2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Cognition-Disorders

We conducted a meta-analysis of relationships between amyloid burden and cognition in cognitively normal, older adult humans.. Methods of assessing amyloid burden included were CSF or plasma assays, histopathology, and PET ligands. Cognitive domains examined were episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Sixty-four studies representing 7,140 subjects met selection criteria, with 3,495 subjects from 34 studies representing independent cohorts. Weighted effect sizes were obtained for each study. Primary analyses were conducted limiting to independent cohort studies using only the most common assessment method (Pittsburgh compound B). Exploratory analyses included all assessment methods.. Episodic memory (r = 0.12) had a significant relationship to amyloid burden. Executive function and global cognition did not have significant relationships to amyloid in the primary analysis of Pittsburgh compound B (r = 0.05 and r = 0.08, respectively), but did when including all assessment methods (r = 0.08 and r = 0.09, respectively). The domains of working memory, processing speed, visuospatial function, and semantic memory did not have significant relationships to amyloid. Differences in the method of amyloid assessment, study design (longitudinal vs cross-sectional), or inclusion of control variables (age, etc.) had little influence.. Based on this meta-analytic survey of the literature, increased amyloid burden has small but nontrivial associations with specific domains of cognitive performance in individuals who are currently cognitively normal. These associations may be useful for identifying preclinical Alzheimer disease or developing clinical outcome measures.

Topics: Aging; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Cognition; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Thiazoles

PET imaging agents such as Pittsburgh compound B (PiB) allow detection of fibrillar β-amyloid (Aβ) in vivo. In addition to quantification of Aβ deposition in mild cognitive impairment and Alzheimer's disease, PiB has also increased our understanding of Aβ deposition in older adults without cognitive impairment. In vivo Aβ deposition has been studied in relation to genotype, structural and functional brain changes, as well as alterations in biomarker levels. To date, several studies have reported changes in Aβ burden over time. This, together with investigation of the relationship between Aβ deposition and cognition, sets the stage for elucidation of the temporal sequence of the neurobiological events leading to cognitive decline. Furthermore, correlation of Aβ levels detected by PiB PET and those obtained from biopsy or postmortem specimens will allow more rigorous quantitative interpretation of PiB PET data in relation to neuropathological evaluation. Since the first human study in 2004, in vivo amyloid imaging has led to advances in our understanding of the role of Aβ deposition in human aging and cognitive decline, as well as provided new tools for patient selection and therapeutic monitoring in clinical trials.

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Cognition Disorders; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography; Thiazoles

A subtle cognitive impairment can be detected early in the course of Parkinson's disease (PD). Executive, memory and visuospatial functions are specifically affected, but the underlying pathophysiological basis is not well elucidated yet and may be heterogeneous. The recent identification of a PD-related cognitive metabolic pattern (PDCP), including hypometabolism in associative frontal, parietal and posterior limbic structures, has integrated the classical notion of a striato-frontal syndrome at the basis of cognitive dys-function. Recent evidence suggests that whilst executive dys-function is seen in virtually all PD patients, visuospatial and memory impairment may share a higher risk for the subsequent development of dementia. By means of perfusion SPECT and [18F]FDG-PET, cortical dys-function may be highlighted since the early stages, it is more evident in PD patients with Mild Cognitive Impairment (MCI), and reaches the maximum in PD dementia (PDD). Posterior temporo-parieto-occipital dys-function in associative and limbic cortex, closely resembling that found in Alzheimer's disease patients, is found in PDD, with a more severe occipital hypometabolism and a relatively milder hypometabolism in medial temporal lobe structures. Furthermore, deficit of acetylcholinesterase (AchE) can be found by means of [11C]MP4A-PET already in early stage of PD, especially in posterior regions, then becoming more severe in PDD and in dementia with Lewy bodies (DLB). Administration of AchE inhibitors to PDD patients increased brain metabolism in bilateral frontal and left parietal regions, and left posterior cingulate. Finally, the recent availability of radiopharmaceuticals able to disclose amyloid brain deposition has allowed to demonstrate amyloid load in a part of patients with PDD, possibly due to diffuse rather than neuritic plaques. Brain PET and SPECT have strongly contributed to the understanding of the pathophysiology of cognitive impairment in PD and may serve as probes to monitor the effects of therapeutic interventions.

Topics: Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Cognition Disorders; Fluorodeoxyglucose F18; Humans; Parkinson Disease; Positron-Emission Tomography; Thiazoles; Tomography, Emission-Computed, Single-Photon

To review the rapidly expanding literature of amyloid PET imaging with particular attention to Pittsburgh compound-B (PIB) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), fronto-temporal dementia (FTD), mild cognitive impairment (MCI) and cognitively normal volunteers.. Literature searches were performed using Medline up to February 2010. Individual articles were then examined for additional references not revealed by automated searches. This yielded 79 articles whose abstracts were read by the authors to select key papers.. Amyloid deposition assessed using PIB-PET is significantly elevated in AD and DLB compared to controls and those with FTD. In MCI, uptake is often intermediate between AD and normal ageing, and excessive amyloid burden in non-demented individuals with MCI are likely to represent high-risk cases. Amyloid deposition appears to be an early event, and as dementia progresses clinical decline seems to be more associated with neurodegeneration than amyloid burden.. PIB-PET imaging is a sensitive and specific marker for underlying Aβ amyloid deposition and represents an important investigative tool for examining the relationship between amyloid burden, clinical symptoms and structural and functional changes in dementia. Amyloid imaging may also be useful for selecting patients for anti-amyloid therapies. However, studies have identified PIB-positive cases in otherwise healthy older individuals (10-30%), limiting diagnostic specificity. Development of biomarkers for investigating other aspects of dementia pathology, i.e. soluble Aβ, tau, synuclein and brain inflammation would further inform our understanding and assist in studying disease-modifying and preventive treatments in dementia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognition Disorders; Dementia; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Lewy Body Disease; Positron-Emission Tomography; Thiazoles

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Abeta1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Abeta amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Biomarkers; Cognition Disorders; Cross-Sectional Studies; Diagnostic Imaging; Homocysteine; Humans; Isoprostanes; Peptide Fragments; Positron-Emission Tomography; Prospective Studies; Reproducibility of Results; tau Proteins; Thiazoles

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Cognition Disorders; Humans; Nitriles; Positron-Emission Tomography; Thiazoles

The neurodegenerative disorder Alzheimer's disease (AD) is the most common form of dementia. It is characterized by progressive impairment of cognitive functions and behavior. To distinguish clinically AD from other forms of dementia is an ongoing challenge. In addition, although mild cognitive impairment (MCI) is recognized as a risk factor for dementia, it remains a challenge to predict on an individual level who will convert to become demented. Amyloid beta (Abeta) is one of the crucial pathological findings in AD. Recently, amyloid tracers for PET imaging have been developed successfully which may offer the unique possibility for measuring fibrillar Abeta load in the living brain. Therefore, in the near future positron emission tomography (PET) may become an important tool for in vivo amyloid imaging contributing to early (differential) diagnosis as well as evaluation of treatment response in AD. Moreover, Abeta may play a role in prediction the conversion of MCI to AD. In this paper we review the recent development of the molecular imaging technique PET and its different radiopharmaceuticals on the trail for imaging amyloid in AD and the conversion of MCI to AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain Mapping; Cognition Disorders; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography; Thiazoles

This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer's disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) define patients who are going to progress rapidly for the purpose of trial enrichment; (2) differentiate disease and therapeutically relevant AD subtypes; (3) assess the potential activity of specific therapies in vivo or ex vivo; and (4) measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measure in clinical trials of symptomatic patients, and (c) decide if further development of a treatment should be stopped if not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context.

Topics: Alzheimer Disease; Aniline Compounds; Biomarkers; Biomarkers, Pharmacological; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Disease Progression; Drug Design; Humans; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Psychotropic Drugs; Radioligand Assay; Thiazoles

The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantly enhance access to this novel technology.. Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of (18)F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for (18)F-flutemetamol and its parent molecule (11)C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of (18)F-flutemetamol SUVRs in 5 of the AD subjects.. Blinded visual assessments of (18)F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-flutemetamol SUVRs and (11)C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%.. (18)F-Flutemetamol performs similarly to the (11)C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Brain; Cognition Disorders; Diagnostic Imaging; Fluorodeoxyglucose F18; Humans; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Thiazoles

The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers.. To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia.. A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment.. Biomarker groups included amyloid β negative (Aβ-)/neurodegeneration negative (ND-), amyloid β positive (Aβ+)/ND-, Aβ-/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education.. Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ-/ND-, 32 (18.3%) were Aβ+/ND-, 35 (20.0%) were Aβ-/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures, the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ-/ND- group, the amyloid deposition alone (Aβ+/ND-) group showed faster decline on tests of verbal and visual memory (-0.3513; 95% CI, -0.5269 to -0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (-0.1934; 95% CI, -0.3520 to -0.0348). The Aβ-/ND+ group showed faster visual memory decline than the Aβ-/ND- reference group (-0.3007; 95% CI, -0.4736 to -0.1279).. In the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ+/ND- and Aβ-/ND+ groups.

Topics: Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Cognition Disorders; Female; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles

It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms.. To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation.. In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers.. We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups.. Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01).. The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.

Topics: Adult; Age Factors; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Carbolines; Cognition Disorders; Colombia; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Mutation; Neuropsychological Tests; Positron-Emission Tomography; Presenilin-1; tau Proteins; Thiazoles

Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing an

Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Brain Mapping; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Models, Neurological; Neural Pathways; Positron-Emission Tomography; Thiazoles

Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures.. We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden.. We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition.. Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness.. Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Atrophy; Cerebral Cortex; Cerebral Small Vessel Diseases; Cognition Disorders; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neural Pathways; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

A subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a 'mixed variant' phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype.. A consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [. Seven out of 12 subjects who had been classified a priori with nonfluent variant PPA showed deficits on conventional single-word comprehension tasks along with speech apraxia and agrammatism, corresponding to a mixed variant phenotype. These mixed variant cases included three females and four males, with a mean age at onset of 65 years (range 44-77 years). Object knowledge and object recognition were additionally affected, although less severely compared with the semantic variant. The mixed variant was characterized by a distributed atrophy pattern in frontal and temporoparietal regions. A more focal pattern of elevated [. A substantial proportion of PPA patients with speech apraxia and agrammatism also have single-word comprehension deficits. At the neurobiological level, the mixed variant shows a high degree of similarity with the pure nonfluent variant of PPA.. EudraCT, 2014-002976-10 . Registered on 13-01-2015.

