding and its relationship to Aβ was only significant in a brain region vulnerable to the development of AD pathology (the superior and middle temporal gyri) but not in an unaffected region (cerebellum). This implies that the amyloid deposited in disease-affected regions may possess fundamental, brain region specific characteristics that may not as yet be fully appreciated. These data support the idea that PiB is a useful diagnostic tool for AD, particularly in the early stage of the disease, and also show that PiB could be a useful agent for the discovery of novel disease-related properties of amyloid.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Frontotemporal Dementia; Humans; Male; Neuropsychological Tests; Organ Size; Positron-Emission Tomography; Thiazoles

The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI.. (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images.. At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function.. Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Caudate Nucleus; Cognition; Cognition Disorders; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Positron-Emission Tomography; Psychometrics; Radiopharmaceuticals; Temporal Lobe; Thiazoles

Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neuropsychological Tests; Thiazoles

Topics: Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cognitive Dysfunction; Dementia; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles

Imaging of brain β-amyloid plaques with (18)F-labeled tracers for PET will likely be available in clinical practice to assist the diagnosis of Alzheimer disease (AD). With the rapidly growing prevalence of AD as the population ages, and the increasing emphasis on early diagnosis and treatment, brain amyloid imaging is set to become a widely performed investigation. All physicians reading PET scans will need to know the complex relationship between amyloid and cognitive decline, how to best acquire and display images for detection of amyloid, and how to recognize the patterns of tracer binding in AD and other causes of dementia. This article will provide nuclear medicine physicians with the background knowledge required for understanding this emerging investigation, including its appropriate use, and prepare them for practical training in scan interpretation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Cognitive Dysfunction; Education, Medical; Fluorine Radioisotopes; Humans; Image Interpretation, Computer-Assisted; Ligands; Molecular Imaging; Nuclear Medicine; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Thiazoles

Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment.. We analyzed cross-sectional data from participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for β-amyloid peptide (Aβ) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers.. No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Aβ (β = 0.181, p < 0.001), tau (β = -0.179, p < 0.001), tau/Aβ ratio (β = -0.180, p < 0.001), and global PiB uptake (β = -0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associated with lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups.. The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Body Mass Index; Cognitive Dysfunction; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Overweight; Positron-Emission Tomography; tau Proteins; Thiazoles

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Cognitive Dysfunction; Humans; Middle Aged; Positron-Emission Tomography; Thiazoles