Topics: Aged; Aged, 80 and over; Aminopyridines; Amyloid beta-Peptides; Aniline Compounds; Aphasia, Primary Progressive; Brain; Cognition Disorders; Comprehension; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Quinolines; Thiazoles; Tomography Scanners, X-Ray Computed; Vocabulary

We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging.. 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias.. To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment.. This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cerebellum; Cognition Disorders; Depression; Female; Fluorodeoxyglucose F18; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Retrospective Studies; Thiazoles

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provid

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Apolipoprotein E4; Cerebral Amyloid Angiopathy; Cerebral Arteries; Cerebral Veins; Cognition Disorders; Echo-Planar Imaging; Female; Humans; Male; Neuroimaging; Positron-Emission Tomography; Prospective Studies; Thiazoles; White Matter

Weight loss is frequently observed in patients with Alzheimer's disease (AD); however, the underlying mechanisms are not well understood.. To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI.. The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping.. In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas.. This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Cognition Disorders; Female; Glucose Metabolism Disorders; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nutritional Status; Positron-Emission Tomography; Prefrontal Cortex; Prodromal Symptoms; Psychiatric Status Rating Scales; Thiazoles

Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (. Clinical PSP patients showed bilaterally elevated

Topics: Aged; Aniline Compounds; Brain; Brain Mapping; Carbolines; Case-Control Studies; Cognition Disorders; Diagnosis; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Severity of Illness Index; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

To assess in a longitudinal study whether subjective cognitive decline (SCD) and brain β-amyloid (Aβ) contribute unique information to cognitive decline.. One hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB-) of Aβ pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables.. SCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD.. PiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Brain; Cognition Disorders; Cohort Studies; Female; Geriatric Assessment; Healthy Volunteers; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

Topics: Adult; Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Cognition Disorders; Female; Genome-Wide Association Study; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Risk Factors; tau Proteins; Thiazoles

Motor slowing appears in preclinical Alzheimer disease (AD), progresses with AD progression, and is associated with AD pathologic findings at autopsy. Whether amyloid-β (Aβ) is associated with gait speed in elderly individuals without dementia and whether cognition and apolipoprotein E ε4 (APOE ε4) influence this association remain unknown.. To examine the association between Aβ and gait speed in elderly individuals without dementia and to study the influence of cognition and APOE ε4 status on this association.. This cross-sectional analysis included 183 elderly individuals without dementia, including a cognitively normal (CN) subsample of 144 adults, enrolled in the Ginkgo Evaluation of Memory study at a university center from January 1, 2000, through December 31, 2009, and enrolled in a follow-up substudy a mean (SD) of 10 (3) months after the initial study closeout. Data analysis was performed from October 1, 2015, to June 1, 2016.. We assessed cerebral Aβ on Pittsburgh Compound B (PiB) positron emission tomography, gait speed over 4.57 m (15 ft), and cognition on the Mini-Mental State Examination and Trail Making Test Parts A and B. We grouped participants into high Aβ (PiB+) and low Aβ (PiB-) groups on standardized global PiB cutoffs and examined group differences. We studied the influence of cognition and APOE ε4 on the global and regional associations between gait speed and Aβ in the whole sample and the CN subsample.. Among the 183 study participants, mean (SD) age was 85.5 (3) years, 76 were women (41.5%), and 177 were white (96.7%). The PiB+ individuals were comparable to the PiB- individuals on demographics, comorbidities, cognition, hippocampal volume, and small-vessel disease but not on gait speed (0.85 vs 0.92 m/s, P = .01) or proportion of APOE ε4 carriers (29 [29.0%] vs 5 [6.0%], P < .001). In the whole sample and the CN subsample, the association between global PiB retention and slower gait withstood adjustment for covariates (β = -0.068, P = .03 and β = -0.074, P = .04, respectively); however, this association was attenuated by Mini-Mental State Examination and Trail Making Test Parts A and B and was rendered statistically nonsignificant by APOE ε4 in both samples (β = -0.055 and β = -0.058, respectively; both P ≥ .10). Several regional associations between gait speed and PiB uptake withstood relevant adjustments; however, APOE ε4 rendered only the medial (β = -0.22, P = .03) and lateral (β = -0.08, P = .03) temporal regions, subcortical white matter (β = -0.13, P = .02), and occipital regions (β = -0.15, P = .03) in the whole sample and the occipital regions (β = -0.21, P = .01) in the CN subsample statistically significant.. Cerebral Aβ deposition is associated with slower gait speed in elderly individuals without dementia; however, this association is weaker in those who are CN. Cognition and APOE ε4 carrier status influence the association between Aβ and gait speed in elderly individuals without dementia.

Topics: Aged, 80 and over; Aging; Amyloid; Aniline Compounds; Apolipoprotein E4; Brain; Carbon Radioisotopes; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Female; Gait Disorders, Neurologic; Genotype; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

To determine the effects of Type 2 diabetes (DM2) on levels of brain amyloidosis and cognition in a community-dwelling cohort of nondemented elderly individuals.. 33 subjects (16 DM2, 17 nondiabetic) were prospectively recruited. Subjects underwent a PET scan using the amyloid tracer, Pittsburgh Compound B, and a neuropsychological evaluation. Associations between DM2, brain amyloidosis, and cognition were assessed using multivariate regressions, adjusting for age and APOE4 status.. DM2 subjects had lower global cognitive function (p=0.018), as measured by the Repeatable Battery for the Assessment of Neuropsychological Status. There was no difference in brain amyloidosis between groups (p=0.25).. Community-dwelling, nondemented individuals with DM2 had greater cognitive deficits, which do not appear to be mediated by brain amyloidosis. Further studies exploring potential mediators of these cognitive deficits should be performed.

Topics: Aged; Amyloidosis; Aniline Compounds; Brain; Case-Control Studies; Cognition Disorders; Diabetes Mellitus, Type 2; Female; Humans; Independent Living; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer's disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimer's disease subjects compared with controls. Longitudinally, Alzheimer's disease subjects showed an increase in microglial activation. In conclusion, this is one of the first longitudinal positron emission tomography studies evaluating longitudinal changes in microglial activation in mild cognitive impairment and Alzheimer's disease subjects. We found there is an initial longitudinal reduction in microglial activation in subjects with mild cognitive impairment, while subjects with Alzheimer's disease showed an increase in microglial activation. This could reflect that activated microglia in mi

Topics: Aged; Alzheimer Disease; Aniline Compounds; Antineoplastic Agents; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Cohort Studies; Female; Humans; Imaging, Three-Dimensional; Isoquinolines; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Positron-Emission Tomography; Thiazoles

Although most previous cognitive studies of β-amyloidopathy in PD focused on cortical plaque deposition, recent postmortem studies point to an important role of striatal β-amyloid plaque deposition. The aim of this study was to investigate the relative contributions of striatal and cortical β-amyloidopathy to cognitive impairment in PD.. Patients with PD (n = 62; age, 68.9 ± 6.4 years; H & Y stage: 2.7 ± 0.5; MoCA score: 25.2 ± 3.0) underwent [(11) C]Pittsburgh compound B β-amyloid, [(11) C]dihydrotetrabenazine monoaminergic, and [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase brain PET imaging and neuropsychological assessment. [(11) C]Pittsburgh compound B β-amyloid data from young to middle-aged healthy subjects were used to define elevated [(11) C]Pittsburgh compound B binding in patients.. Elevated cortical and striatal β-amyloid deposition were present in 37% and 16%, respectively, of this predominantly nondemented cohort of patients with PD. Increased striatal β-amyloid deposition occurred in half of all subjects with increased cortical β-amyloid deposition. In contrast, increased striatal β-amyloid deposition did not occur in the absence of increased cortical β-amyloid deposition. Analysis of covariance using global composite cognitive z scores as the outcome parameter showed significant regressor effects for combined striatal and cortical β-amyloidopathy (F = 4.18; P = 0.02) after adjusting for covariate effects of cortical cholinergic activity (F = 5.67; P = 0.02), caudate nucleus monoaminergic binding, duration of disease, and age (total model: F = 3.55; P = 0.0048). Post-hoc analysis showed significantly lower cognitive z score for combined striatal and cortical β-amyloidopathy, compared to cortical-only β-amyloidopathy and non-β-amyloidopathy subgroups.. The combined presence of striatal and cortical β-amyloidopathy is associated with greater cognitive impairment than cortical β-amyloidopathy alone in PD.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Carbon Isotopes; Cerebral Cortex; Cognition Disorders; Corpus Striatum; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Tetrabenazine; Thiazoles

APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.. To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.. 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.. Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).. Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

Topics: Aged; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Benzothiazoles; Brain; Cognition Disorders; Female; Genotyping Techniques; Heterozygote; Humans; Logistic Models; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Apolipoproteins E; Brain; Cognition Disorders; Ethylene Glycols; Female; Humans; Male; Positron-Emission Tomography; Psychiatric Status Rating Scales; tau Proteins; Thiazoles; Young Adult

Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD.. To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls.. A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015.. Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time.. A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: β estimate, 0.29; P = .001; global composite scores: β estimate, -0.11; P = .001; episodic memory scores: β estimate, -0.18; P < .001; and semantic memory scores: β estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181.. The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Atrophy; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Disease Progression; Female; Humans; Independent Living; Male; Middle Aged; Neurocalcin; Neurogranin; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Predictive Value of Tests; ROC Curve; Severity of Illness Index; Statistics, Nonparametric; tau Proteins; Thiazoles

To decipher the cognitive and linguistic feature of logopenic variant primary progressive aphasia (lv-PPA) and nonfluent variant primary progressive aphasia (nfv-PPA) and to explore the extent to which cognitive and language impairment contribute to the dysfunction of activity of daily living(ADL).. Seven lv-PPA and five nfv-PPA were enrolled in memory clinic of Xuanwu Hospital, Capital Medical University from January 2015 to January 2016 accordig to the international consensus criteria for PPA and its three subtypes. 20 age-matched normal controls (NC) were included. Both the patients and the NC completed a battery of neuropsychological test, lingusitic test and brain magnetic resonance imaging. All the patients conducted (11)C Pittsburgh compound B (PiB) PET imaging.. Lv-PPA patients were characterized by deficits in lexical retrieval and long sentenses repetition, while nfv-PPA were with motor speech apraxia and phonetic distortion. Compared with nfv-PPA, lv-PPA patient displayed more severe cognitive deficit with younger onset of age (56±5 vs 61±5, P<0.05) , rapid decline of MMSE score within 1.5 years and pariental cortex dysfunctions such as ideomotor praxis, Gerstmann syndrome and contructional apraxia. Correlation analysis indicated that there was more significant association between pariental cortex dysfunction and ADL/mini-mental state examination(MMSE) than that of language deficit(r=-0.868, r=-0.922; r=0.312, r=-0.257). All seven lv-PPA were PiB-PET positive and five nfv-PPA were negative.. This study enriched the chinical and linguistic characterization of lv-PPA and nfv-PPA, which has implication for diagnosis, disease management and treatment for clinicians.

Topics: Aniline Compounds; Aphasia, Primary Progressive; Cognition; Cognition Disorders; Humans; Language; Magnetic Resonance Imaging; Memory; Neuropsychological Tests; Thiazoles

To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with β-amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of disease-modifying therapy.

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Chromatography, High Pressure Liquid; Cognition Disorders; Female; Humans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiamine; Thiazoles

We investigated the independent effects of Alzheimer's disease (AD) and cerebrovascular disease (CVD) pathologies on brain structural changes and cognition.. Amyloid burden (Pittsburgh compound B [PiB] retention ratio), CVD markers (volume of white matter hyperintensities [WMH] and number of lacunae), and structural changes (cortical thickness and hippocampal shape) were measured in 251 cognitively impaired patients. Path analyses were utilized to assess the effects of these markers on cognition.. PiB retention ratio was associated with hippocampal atrophy, which was associated with memory impairment. WMH were associated with frontal thinning, which was associated with executive and memory dysfunctions. PiB retention ratio and lacunae were also associated with memory and executive dysfunction without the mediation of hippocampal or frontal atrophy.. Our results suggest that the impacts of AD and CVD pathologies on cognition are mediated by specific brain regions.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Atrophy; Brain; Cerebrovascular Disorders; Cognition Disorders; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles

Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or 'cascades,' reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-β (Aβ) deposition (PiB-positron emission tomography). We analyzed data from 80 older adults with remitted major depression (36 with mild cognitive impairment (LLD+MCI) and 44 with normal cognitive (LLD+NC)) function. LLD+MCI was associated with differential expression of 24 proteins (P<0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P=0.015). We observed no differences in gray matter volume or brain Aβ deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12 and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75% and specificity of 86.4% in discriminating participants with MCI from those with NC function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Cognition Disorders; Depression; Female; Humans; Image Processing, Computer-Assisted; Machine Learning; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Proteins; Proteomics; Psychiatric Status Rating Scales; Thiazoles

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ(-) or Aβ(+). Relative to Aβ(-)ɛ4(-), Aβ(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ(-)ɛ4(-) and Aβ(-)ɛ4(+) groups. Among Aβ(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ(-) and Aβ(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain-Derived Neurotrophic Factor; Cognition Disorders; Female; Follow-Up Studies; Genetic Engineering; Genotype; Humans; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

There is growing evidence that the human brain is a large scale complex network. The structural network is reported to be disrupted in cognitively impaired patients. However, there have been few studies evaluating the effects of amyloid and small vessel disease (SVD) markers, the common causes of cognitive impairment, on structural networks. Thus, we evaluated the association between amyloid and SVD burdens and structural networks using diffusion tensor imaging (DTI). Furthermore, we determined if network parameters predict cognitive impairments. Graph theoretical analysis was applied to DTI data from 232 cognitively impaired patients with varying degrees of amyloid and SVD burdens. All patients underwent Pittsburgh compound-B (PiB) PET to detect amyloid burden, MRI to detect markers of SVD, including the volume of white matter hyperintensities and the number of lacunes, and detailed neuropsychological testing. The whole-brain network was assessed by network parameters of integration (shortest path length, global efficiency) and segregation (clustering coefficient, transitivity, modularity). PiB retention ratio was not associated with any white matter network parameters. Greater white matter hyperintensity volumes or lacunae numbers were significantly associated with decreased network integration (increased shortest path length, decreased global efficiency) and increased network segregation (increased clustering coefficient, increased transitivity, increased modularity). Decreased network integration or increased network segregation were associated with poor performances in attention, language, visuospatial, memory, and frontal-executive functions. Our results suggest that SVD alters white matter network integration and segregation, which further predicts cognitive dysfunction.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognition Disorders; Dementia, Vascular; Diffusion Tensor Imaging; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neural Networks, Computer; Neural Pathways; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; White Matter

The earliest sites of brain atrophy in Alzheimer's disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, amyloid-β-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields occurs preferentially with amyloid-β accumulation.

Topics: Aged; Amyloidogenic Proteins; Aniline Compounds; Cognition Disorders; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Thiazoles

Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories ad

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Cerebrovascular Disorders; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles; Tomography Scanners, X-Ray Computed

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

We hypothesized that comorbid amyloid-beta (Aβ) deposition played a key role in long-term cognitive decline in subjects with stroke/transient ischemic attack.. We recruited 72 subjects with cognitive impairment after stroke/transient ischemic attack to receive Carbon-11-labeled Pittsburgh compound B positron emission tomography. We excluded subjects with known clinical Alzheimer's disease. Those with and without Alzheimer's disease-like Aβ deposition were classified as mixed vascular cognitive impairment (mVCI, n=14) and pure VCI (pVCI, n=58), respectively. We performed Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment to evaluate global cognition and cognitive domains (memory, visuospatial function, language, attention, and executive function) at 3 to 6 months (baseline) and annually for 3 years after the index event. We compared cognitive changes between mVCI and pVCI using linear mixed models and analysis of covariance adjusted for age and education.. Over 3 years, there were significant differences between mVCI and pVCI on change of MMSE score over time (group×time interaction, P=0.007). We observed a significant decline on MMSE score (P=0.020) in the mVCI group but not in the pVCI group (P=0.208). The annual rates of decline on MMSE (P=0.023) and Montreal Cognitive Assessment score (P=0.003) were greater in the mVCI group than in the pVCI group. Memory, visuospatial, and executive function domain scores on the Montreal Cognitive Assessment were related to Aβ deposition.. Compared with subjects without Alzheimer's disease-like Aβ deposition, those with Aβ deposition experienced a more severe and rapid cognitive decline over 3 years after stroke/transient ischemic attack. Aβ was associated with changes in multiple cognitive domains.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Carbon Radioisotopes; Cognition Disorders; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Longitudinal Studies; Male; Positron-Emission Tomography; Registries; Stroke; Thiazoles; Time Factors

Subjective cognitive decline (SCD) in otherwise normal aging may be identified via symptom inventories in a research setting ('questionnaire-discovered complaints') or via patients seeking evaluation/services in a clinical setting ('presenting complainers'). Most studies of SCD and amyloid-β (Aβ) imaging to date have used the former approach, with inconsistent results.. To test whether 'presenting SCD' participants in an academic memory clinic setting show increased brain Aβ deposition on imaging.. Fourteen patients (mean age 68.1, SD 4.0 years) diagnosed with subjective cognitive complaints with normal neuropsychological testing were recruited into a Pittsburgh compound B (PiB)-PET study. Detailed self-report inventories and additional cognitive tests were administered. Results were compared to a reference cohort of cognitively normal volunteers (NC) from an independent neuroimaging study (mean age 73.6, SD 5.8 years).. 57% (8/14) of SCD participants were PiB-positive by a sensitive, regionally-based definition, compared to 31% (26/84) of the NC cohort. SCD participants had significantly higher PiB retention (SUVR) than NC in three of six regions of interest: frontal cortex (p = 0.02), lateral temporal cortex (p = 0.02), and parietal cortex (p = 0.04). SCD participants showed measurable deviations on questionnaires reflecting high negative affect (i.e., depressive symptoms and neuroticism). Findings were suggestive that deficits on verbal associative binding may be specific to Aβ-positive versus Aβ-negative SCD.. Older participants with SCD presenting to a memory clinic in this pilot study sample have higher brain Aβ deposition compared to normal aging study volunteers unselected on complaints. Further study of presenting SCD are warranted to determine the prognostic significance of Aβ deposition in this context.

Topics: Aged; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Apolipoproteins E; Cognition Disorders; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neuropsychological Tests; Pilot Projects; Positron-Emission Tomography; Self Report; Surveys and Questionnaires; Thiazoles

The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD.

Topics: Adult; Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Exercise Test; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Oxygen Consumption; Peptide Fragments; Physical Fitness; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles; Verbal Learning

It is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status.. From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden.. At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners.. Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

Topics: Aged; Amyloid; Aniline Compounds; Apolipoprotein E4; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Observation; Positron-Emission Tomography; Prospective Studies; Thiazoles

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB-positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cerebrovascular Disorders; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

The objective of this study was to evaluate the contribution of amyloid imaging with (11)C-Pittsburgh compound B ((11)C-PIB) and of glucose metabolism on F-fluorodeoxyglucose ((18)F-FDG) PET/CT to the study of cognitive impairment in the clinical setting.. Thirty-four patients (15 male, 19 female) were enrolled in the study. They were classified according to their clinically presented symptoms. Six patients had subjective memory complaints, five had nonamnestic mild cognitive impairment (MCI), seven had amnestic MCI, seven had prodromal Alzheimer's disease (AD), five had frontotemporal dementia, two had dementia with Lewy bodies, and two had cortical degeneration. All the scans were conducted to determine the likelihood of AD or to differentiate between AD and other dementia. Static 30-min (11)C-PIB and 15-min (18)F-FDG PET/CT scans were obtained. A visual analysis of images was performed.. Three of the six patients with subjective memory complaints had positive (11)C-PIB scans and one of them also had (18)F-FDG hypometabolism. All five nonamnestic MCI patients had normal (11)C-PIB and (18)F-FDG. Four of the seven amnestic MCI patients showed (11)C-PIB cortical retention but only one had positive (18)F-FDG. Positive (11)C-PIB and (18)F-FDG were detected in five of the seven prodromal AD patients. All the five patients with FDT had positive (18)F-FDG scans, but only one of the five had (11)C-PIB cortical retention. Both dementia with Lewy bodies and cortical degeneration patients had positive (11)C-PIB and (18)F-FDG scans.. The combined use of (11)C-PIB and (18)F-FDG PET provides relevant information for the clinical management of cognitive impairment. The detection of positive (11)C-PIB cortical retention in patients may be an indicator of the need for further clinical assessment and monitoring.

Topics: Adult; Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Benzothiazoles; Cognition Disorders; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Multimodal Imaging; Neuroimaging; Positron-Emission Tomography; Thiazoles; Tomography, X-Ray Computed

We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer's disease (AD) when coupled to neuroimaging and neuropsychological parameters.. Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months.. Comparisons of plasma Aβ levels between the transition and non-transitional groups showed Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01).. We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Cognition Disorders; Cohort Studies; Disease Progression; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neocortex; Neuroimaging; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

To evaluate the effect of amyloid imaging on clinical decision making.. We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ(2) and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).. Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.. PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Severity of Illness Index; Thiazoles

Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11C-Pittsburgh compound B (PiB) PET. We recruited 53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10-3, p = 0.034) while no significant correlation was found in APOE4 carriers (β = -9.0 × 10-3, p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognition Disorders; Dementia, Vascular; Female; Humans; Leukoencephalopathies; Male; Neuropsychological Tests; Positron-Emission Tomography; Regression Analysis; Retrospective Studies; Statistics as Topic; Thiazoles

High β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression.. Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later.. Compared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups.. In healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Learning; Linear Models; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Positron-Emission Tomography; Prodromal Symptoms; Psychiatric Status Rating Scales; Thiazoles

To disentangle the clinical heterogeneity of nonsemantic variants of primary progressive aphasia (PPA) and to identify a coherent linguistic-anatomical marker for the logopenic variant of PPA (lv-PPA).. Key speech and language features of 14 cases of lv-PPA and 18 cases of nonfluent/agrammatic variant of PPA were systematically evaluated and scored by an independent rater blinded to diagnosis. Every case underwent a structural MRI and a Pittsburgh compound B (PiB)-PET scan, a putative biomarker of Alzheimer disease. Key speech and language features that showed association with the PiB-PET status were entered into a hierarchical cluster analysis. The linguistic features and patterns of cortical thinning in each resultant cluster were analyzed.. The cluster analysis revealed 3 coherent clinical groups, each of which was linked to a specific PiB-PET status. The first cluster was linked to high PiB retention and characterized by phonologic errors and cortical thinning focused on the left superior temporal gyrus. The second and third clusters were characterized by grammatical production errors and motor speech disorders, respectively, and were associated with low PiB brain retention. A fourth cluster, however, demonstrated nonspecific language deficits and unpredictable PiB-PET status.. These findings suggest that despite the clinical and pathologic heterogeneity of nonsemantic variants, discrete clinical syndromes can be distinguished and linked to specific likelihood of PiB-PET status. Phonologic errors seem to be highly predictive of high amyloid burden in PPA and can provide a specific clinical marker for lv-PPA.

Topics: Aged; Aniline Compounds; Aphasia, Primary Progressive; Articulation Disorders; Cerebral Cortex; Cluster Analysis; Cognition Disorders; Female; Humans; Language Tests; Magnetic Resonance Imaging; Male; Middle Aged; Neurologic Examination; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Speech; Thiazoles

Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course.

Topics: Adult; Aged; Aged, 80 and over; Aniline Compounds; Basal Ganglia; Cerebral Cortex; Cognition Disorders; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Positron-Emission Tomography; Severity of Illness Index; Statistics, Nonparametric; Thiazoles

Inflammation is a hallmark of Alzheimer's disease (AD). Whether directly involved in the pathogenesis, or a downstream consequence of neuronal death, the blood neutrophil-lymphocyte ratio (NLR) is reported to be a putative, non-invasive peripheral biomarker for AD. The aim of this study was to re-evaluate the diagnostic utility of longitudinal measures of the NLR. The NLR was stable across all time-points and weakly correlated with neocortical amyloid burden (R=0.21 at baseline, 0.27 at 18 months, 0.20 at 36 months and 0.10 at 54 months). Cross-sectionally, the NLR was significantly elevated in AD participants as compared to HC participants at baseline (p<0.0001), 18 months (p<0.0001), 36 months (p=0.002) and at 54 months (p=0.007), however only prior to adjustment for age, sex and APOEε4 allele status (p>0.05 at all time-points except for 18 months; p<0.0001). Longitudinally, the NLR was not significantly different between HC and AD participants (p>0.05) adjusted for age, sex and APOEε4 allele status. Comparing the NLR between cognitive transition groups over time (transition towards an AD type dementia), there was no significant difference in the NLR levels between those participants, who did not transition and those participants who did transition, or those in the stable AD group after adjusting for age, sex and APOEε4 allele status (p>0.05). Despite inflammation being a hallmark in AD and previous reports showing that the NLR can discriminate HC from AD patients, our results suggest that the sensitivity of the NLR itself is not robust enough for diagnostic utility. We identified significant relationships cross sectionally (p<0.05 at baseline, 18 months and 36 months) between the NLR and neocortical amyloid burden, but this relationship was lost after longitudinal analyses (p>0.5). The NLR also had limited association with cognitive decline, although in our cohort, the number of participants transitioning was relatively small. In conclusion, the NLR may reflect AD-related inflammatory processes in the periphery, but age and sex are dominant covariates which need to be controlled for in population-based screening.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Chi-Square Distribution; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Longitudinal Studies; Lymphocytes; Male; Memory, Episodic; Neocortex; Neutrophils; Psychiatric Status Rating Scales; Radionuclide Imaging; Thiazoles

Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-β deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-β deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-β deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-β deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

Topics: Adult; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition Disorders; Down Syndrome; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET) would correlate with the extent of magnetic resonance imaging (MRI) white matter hyperintensities (WMH; or leukoaraiosis) in patients with high vascular amyloid deposition (cerebral amyloid angiopathy [CAA]) but not in patients with high parenchymal amyloid deposition (Alzheimer disease [AD]; mild cognitive impairment [MCI]) or in healthy elderly (HE) subjects.. Forty-two nondemented CAA patients, 50 HE subjects, and 43 AD/MCI patients had brain MRI and PiB PET. Multivariate linear regression was used to assess the independent association between PiB retention and white matter disease volume, controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group.. CAA patients were younger than HE and AD subjects (68 ± 10 vs 73.3 ± 7 and 74 ± 7.4, p < 0.01) but had higher amounts of WMH (median = 21 vs 3.2 and 10.8 ml, respectively, p < 0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho = 0.52, p < 0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity, also remained as an independent predictor of WMH volume.. Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlates with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Apolipoprotein E4; Cerebral Amyloid Angiopathy; Cognition Disorders; Female; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Statistics, Nonparametric; Thiazoles

Alzheimer's disease (AD) pathology of amyloid β (Aβ) accumulation and neurodegeneration may be relevant to preclinical cognitive decline. The objective of this study was to relate AD-sensitive biomarkers of Aβ and neurodegeneration and their interaction to longitudinal cognitive change in cognitively normal elderly.. Thirty-eight older people completed at least three consecutive neuropsychological examinations. Using positron emission tomography (PET), Aβ plaque burden was measured with [(11)C]Pittsburgh compound B (PiB). PiB retention was dichotomized into a positive (n = 13) and negative (n = 25) PiB status. Neurodegenerative biomarkers were extracted within AD-vulnerable regions of interest (ROIs)-namely, the hippocampus and temporoparietal cortical areas. Within each ROI, metabolism was quantified with [(18)F] fluorodeoxyglucose (FDG) PET, and the gray matter structure was evaluated using volume (hippocampus) or thickness (cortical regions). ROI-specific functional and structural biomarkers were combined further into cross-modality neurodegenerative composite measures. Using hierarchical regression models, PiB and the neurodegenerative biomarkers were related to cognitive trajectories.. PiB positivity was associated with memory and nonmemory worsening. The neurodegenerative biomarkers modified these relationships. Longitudinal cognitive decline was accelerated in those individuals who exhibited both PiB positivity and lower neurodegenerative biomarker scores, although the two measures appeared to be independent. PiB retention interacted predominantly with the cortical neurodegenerative composite for nonmemory change. Memory decline was best explained by the interaction between PiB and the hippocampal neurodegenerative composite, suggesting regional specificity of the neurodegenerative modulations.. Our findings indicate that cognitive trajectories deteriorate at a faster rate in cognitively normal individuals expressing Aβ burden and neurodegeneration within specific AD-sensitive regions.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain; Cognition Disorders; Cohort Studies; Female; Fluorodeoxyglucose F18; Genotype; Geriatric Assessment; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Regression Analysis; Thiazoles

Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment.. We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes.. Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001).. Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Cognition Disorders; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Stroke, Lacunar; Thiazoles

To determine whether a high prevalence (55%) of Aβ deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging.. A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aβ status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models.. At GEMS screening (2000-2002), participants who were Aβ-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aβ-positive relative to Aβ-negative participants (ps < 0.05).. Highly prevalent Aβ deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aβ-status groups may be detectable 7-9 years before neuroimaging.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Cognition Disorders; Cross-Sectional Studies; Dementia; Double-Blind Method; Female; Ginkgo biloba; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Phytotherapy; Plant Preparations; Positron-Emission Tomography; Psychiatric Status Rating Scales; Retrospective Studies; Thiazoles

β-Amyloid (Aβ) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aβ deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aβ burden for brain regions that are most affected in AD.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid; Analysis of Variance; Aniline Compounds; Biomarkers; Brain Mapping; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Radioisotopes; Reproducibility of Results; Thiazoles

Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1β, and tumor necrosis factor (TNF)-α. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1β and 21%-27% higher TNF-α compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low β-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-α and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.

Topics: Acetylcholine; Acetylcholinesterase; Aged; Alzheimer Disease; Aniline Compounds; Astrocytes; Butyrylcholinesterase; Calcium-Binding Proteins; Cells, Cultured; Cognition Disorders; Complement System Proteins; Cytokines; DNA-Binding Proteins; Female; Fluorodeoxyglucose F18; Glial Fibrillary Acidic Protein; Humans; Male; Mental Status Schedule; Microfilament Proteins; Neuropsychological Tests; Polymorphism, Single Nucleotide; Radionuclide Imaging; S100 Calcium Binding Protein beta Subunit; Thiazoles

The relationship between the apolipoprotein E ε4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimer's disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB(-) SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79-2.84), whereas APOE4 increased the risk of PiB(+) SVCI (OR, 4.52; 95% CI, 1.70-11.97) and PiB(+) ADCI (odds ratio, 4.84; 95% CI, 2.54-7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognition Disorders; Female; Genotype; Humans; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Fibers, Myelinated; Neuropsychological Tests; Prospective Studies; Radionuclide Imaging; Thiazoles; Vascular Diseases

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine the relationship between BDNF Val66Met and beta-amyloid (Aβ) on cognitive decline, hippocampal atrophy, and Aβ accumulation over 36 months in 165 healthy adults enrolled in the Australian Imaging, Biomarkers and Lifestyle study. In healthy adults with high Aβ, Met carriers showed significant and moderate-to-large declines in episodic memory, executive function, and language, and greater hippocampal atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippocampal volume in healthy adults with low Aβ. BDNF Val66Met did not relate to the amount of Aβ or to the rate of Aβ accumulation in either group. High Aβ levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippocampal degeneration in individuals in the preclinical stage of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Australia; Brain-Derived Neurotrophic Factor; Cognition Disorders; Female; Genotype; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory, Episodic; Methionine; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles; Valine

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Pyrimidines; Receptors, GABA; Statistics as Topic; Thiazoles

The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue ((11)C-PiB) positron emission tomography data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allowed us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression--here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance, and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, the use of which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications.

Topics: Aged; Aged, 80 and over; Amyloidogenic Proteins; Aniline Compounds; Biomarkers; Carbon Radioisotopes; Cerebral Cortex; Cognition Disorders; Disease Progression; Female; Humans; Male; Memory; Molecular Imaging; Radiopharmaceuticals; Thiazoles; Tomography, Emission-Computed

Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear.. To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11–labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy.. Scores calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study.. Prospective, serially assessed cohort of community-dwelling subjects.. Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography.. Autopsy and 11C-PiB positron emission tomography.. The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses.. We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole.. In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Baltimore; Benzothiazoles; Cognition Disorders; Female; Glucose Intolerance; Humans; Insulin Resistance; Longitudinal Studies; Male; Prospective Studies; Radionuclide Imaging; Thiazoles

Most subjects with logopenic variant of primary progressive aphasia (lvPPA) have β-amyloid (Aβ) deposition on Pittsburgh Compound B positron emission tomography (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.. To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.. Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and presence and distribution of microbleeds and white matter hyperintensities (WMHs) were assessed.. Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.. Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Aphasia, Primary Progressive; Atrophy; Case-Control Studies; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Intracranial Hemorrhages; Male; Middle Aged; Nerve Fibers, Myelinated; Neuroimaging; Neuropsychological Tests; Occipital Lobe; Radionuclide Imaging; Thiazoles

Topics: Amyloid; Aniline Compounds; Cognition Disorders; Humans; Neurodegenerative Diseases; Positron-Emission Tomography; Thiazoles

Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.. Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.. Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.. For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).. Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.. Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Cognition Disorders; Cohort Studies; Community-Based Participatory Research; Cross-Sectional Studies; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Neurodegenerative Diseases; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Brain Mapping; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Sensitivity and Specificity; Thiazoles

Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer's disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects.. Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status.. There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003).. Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Ceruloplasmin; Cognition Disorders; Copper; Female; Humans; Linear Models; Longitudinal Studies; Male; Mass Spectrometry; Middle Aged; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

We aimed to characterize the nature and magnitude of cognitive decline in a group of healthy older adults with high and low levels of amyloid-β (Aβ) and who were APOE ε4 carriers and non-carriers. Healthy older adults underwent positron emission tomography neuroimaging for Aβ, APOE genotyping, and cognitive and clinical assessment as part of their baseline assessment in the Australian Imaging, Biomarker, and Lifestyle study. Cognitive function and clinical ratings were reassessed 18 months later. Linear mixed model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, healthy older adults with high Aβ showed greater decline in episodic memory and language at 18 months. No decline on any measure of executive function, attention, or clinical rating was observed for healthy older adults with high Aβ levels. Compared to non-carriers, APOE ε4 carriers showed a greater decline only on the task of visual memory at the 18 month assessment. Importantly though, no interaction between APOE ε4 and Aβ was observed on any measure of cognitive function. The results of this study suggest that high Aβ load was associated with greater decline in episodic memory and language, that the magnitude of this decline was moderate and equivalent across both domains, and that APOE ε4 carriage did not moderate the relationship between Aβ and decline in memory and language functions.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Cognition; Cognition Disorders; Female; Humans; Linear Models; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

To evaluate whether the amyloid-binding agent carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants.. (11)C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both χ(2) and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer's Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-β protein 1-42 (Aβ42) using (11)C-PiB.. An ADRC and HIV clinic.. Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD).. Mean and regional (11)C-PiB binding potentials.. Participants with symptomatic AD were older (P < .001), had lower CSF Aβ42 levels (P < .001), and had higher CSF tau levels (P < .001) than other groups. Regardless of degree of impairment, HIV-positive participants did not have increased (11)C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P < .001).. Middle-aged HIV-positive participants, even with HAND, do not exhibit increased (11)C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. (11)C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross-sectional and longitudinal studies are required to assess the utility of (11)C-PiB in older individuals with HAND.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Benzothiazoles; Case-Control Studies; Cerebral Cortex; Cognition Disorders; Female; HIV Infections; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Thiazoles

To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB), in healthy older individuals.. Cross-sectional clinical study.. Berkeley, California.. Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.. Cortical [(11)C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.. Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [(11)C]PiB uptake (P<.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [(11)C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [(11)C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [(11)C]PiB uptake.. Individuals with greater early- and middle-life cognitive activity had lower [(11)C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [(11)C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles; Young Adult

To study the relationship between subjective cognition and the neuropathological hallmark of Alzheimer disease (AD), amyloid-β (Aβ) deposition, using carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography in normal elderly individuals.. Cross-sectional analysis.. Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations, magnetic resonance imaging, and positron emission tomography.. Berkeley Aging Cohort Study.. Relationship between PiB uptake and subjective cognition measures.. Subjects with high PiB uptake showed significantly lower performance than those with low PiB uptake on an episodic memory measure and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB uptake groups did not differ on the accuracy of their cognitive self-reports compared with objective cognitive performance. General memory self-reports from the whole group were significantly correlated with regional PiB uptake in the right medial prefrontal cortex and anterior cingulate cortex and in the right precuneus and posterior cingulate cortex. Reduced confidence about memory abilities was associated with greater PiB uptake in these brain regions. All results were independent of demographic variables and depressive affects.. A decrease of self-confidence about memory abilities in cognitively normal elderly subjects may be related to the neuropathological hallmark of AD measured with PiB-positron emission tomography. Subjective cognitive impairment may represent a very early clinical manifestation of AD.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cerebral Cortex; Cognition; Cognition Disorders; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prefrontal Cortex; Radiopharmaceuticals; Reference Values; Thiazoles

This article investigates longitudinal imaging characteristics of early cognitive decline during normal aging, leveraging on high-dimensional imaging pattern classification methods for the development of early biomarkers of cognitive decline. By combining magnetic resonance imaging (MRI) and resting positron emission tomography (PET) cerebral blood flow (CBF) images, an individualized score is generated using high-dimensional pattern classification, which predicts subsequent cognitive decline in cognitively normal older adults of the Baltimore Longitudinal Study of Aging. The resulting score, termed SPARE-CD (Spatial Pattern of Abnormality for Recognition of Early Cognitive Decline), analyzed longitudinally for 143 cognitively normal subjects over 8 years, shows functional and structural changes well before (2.3-2.9 years) changes in neurocognitive testing (California Verbal Learning Test [CVLT] scores) can be measured. Additionally, this score is found to be correlated to the [(11)C] Pittsburgh compound B (PiB) PET mean distribution volume ratio at a later time. This work indicates that MRI and PET images, combined with advanced pattern recognition methods, may be useful for very early detection of cognitive decline.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Aniline Compounds; Brain; Brain Mapping; Cerebrovascular Circulation; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Statistics as Topic; Thiazoles

Progressive intraindividual decline in memory and cognition is characteristic of dementia and may be useful in detecting very early Alzheimer's disease pathology.. This study evaluated the slopes of cognitive performance over a 12-month period in 263 healthy, community-dwelling, adult volunteers aged ≥50 years. Participants completed a brief computerized battery of cognitive tests (CogState) at baseline and during 3-, 6-, 9-, and 12-month follow-up assessments. Linear mixed models were used to estimate age-adjusted mean slopes and 95% confidence intervals of change for each of the cognitive measures.. By defining age-adjusted mean slopes, and 95% confidence intervals for a measure of episodic memory, individuals with greater than expected decline (equal to or lower than the fifth percentile level of decline) were identified. From these, four individuals completed a full medical, neurologic, and neuropsychological evaluation, with none of them fulfilling criteria for mild cognitive impairment, but three (75%) having positive amyloid-positron emission tomographic scans.. Intraindividual decline in cognitive performance can be detected in otherwise healthy, community-dwelling, older persons, and this may deserve further study as a potential indicator of early Alzheimer's disease pathology.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Cognition Disorders; Diagnosis, Computer-Assisted; Disease Progression; Female; Follow-Up Studies; Humans; Male; Memory, Episodic; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Positron-Emission Tomography; Residence Characteristics; Thiazoles; Time Factors

To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score.. Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative.. Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease dementia. Subgroup analyses were performed in members of both cohorts (n = 243 and n = 328) who were amyloid positive at baseline.. The shape of biomarker trajectories as a function of MMSE score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging.. Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model.. Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Biomarkers; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Immunoassay; Magnetic Resonance Imaging; Male; Mental Status Schedule; Nonlinear Dynamics; Peptide Fragments; Positron-Emission Tomography; tau Proteins; Thiazoles

Age-related decline is common in multiple cognitive domains. β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aβ on cognition during aging. Using positron emission tomography (PET) imaging with the radiotracer Pittsburgh Compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Aβ. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Aβ and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Aβ on cognitive changes in normal elderly.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Area Under Curve; Brain; Cognition Disorders; Discriminant Analysis; Executive Function; Female; Humans; Magnetic Resonance Imaging; Male; Memory; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Principal Component Analysis; ROC Curve; Thiazoles; Verbal Learning; Young Adult

A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.. We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.. The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.. This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Brain; Cognition Disorders; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Longitudinal Studies; Male; Mental Status Schedule; National Institute on Aging (U.S.); Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; United States

Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of β-amyloid. Stage 2 represents abnormal levels of β-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity.. Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or [(18)F]fluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year.. Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001).. Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Chi-Square Distribution; Cognition Disorders; Disease Progression; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; National Institute on Aging (U.S.); Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles; United States

Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (st

Topics: Age of Onset; Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoproteins E; Brain Mapping; Carbon Radioisotopes; Case-Control Studies; Cognition Disorders; Female; Fluorodeoxyglucose F18; Genotype; Glucose; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Parietal Lobe; Positron-Emission Tomography; Radiopharmaceuticals; 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

In order to evaluate the role of positron emission tomography (PET) with N-methyl-[(11)C]-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, also known as Pittsburgh compound B (PIB), in the early diagnosis of Alzheimer's disease (AD). Clinical data were collected, and PIB PET cerebral imaging was performed in patients with AD (n = 6), mild cognitive impairment (MCI) (n = 7), and elderly, mentally normal controls (NCs) (n = 7). PET images of the subjects were then analyzed. Visual analysis showed that the radioactivity clearance rate in AD patients was significantly different from that found in the NC group. Furthermore, the radioactivity clearance rate 45 min after PIB injection was significantly lower than the NC group. Images from the MCI group presented heterogeneous results, overlapping with those from both the AD and NC groups. Statistical analysis showed that the radioactivity clearance rate during 5-45 min post-injection was significantly lower in the AD group (41-77%) than the control group (75-81%) (P > 0.05) and the MCI group (59-77%). The radioactivity clearance rate in the bilateral parietal lobes, frontal, temporal, and right occipital lobes, and the bilateral corpora striata in MCI group were lower than that in control group (P < 0.05). PIB PET brain imaging can differentiate early AD patients from NCs and may have certain value in identifying patients progressing to MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.. Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57.. At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI.. Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Plaque, Amyloid; Polymorphism, Genetic; Positron-Emission Tomography; Severity of Illness Index; Thiazoles

The relationship between β-amyloid deposition and memory deficits in early Alzheimer's disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional β-amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimer's disease, i.e. with β-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and β-amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical β-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for β-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal β-amyloid deposition provided independent contributions to memory deficits. In contrast to global β-amyloid deposition, temporal β-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical β-amyloid. In the pre-dementia stage of Alzheimer's disease, subtle episodic memory impairment is related to β-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Regression Analysis; Thiazoles

Patients with amnestic mild cognitive impairment (MCI) have greater risk of conversion to Alzheimer disease (AD). Increased brain amyloid burden in AD and MCI has been demonstrated with PET using [(11)C] Pittsburgh compound B (PiB) as a tracer.. To evaluate change in β-amyloid deposition in with MCI during 2-year follow-up.. Patients with MCI and controls were studied with [(11)C] PiB PET, MRI, and neuropsychometry at baseline and these investigations were repeated in patients with MCI after follow-up.. Those patients with MCI converting to AD during follow-up had greater [(11)C] PiB retention in the posterior cingulate (p=0.020), in the lateral frontal cortex (p=0.006), in the temporal cortex (p=0.022), in the putamen (p=0.041), and in the caudate nucleus (p=0.025) as compared to nonconverters. In converters, there was no significant change in [(11)C] PiB uptake, whereas an increase was seen as compared to baseline in nonconverters in the anterior and posterior cingulate, temporal and parietal cortices, and putamen. Hippocampal atrophy was greater in converters at baseline than in nonconverters, but increased significantly in both groups during follow-up.. Hippocampal atrophy and amyloid deposition seem to dissociate during the evolution of MCI, the atrophy increasing clearly and [(11)C] PiB retention changing modestly when conversion to AD occurs. Longer follow-up is needed to determine whether nonconverters would convert to AD later, which would suggest accelerated [(11)C] PiB retention preceding clinical conversion.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Brain; Carbon Radioisotopes; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

There is mounting evidence for the contribution of apoE to the pathophysiology of Alzheimer disease (AD). Studies also indicate that plasma apoE levels may reflect disease status, suggesting that apoE is a potential AD biomarker. However, while some studies of apoE levels in plasma have presented correlations with AD pathology, others have not. Thus, there is a lack of consensus as to the suitability of plasma apoE as an AD biomarker. The major objective of this cross-sectional study was to investigate total plasma apoE as well as levels of the apoE4 form in a large, highly characterized cohort which included both healthy controls and participants with early-stage AD.. Total apoE and apoE4 were measured in 1,079 individuals drawn from the highly characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Total and isoform-specific plasma apoE levels were then compared with cerebral Aβ load, as assessed by PET using Pittsburgh compound B (PiB).. Total apoE and apoE4 levels were found to be significantly lower in patients with AD in the entire cohort, and decrease with Aβ load in the PiB-PET subset. ApoE levels were significantly lower among ε4 homozygous individuals. In APOE ε3/ε4 heterozygote carriers, apoE4 levels decrease, indicating that apoE3 levels increase with disease.. Analysis of cross-sectional data from the AIBL study indicates that plasma apoE levels are altered in AD and correlate with AD pathology level. The significance of these findings will be determined in the AIBL longitudinal study of aging.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Apolipoproteins E; Biomarkers; Brain; Carbon Radioisotopes; Cognition Disorders; Cross-Sectional Studies; Heterozygote; Homozygote; Humans; Positron-Emission Tomography; Risk Factors; Thiazoles

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain Mapping; Cerebral Cortex; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen; Positron-Emission Tomography; Statistics as Topic; Thiazoles

The 'preclinical' phase of Alzheimer's disease is a future target for treatment, but additional research is essential to understand the relationship between β-amyloid burden and cognition during this time. We investigated this relationship using a large sample of apparently healthy older adults (N=177), which also enabled examination of whether the relationship differed according to age, gender, years of education, apolipoprotein E status, and the presence of subjective memory complaints. In addition to episodic memory, a range of cognitive measures (global cognition, semantic memory, visuospatial performance, and executive function) were examined. Participants were aged over 60 years with no objective cognitive impairment and came from the imaging arm of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. (11)C-PiB PET was used to measure β-amyloid burden and a PiB 'cut-off' level of 1.5 was used to separate participants with low PiB retention from those with high PiB retention. Thirty-three percent of participants had a PiB positive scan. PiB positive participants were 5 years older, twice as likely to carry an apolipoprotein E ɛ4 allele, and their composite episodic memory was 0.26 SD worse than PiB negative volunteers. Linear regressions with β-amyloid burden as a dichotomous predictor, revealed an interaction between β-amyloid burden and gender, as well as age and education effects, in predicting episodic memory and visuospatial performance. In females, but not in males, increased β-amyloid was related to worse episodic memory and visuospatial performance. Furthermore, an interaction between β-amyloid burden and APOE status was found in predicting visuospatial performance, whereby there was a trend for increased β-amyloid to relate to worse visuospatial performance for those without an APOE ɛ4 allele. There were no other main or interaction effects of β-amyloid on any of the other composite cognitive measures. These cross-sectional findings suggest that β-amyloid burden does not have a large effect on cognition in this subset of apparently healthy older people. The finding of gender differences deserves further research to answer definitively the important question of gender susceptibility to adverse cognitive effects from β-amyloid.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Carbon Radioisotopes; Case-Control Studies; Cerebral Cortex; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Early Diagnosis; Female; Humans; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Radionuclide Imaging; Reference Values; Sex Factors; Thiazoles

The aim of this study was to investigate whether cognitively preserved monozygotic or dizygotic cotwins of persons with Alzheimer disease (AD) exhibit increased brain amyloid accumulation.. We performed a cross-sectional carbon-11 labeled 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ((11)C)-Pittsburgh compound B (PiB) PET study on 9 monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment as well as on 9 healthy elderly control subjects. (11)C-PiB uptake was analyzed with Statistical Parametric Mapping and with region of interest analysis with the region-to-cerebellum ratio as a measure of tracer uptake.. Cognitively preserved monozygotic cotwins of cognitively impaired probands had increased cortical (11)C-PiB uptake (117%-121% of control mean) in their temporal and parietal cortices and the posterior cingulate. Cognitively preserved dizygotic subjects did not differ from the controls. Further, the cognitively preserved monozygotic subjects showed similar (11)C-PiB uptake patterns as their cognitively impaired cotwins. The cognitively impaired subjects (monozygotic and dizygotic individuals combined) showed typical Alzheimer-like patterns of (11)C-PiB uptake.. Genetic factors appear to influence the development of Alzheimer-like β-amyloid plaque pathology. The dissociation between cognitive impairment and brain β-amyloidosis in monozygotic twins implies that there may be important environmental/acquired factors that modulate the relationship between brain amyloidosis and neurodegeneration. AD may be detectable in high-risk individuals in its presymptomatic stage with (11)C-PiB PET, but clinical follow-up will be needed to confirm this.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Cognition Disorders; Cross-Sectional Studies; Diseases in Twins; Early Diagnosis; Female; Finland; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Thiazoles

Incidental cerebral microhemorrhage (MH) is frequently found in older individuals scanned with susceptibility-weighted MRI (SWI) or gradient-recalled echo MRI. MH have been linked with β-amyloid (Aβ) deposition using (11)C-Pittsburgh compound B (PiB) PET in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). We hypothesized that Aβ deposition in asymptomatic elderly individuals is associated with lobar MH (LMH).. This was a cross-sectional study of 84 elderly healthy controls (HC), 28 subjects with mild cognitive impairment (MCI), and 26 subjects with probable AD who underwent 3-T SWI and (11)C-PiB PET. (11)C-PiB cortical binding was quantified normalized to cerebellar cortex (standardized uptake value ratio [SUVR]) and scans classified as positive (PiB+) or negative (PiB-) by visual inspection. MH were manually counted and categorized by region and as lobar or nonlobar.. LMH were present in 30.8% of AD, 35.7% of MCI, and 19.1% of HC. The prevalence of LMH among PiB+ subjects was similar, regardless of clinical classification (AD 30.8%, MCI 38.9%, HC 41.4%, p > 0.7). HC with LMH had significantly higher mean neocortical SUVR (1.7 ± 0.5) than HC without LMH (1.3 ± 0.3, p ± 0.01). In HC, there was a positive correlation between number of LMH and SUVR, and between LMH and age. In HC, PiB+ (odds ratio [OR] 7.3, 95% confidence interval [CI] 1.6-33.7, p = 0.01) and age (OR 1.2, 95% CI 1.03-1.3, p = 0.02) both independently predicted the occurrence of LMH using logistic regression.. Asymptomatic Aβ deposition in older adults is strongly associated with LMH.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Benzothiazoles; Brain; Brain Mapping; Carbon Radioisotopes; Cerebral Hemorrhage; Cognition Disorders; Female; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Positron-Emission Tomography; Psychiatric Status Rating Scales; Thiazoles

To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aβ in patients with mild cognitive impairment (MCI) and similarly aged controls.. In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP(nd)) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aβ levels measured in duplicate was analyzed.. Plasma Aβ42/Aβ40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aβ40 (p = 0.3) and Aβ42 (p = 0.06) levels did not differ between the 2 groups. PiB BP(nd) was increased in MCI compared to controls in the cingulate (p = 0.02), parietal (p = 0.02), and total brain (p = 0.03), but not in prefrontal cortex (p = 0.08) or parahippocampal gyrus (p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aβ42/Aβ40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01< p ≤ 0.05). These associations between PiB binding and the Aβ42/Aβ40 ratio were strongest in PiB-positive subjects and within the MCI group.. Though cross-sectional, the findings support the "sink" hypothesis that increased brain Aβ is accompanied by lower peripheral levels of Aβ, particularly the Aβ42/Aβ40 ratio in patients with MCI. The association between PiB binding and the plasma Aβ42/Aβ40 ratio suggests possible use of plasma Aβ combined with PiB binding as a risk biomarker with potential clinical application.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognition Disorders; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Retrospective Studies; Thiazoles

To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities.. Adult Children Study.. Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center.. A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD.. Clinical and cognitive measures, magnetic resonance imaging-based brain volumes, diffusion tensor imaging-based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [(11)C] benzothiazole tracer, Pittsburgh compound B.. A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aβ42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum.. Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Attention; Biomarkers; Brain; Carbon Radioisotopes; Cognition Disorders; Cohort Studies; Disease Progression; Family Health; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; Reaction Time; Residence Characteristics; Statistics as Topic; Thiazoles

We hypothesize that Pittsburgh compound B (PIB) binding is common in poststroke dementia (PSD) and that cognitive decline may be faster in PIB positive patients. We performed PIB positron emission tomography (PET) among 17 subjects: 10 PSD patients, 4 Alzheimer's disease (AD) patients, and 3 healthy controls. We also compared the rate of change in mini-mental state examination (MMSE) between PIB positive and negative patients. We detected AD-like PIB binding in 4 PSD patients (40%), all the AD patients, and 1 healthy control. The global PIB retention standardized uptake value (SUV) at 35-45 min for PIB positive stroke patients was 1.67 (range 1.56-1.82), which was similar to the AD patients (1.65; range 1.46-1.88) and was lower than PIB negative patients (1.29, range 1.24-1.34). Mean annual MMSE decline for the 4 PIB positive patients was 2.9 and that for the 6 PIB negative patients was 1. This pilot study suggests that PIB PET is feasible for the evaluation of PSD and PIB binding may be common in PSD. Whether presence of PIB binding is associated with a more rapid cognitive decline in PSD requires further study to confirm.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Binding, Competitive; Biomarkers; Brain; Cognition Disorders; Dementia, Vascular; Disability Evaluation; Female; Humans; Male; Neuropsychological Tests; Pilot Projects; Positron-Emission Tomography; Predictive Value of Tests; Severity of Illness Index; Stroke; Thiazoles

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognition Disorders; Female; Humans; Male; Middle Aged; Neurofibrillary Tangles; Nitriles; Plaque, Amyloid; Positron-Emission Tomography; Temporal Lobe; Thiazoles

The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.. We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.. The evaluation of visual classification as "normal" or "abnormal" showed good interobserver agreement (kappa = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p < 0.001). The most difficult visually assessed brain area was the putamen (kappa = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60).. Our study shows that visual evaluation of [(11)C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Benzothiazoles; Cognition Disorders; Dementia; Female; Humans; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Reference Standards; Thiazoles

To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia.. [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations.. [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions.. Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles

Elucidating the role of aggregated beta-amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship.. Brain magnetic resonance imaging and [(11)C]Pittsburgh compound B (PiB)-positron emission tomography scans were obtained from 94 healthy elderly subjects (49 with subjective cognitive impairment), 34 patients with mild cognitive impairment, and 35 patients with Alzheimer disease. The correlations between global and regional neocortical PiB retention and atrophy were analyzed in each clinical group.. Global and regional atrophy were strongly related to beta-amyloid load in participants with subjective cognitive impairment but not in patients with mild cognitive impairment or Alzheimer disease. Global neocortical beta-amyloid deposition correlated to atrophy in a large brain network including the hippocampus, medial frontal and parietal areas, and lateral temporoparietal cortex, whereas regional beta-amyloid load was related to local atrophy in the areas of highest beta-amyloid load only, that is, medial orbitofrontal and anterior and posterior cingulate/precuneus areas.. There is a strong relationship between beta-amyloid deposition and atrophy very early in the disease process. As the disease progresses to mild cognitive impairment and Alzheimer disease clinical stages, pathological events other than, and probably downstream from, aggregated beta-amyloid deposition might be responsible for the ongoing atrophic process. These findings suggest that antiamyloid therapy should be administered very early in the disease evolution to minimize synaptic and neuronal loss.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Benzothiazoles; Biomarkers; Brain; Cognition Disorders; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Prognosis; Severity of Illness Index; Thiazoles

To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.. In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies.. We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test.. Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cognition; Cognition Disorders; Disability Evaluation; Disease Progression; Female; Humans; Longitudinal Studies; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Reference Values; Severity of Illness Index; Thiazoles

Amyloid load in the brain using Pittsburgh compound B ((11)C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose ((18)F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). ( 11)C-PIB binding potential (BP(ND)) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For (18)F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BP(ND) area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. ( 11)C-PIB PET BP(ND) clearly distinguished diagnostic groups and combined with (18)F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Area Under Curve; Brain; Cerebellum; Chromatography, High Pressure Liquid; Cognition Disorders; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; Thiazoles

Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20).. In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42.. Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions.. Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.

Topics: Adult; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Carbon Radioisotopes; Case-Control Studies; Chi-Square Distribution; Cognition Disorders; Female; HIV; HIV Infections; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neuropsychological Tests; Radionuclide Imaging; Thiazoles

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognition Disorders; Diagnosis, Differential; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Severity of Illness Index; Statistics, Nonparametric; Thiazoles

Olfactory deficits and increased amyloid-β (Aβ) burden are observed in people with amnestic mild cognitive impairment (aMCI); both factors may be predictive of Alzheimer's disease (AD). We explored whether olfactory identification is related to in vivo measures of Aβ burden using Pittsburgh Compound B (PiB) PET. Nineteen control, 24 aMCI, and 20 AD participants completed an olfactory identification task and underwent PiB PET scanning. Control participants performed better on olfactory identification and showed lower PiB binding than aMCI patients. There was a significant correlation between both factors when pooling all groups together but not when considering each group separately. In addition, the olfactory identification score did not differ between aMCI participants who were PiB-positive and those who were PiB-negative. We conclude that AD-related olfactory identification deficits are not directly related to Aβ burden.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olfaction Disorders; Olfactory Perception; Radionuclide Imaging; Thiazoles

Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI).. To characterize in vivo with (11)C-(R)-PK11195 and (11)C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI.. Fourteen subjects with MCI had (11)C-(R)-PK11195 and (11)C-PIB PET with psychometric tests.. Seven out of 14 (50%) patients with MCI had increased cortical (11)C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased (11)C-(R)-PK11195 uptake. The MCI subgroup with increased (11)C-PIB retention also showed increased cortical (11)C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of (11)C-(R)-PK11195 and (11)C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased (11)C-(R)-PK11195 binding had increased levels of (11)C-PIB retention.. Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Female; Follow-Up Studies; Humans; Isoquinolines; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Alzheimer disease (AD) is defined neuropathologically by the presence of neurofibrillary tangles and plaques associated with tau and beta-amyloid protein deposition. The colocalization of microglia and beta-amyloid plaques has been widely reported in pathological examination of AD and suggests that neuroinflammation may play a role in pathogenesis and/or progression. Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood.. To image microglial activation and beta-amyloid deposition in the brains of subjects with and without AD.. Using two carbon 11 ([11C])-labeled positron emission tomographic imaging agents, Pittsburgh Compound B (PiB) and (R)-PK11195, we examined the relationship between amyloid deposition and microglial activation in different stages of AD using 5 control subjects, 6 subjects diagnosed with mild cognitive impairment, and 6 patients with mild to moderate AD.. Consistent with prior reports, subjects with a clinical diagnosis of probable AD showed significantly greater levels of [11C]PiB retention than control subjects, whereas patients with mild cognitive impairment spanned a range from control-like to AD-like levels of [11C]PiB retention. Additionally, 2 asymptomatic control subjects also exhibited evidence of elevated PiB retention in regions associated with the early emergence of plaques in AD and may represent prodromal cases of AD. We observed no differences in brain [11C](R)-PK11195 retention when subjects were grouped by clinical diagnosis or the presence or absence of beta-amyloid pathological findings as indicated by analyses of [11C]PiB retention.. These findings suggest that either microglial activation is limited to later stages of severe AD or [11C](R)-PK11195 is too insensitive to detect the level of microglial activation associated with mild to moderate AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Antineoplastic Agents; Brain; Carbon Radioisotopes; Cognition Disorders; Disease Progression; Encephalitis; Female; Gliosis; Humans; Isoquinolines; Male; Microglia; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

11C-Pittsburgh Compound-B (11C-PIB) and 18F-(2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) (18F-FDDNP) have been developed as PET tracers for in vivo imaging of pathology in Alzheimer's disease (AD). The purpose of this study was to directly compare these tracers in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls.. Paired 11C-PIB and 18F-FDDNP scans were acquired in 14 patients with AD, 11 patients with amnestic MCI, and 13 controls. For both tracers, parametric images of binding potential (BPND) were generated. Global cortical BPND was assessed using ANOVA. In addition, regional patterns of BPND were compared between diagnostic groups using ANOVA for repeated measures.. Global cortical BPND of 11C-PIB showed higher binding in patients with AD than in controls and patients with MCI. 18F-FDDNP uptake was higher in patients with AD than in controls, but MCI could not be distinguished from AD or from controls. Global BPND values of both tracers were moderately correlated (r=0.45; P=0.005). In MCI, BPND of 11C-PIB showed a bimodal distribution, whereas values for 18F-FDDNP were more widespread, with more MCI patients demonstrating increased uptake. Regional 11C-PIB binding showed different patterns across diagnostic groups, as AD patients showed an overall increase in binding, with the lowest binding in the medial temporal lobe. With 18F-FDDNP, patterns were similar across diagnostic groups. For all groups, highest values were observed in the medial temporal lobe.. Differences in BPND between patients with AD, patients with MCI, and controls were more pronounced for 11C-PIB. The difference in regional binding, the moderate correlation, and the discrepant findings in MCI suggest that they measure related, but different, characteristics of the disease.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Carbon Radioisotopes; Case-Control Studies; Cerebral Cortex; Cognition Disorders; Female; Fluorine Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nitriles; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

The standardized uptake value ratio (SUVR, or summed tissue ratio) has been used effectively in Pittsburgh compound B (PiB) PET studies to distinguish subjects who have significant amyloid-beta deposition in their brain from those who do not. Relative to quantitative measurements, advantages of the SUVR are improved study feasibility and low test-retest variation; disadvantages include inherent bias (PiB retention overestimation) and potential for time-varying outcomes. The PiB SUVR has proven to be highly correlated with quantitative outcomes and to allow reliable detection of significant group differences (or effective contrasts). In this work, regional PiB SUVRs were examined across 9 time windows to select the window that provided the best trade-offs between bias, correlation, and effective contrast.. A total of 40 dynamic PiB PET studies were performed on controls (n = 16), patients with Alzheimer disease (AD; n = 11), and patients with mild cognitive impairment (MCI; n = 13) (555 MBq [15 mCi], 90-min scan, and arterial blood sampling). The SUVR was computed for five 20-min and four 30-min windows that spanned the 30- to 90-min postinjection period. The SUVRs were compared with Logan graphical distribution volume ratio (DVR) measurements (35-90 min), determined with arterial blood as input and without arterial blood as input (cerebellum as reference).. Greater correlation and more bias were generally observed for the SUVR measurement at later times than at earlier times (relative to DVR). The effective contrast between the control and AD PiB SUVRs was slightly better for earlier data than for later data. The temporal dynamics of the SUVR measurement indicated greater stability in the measurement at 40 min after injection.. The 50- to 70-min time window provided a good compromise between physiologic validity, stability, sensitivity, and clinical feasibility across the control, MCI, and AD subject data examined in this study. The 40- to 60-min period demonstrated many advantages and should be used in studies limited by low injected dose. Although more biased than the 40- to 60-min SUVR, the 50- to 70-min SUVR was thought to be optimal because of greater measurement stability, which may prove to be important for longitudinal multisite studies performed in control, MCI, and AD subjects that are not dose-limited.

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognition Disorders; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Brain; Carbon Radioisotopes; Case-Control Studies; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Statistics, Nonparametric; Thiazoles; Time Factors

The purpose of this study was to compare the diagnostic accuracy of glucose metabolism and amyloid deposition as demonstrated by (18)F-FDG and Pittsburg Compound B (PiB) PET to evaluate subjects with cognitive impairment.. Subjects were selected from existing participants in the Mayo Alzheimer's Disease Research Center or Alzheimer's Disease Patient Registry programs. A total of 20 healthy controls and 17 amnestic mild cognitive impairment (aMCI), 6 nonamnestic mild cognitive impairment (naMCI), and 13 Alzheimer disease (AD) subjects were imaged with both PiB and (18)F-FDG PET between March 2006 and August 2007. Global measures for PiB and (18)F-FDG PET uptake, normalized to cerebellum for PiB and pons for (18)F-FDG, were compared. Partial-volume correction, standardized uptake value (SUV), and cortical ratio methods of image analysis were also evaluated in an attempt to optimize the analysis for each test.. Significant discrimination (P < 0.05) between controls and AD, naMCI and aMCI, naMCI and AD, and aMCI and AD by PiB PET measurements was observed. The paired groupwise comparisons of the global measures demonstrated that PiB PET versus (18)F-FDG PET showed similar significant group separation, with only PiB showing significant separation of naMCI and aMCI subjects.. PiB PET and (18)F-FDG PET have similar diagnostic accuracy in early cognitive impairment. However, significantly better group discrimination in naMCI and aMCI subjects by PiB, compared with (18)F-FDG, was seen and may suggest early amyloid deposition before cerebral metabolic disruption in this group.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognition Disorders; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome.. Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 +/- 16.0 [standard deviation] months) subsequent to their PiB scan.. Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered "amyloid-positive." All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients "reverted to normal.". These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD.

Topics: Aged; Aged, 80 and over; Amyloid; Aniline Compounds; Brain Mapping; Cognition Disorders; Female; Follow-Up Studies; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Psychometrics; Thiazoles

Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). (11)C-PIB PET is an in vivo marker of brain amyloid load.. To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters.. Thirty-one subjects with MCI with baseline (11)C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 +/- 0.6 years). Raised cortical (11)C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping.. Seventeen of 31 (55%) subjects with MCI had increased (11)C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were epsilon4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035).. PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

Topics: Aged; Alzheimer Disease; Amnesia; Aniline Compounds; Carbon Radioisotopes; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles; Time Factors

The purpose of this study was to investigate the potential relationships between cerebrospinal fluid (CSF) measurements of beta-amyloid-1-42 (Abeta(1-42)) and total tau to (11)C-Pittsburgh compound B ((11)C-PiB) and 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ((18)F-FDDNP) binding as measured using PET.. A total of 37 subjects were included, consisting of 15 patients with Alzheimer disease (AD), 12 patients with mild cognitive impairment, and 10 healthy controls. All subjects underwent a lumbar puncture and PET using both (11)C-PiB and (18)F-FDDNP. For both PET tracers, parametric images of binding potential were generated. Potential associations of CSF levels of Abeta(1-42) and tau with (11)C-PiB and (18)F-FDDNP binding were assessed using Pearson correlation coefficients and linear regression analyses.. For both global (11)C-PiB and (18)F-FDDNP binding, significant correlations with CSF levels of Abeta(1-42) (r = -0.72 and -0.37, respectively) and tau (r = 0.58 and 0.56, respectively) were found across groups (all P < 0.001, except P < 0.05 for correlation between (18)F-FDDNP and Abeta(1-42)). Linear regression analyses showed that, adjusted for regional volume, age, sex, and diagnosis, global (11)C-PiB uptake had an inverse association with Abeta(1-42) CSF levels (standardized beta = -0.50, P < 0.001), whereas there was a positive association between global (18)F-FDDNP binding and tau CSF levels (standardized beta = 0.62, P < 0.01).. The good agreement between these 2 different types of biomarkers (i.e., CSF and PET) provides converging evidence for their validity. The inverse association between (11)C-PiB and CSF tau Abeta(1-42) confirms that (11)C-PiB measures amyloid load in the brain. The positive association between (18)F-FDDNP and CSF tau suggests that at least part of the specific signal of (18)F-FDDNP in AD patients is due to tangle formation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Cognition Disorders; Female; Humans; Male; Nitriles; Peptide Fragments; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Statistics as Topic; tau Proteins; Thiazoles; Tissue Distribution

PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.. Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts.. Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42).. PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Case-Control Studies; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Male; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; tau Proteins; Thiazoles

To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD.. A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).. The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri.. One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline.. Progression from CDR 0 to CDR 0.5 status (very mild dementia).. Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0.. Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Carbon Radioisotopes; Cognition; Cognition Disorders; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

To examine the relation of amyloid-beta peptide (Abeta) levels in the cerebral cortex with structural brain integrity and cognitive performance in cognitively healthy older people.. Longitudinal study from May 22, 1985, through October 15, 2008.. Washington University Alzheimer Disease Research Center.. A total of 135 individuals aged 65 to 88 years with a Clinical Dementia Rating of 0.. The relations between mean cortical carbon 11 ((11)C)-labeled Pittsburgh compound B (PiB) binding potential values, proportional to the density of fibrillar Abeta binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal cognitive performance in multiple domains.. Elevated cerebral Abeta levels, in some cases comparable to those seen in individuals with Alzheimer disease, were observed in 29 participants, who also had smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate. Concurrent cognitive performance was unrelated to Abeta levels but was related to regional brain volumes with the exception of the caudate. Longitudinal cognitive decline in episodic and working memory and visuospatial ability was associated with elevated Abeta levels and decreased hippocampal volume.. The in vivo measure of cerebral amyloidosis known as [(11)C]PiB is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline in multiple cognitive domains that occur before the clinical diagnosis of Alzheimer disease. These findings contribute to the understanding of the cognitive and structural consequences of Abeta levels in cognitively healthy older adults.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Carbon Radioisotopes; Cerebral Cortex; Cognition Disorders; Follow-Up Studies; Humans; Longitudinal Studies; Organ Size; Peptide Fragments; Protein Binding; Radionuclide Imaging; Thiazoles

To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained.. To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD.. Case report.. Alzheimer disease research center.. Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments.. Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy.. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 88(1/2) years, but at age 89(1/2) years there was reduced amyloid beta 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid beta plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection.. Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid beta using amyloid imaging agents such as PiB that primarily label fibrillar amyloid beta plaques.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Carbon Radioisotopes; Cerebral Cortex; Cognition Disorders; Follow-Up Studies; Humans; Longitudinal Studies; Male; Radionuclide Imaging; Thiazoles

To evaluate associations of [(11)C]Pittsburgh compound B (PIB) and [(18)F]FDDNP with impairment in specific cognitive domains over the broader spectrum comprising cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD).. Twelve patients with AD, 13 patients with MCI, and 15 cognitively normal elderly subjects were included. Paired [(11)C]PIB and [(18)F]FDDNP PET scans were performed in all subjects. Binding potential (BP(ND)) was calculated using parametric images of BP(ND) for global, frontal, parietal, and temporal cortex; medial temporal lobe; and posterior cingulate. Cognitive functions were assessed using a battery of neuropsychological tests. Linear regression analyses were used to assess associations of [(11)C]PIB and [(18)F]FDDNP binding with cognitive measures.. Adjusted for age, sex, and [(18)F]FDDNP binding, higher global [(11)C]PIB binding was associated with lower scores on the Mini-Mental State Examination, immediate and delayed recall of the Rey Auditory Verbal Learning Task (RAVLT), Visual Association Task, and Trail Making Test part B. Conversely, higher [(18)F]FDDNP binding was independently associated with lower scores on immediate recall of the RAVLT. After additional adjustment for diagnosis, higher [(11)C]PIB binding remained independently associated with delayed recall (standardized beta = -0.39, p = 0.01), whereas higher [(18)F]FDDNP binding remained independently associated with immediate recall (standardized beta = -0.32, p = 0.03). When regional binding was assessed using stepwise models, both increased frontal [(11)C]PIB and temporal [(18)F]FDDNP binding were associated with memory, whereas increased parietal [(11)C]PIB binding was associated with nonmemory functions.. Increased [(18)F]FDDNP binding is specifically associated with impairment of episodic memory, whereas increased [(11)C]Pittsburgh compound B binding is associated with impairment in a broader range of cognitive functions.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Carbon Radioisotopes; Cognition Disorders; Female; Fluorine Radioisotopes; Humans; Linear Models; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Neuropsychological Tests; Nitriles; Positron-Emission Tomography; Regression Analysis; Thiazoles

The objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL).. AD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI).. AD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps < 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%.. For AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Brain; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Positron-Emission Tomography; Regression Analysis; Sensitivity and Specificity; Thiazoles

We evaluated the region-to-region correlation, laterality and asymmetry of amyloid deposition in subjects with mild cognitive impairment (MCI) or Alzheimer's disease (AD) using the amyloid tracer, Pittsburgh Compound B (PiB). Seventeen subjects, including 7 with MCI (MMSE 26.7+/-2.4) and 10 with AD (MMSE of 24.8+/-2.7) underwent PiB imaging. Measures of laterality (i.e., group-wise predilection for right or left) and asymmetry (i.e., group-wise predilection for unequal PiB retention between the two hemispheres) were calculated for 17 Regions of Interest (ROIs). Regional correlations were calculated along with within-group and between-groups statistical analyses of laterality and asymmetry metrics. The median correlation between PiB retention across all pairs of ROIs was 0.65, with highest correlations found in areas of highest PiB retention (r=0.74). Overall, PiB retention was symmetric bilaterally, but there was PiB laterality in MCI in dorsal frontal cortex [(t(6)=3.05, p=0.02, L>R] and sensory-motor area [t(6)=3.10, p=0.02, L>R] and in AD in the occipital pole (t(9)=-2.63, p=0.03, R>L). The most significant asymmetries in PiB retention were found in sub-cortical white matter (t(6)=3.99, p=0.01) and middle precuneus [(t(6)=3.57, p=0.01] in MCI, and in lateral temporal cortex (t(9)=3.02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42].

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Basal Ganglia; Brain Mapping; Cerebral Cortex; Cognition Disorders; Female; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Plaque, Amyloid; Positron-Emission Tomography; Staining and Labeling; Thiazoles

Beta-amyloid (Abeta) deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), Abeta burden can be quantified using (11)C PiB PET. Neuropathological studies have shown that the initial plaques are located in the temporal and orbitofrontal cortices, extending later to the cingulate, frontal and parietal cortices (Braak and Braak, 1997). Previous studies have shown an overlap in (11)C PiB PET retention between AD, mild cognitive impairment (MCI) patients and normal elderly control (NC) participants. It has also been shown that there is a relationship between Abeta deposition and memory impairment in MCI patients. In this paper we explored the variability seen in 15 AD, 15 MCI and 18 NC by modeling the voxel data from spatially and uptake normalized PiB images using principal component analysis. The first two principal components accounted for 80% of the variability seen in the data, providing a clear separation between AD and NC, and allowing subsequent classification. The MCI cases were distributed along an apparent axis between the AD and NC group, closely aligned with the first principal component axis. The NC cases that were PiB(+) formed a distinct cluster that was between, but separated from the AD and PiB(-) NC clusters. The PiB(+) MCI were found to cluster with the AD cases, and exhibited a similar deposition pattern. The primary principal component score was found to correlate with episodic memory scores and mini mental status examination and it was observed that by varying the first principal component, a change in amyloid deposition could be derived that is similar to the expected progression of amyloid deposition observed from post mortem studies.

Topics: Aged; Aging; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Image Processing, Computer-Assisted; Male; Models, Neurological; Neuropsychological Tests; Positron-Emission Tomography; Principal Component Analysis; Radiopharmaceuticals; Thiazoles

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biopsy; Brain; Cognition Disorders; Diagnosis, Differential; Disease Progression; Early Diagnosis; False Negative Reactions; Humans; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Reproducibility of Results; Thiazoles

In mild cognitive impairment (MCI), Alzheimer's disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [(11)C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI.. We studied 15 patients with amnestic MCI and 22 controls with PET using [(11)C]PIB. In MCI patients, CSF levels of Abeta42, pTAU, totalTAU and the Abeta42/pTAU ratio were measured.. In MCI patients, CSF Abeta42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Abeta42/pTAU ratio in 64%. A composite neocortical [(11)C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [(11)C]PIB-positive subjects showed AD-type Abeta42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Abeta42 was found in 3 patients, pTAU in 3 patients and Abeta42/pTAU ratio in 4 patients.. Follow-up studies are needed to confirm whether [(11)C]PIB uptake might be more sensitive than CSF Abeta42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Cognition Disorders; Female; Humans; Ligands; Male; Neocortex; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; tau Proteins; Thiazoles

Beta-amyloid (Abeta) plaques are one of the neuropathological hallmarks of Alzheimer's disease (AD) and can be quantified using the marker 11C PiB. As l1C PiB PET images have limited anatomical information, an Magnetic Resonance Image (MRI) is usually acquired to perform the spatial normalization needed for population analysis. We designed and evaluated a high dimensional spatial normalization approach that only uses the 11C PiB PET image. The non-rigid registration (NRR) is based on free form deformation (FFD) modelled using B-splines. To compensate for the limited anatomical information, the FFD is constrained to an allowable transform space using a model trained from MR registrations. Abeta deposition is dependent on disease staging, so a spatially normalized 11C PiB PET appearance model selects and refines the atlas. The approach was compared with MR NRR using data from healthy elderly, mild cognitive impaired and Alzheimer disease participants. Using segmentation propagation, an average Dice similarity coefficient of 0.64 and 0.73 was obtained for white and gray matter. The R-squared correlation between the uptake obtained in the frontal, parietal, occipital and temporal was 0.789, 0.843, 0.871 and 0.964. These are very promising results, considering the low resolution of 11C PiB PET images.

Topics: Algorithms; Alzheimer Disease; Aniline Compounds; Artificial Intelligence; Benzothiazoles; Brain; Carbon Isotopes; Cognition Disorders; Computer Simulation; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Models, Biological; Models, Statistical; Pattern Recognition, Automated; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Thiazoles

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps<0.01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cognition Disorders; Disease Progression; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Prognosis; Thiazoles

To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardles

Topics: Aged; Alzheimer Disease; Amnesia; Aniline Compounds; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Diagnosis, Differential; Female; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Patients with mild cognitive impairment (MCI) have increased risk to develop Alzheimer disease (AD). In AD increased brain amyloid burden has been demonstrated in vivo with PET using N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) as a tracer.. To investigate whether patients with amnestic MCI would show increased [(11)C]PIB uptake, indicating early AD process.. We studied 13 patients with amnestic MCI and 14 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum ratio in each voxel over 60 to 90 minutes. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis.. The SPM analysis showed that patients with MCI had significantly higher [(11)C]PIB uptake vs control subjects in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate showing the most prominent differences. These results were supported by the automated ROI analysis in which MCI patients showed in comparison with healthy control subjects increased [(11)C]PIB uptake in the frontal cortex (39% increase from the control mean, p < 0.01), the posterior cingulate (39%, p < 0.01), the parietal (31%, p < 0.01) and lateral temporal (28%, p < 0.001) cortices, putamen (17%, p < 0.05), and caudate (25%, p < 0.05). Individually, in the frontal cortex and posterior cingulate, 8 of 13 patients with MCI had [(11)C]PIB uptake values above 2 SD from the control mean. MCI subjects having at least one APOE epsilon4 allele tended to have higher [(11)C]PIB uptake than MCI subjects without APOE epsilon4.. At group level the elevated N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) uptake in patients with mild cognitive impairment (MCI) resembled that seen in Alzheimer disease (AD). At the individual level, about half of the MCI patients had [(11)C]PIB uptake in the AD range, suggestive of early AD process.

Topics: Aged; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias.. Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio.. Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis.. Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain Chemistry; Carbon Radioisotopes; Cognition Disorders; Dementia; Female; Gyrus Cinguli; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Benzothiazoles; Biomarkers; Carbon Radioisotopes; Case-Control Studies; Cerebellar Cortex; Chi-Square Distribution; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Mutation; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles