florbetapir-f-18 and 2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole

We performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA).. In a PubMed systematic search, we identified case-control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer's disease. To circumvent PET studies' methodological variation, we generated and used 'fold change', that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse.. Seven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer's disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer's disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity.. Our analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.

Topics: Amyloid beta-Peptides; Aniline Compounds; Cerebral Amyloid Angiopathy; Ethylene Glycols; Humans; Positron-Emission Tomography; Thiazoles

Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially,

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Clinical Trials as Topic; Ethylene Glycols; Humans; Nitriles; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Stilbenes; Thiazoles; Translational Research, Biomedical

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

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

Alzheimer's disease (AD) is defined histologically by the presence of extracellular β-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using [(18)F]fluorodeoxyglucose (FDG). These techniques, however, are not specific for AD. Based on the chemistry of histologic staining dyes, several Aβ-specific positron-emitting radiotracers have been developed to image neuropathology of AD. Among these, [(11)C]PiB is the most studied Aβ-binding PET radiopharmaceutical in the world. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between Aβ-containing amyloid plaques and in vivo [(11)C]PiB retention measured by PET imaging. Because (11)C is not ideal for commercialization, several (18)F-labeled tracers have been developed. At this time, [(18)F]3'-F-PiB (Flutemetamol), (18)F-AV-45 (Florbetapir), and (18)F-AV-1 (Florbetaben) are undergoing extensive phase II and III clinical trials. This article provides a brief review of the amyloid biology and chemistry of Aβ-specific (11)C and (18)F-PET radiopharmaceuticals. Clinical trials have clearly documented that PET radiopharmaceuticals capable of assessing Aβ content in vivo in the brains of AD subjects and subjects with mild cognitive impairment will be important as diagnostic agents to detect in vivo amyloid brain pathology. In addition, PET amyloid imaging will also help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of antiamyloid therapeutics currently under development in clinical trials.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzothiazoles; Cerebral Cortex; Dementia; Ethylene Glycols; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Neurofibrillary Tangles; Nitriles; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non-Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences.. Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs-fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area-based SES were included in mediation analyses.. Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f. Modifiable factors, such as differences in social contexts and resources, particularly area-level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254-265.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Black or African American; Brain; Carbolines; Cerebral Small Vessel Diseases; Ethylene Glycols; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Mediation Analysis; Middle Aged; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Social Class; tau Proteins; Thiazoles; White

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

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

There is a growing need in clinical research domains for direct comparability between amyloid-beta (Aβ) Positron Emission Tomography (PET) measures obtained via different radiotracers and processing methodologies. Previous efforts to provide a common measurement scale fail to account for non-linearities between measurement scales that can arise from these differences. We introduce a new application of distribution mapping, based on well established statistical orthodoxy, that we call Nonlinear Distribution Mapping (NoDiM). NoDiM uses cumulative distribution functions to derive mappings between Aβ-PET measurements from different tracers and processing streams that align data based on their location in their respective distributions.. Utilizing large datasets of Florbetapir (FBP) from the Alzheimer's Disease Neuroimaging Initiative (n = 349 female (%) = 53) and Pittsburgh Compound B (PiB) from the Harvard Aging Brain Study (n = 305 female (%) = 59.3) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (n = 184 female (%) = 53.3), we fit explicit mathematical models of a mixture of two normal distributions, with parameter estimates from Gaussian Mixture Models, to each tracer's empirical data. We demonstrate the accuracy of these fits, and then show the ability of NoDiM to transform FBP measurements into PiB-like units.. A mixture of two normal distributions fit both the FBP and PiB empirical data and provides a strong basis for derivation of a transfer function. Transforming Aβ-PET data with NoDiM results in FBP and PiB distributions that are closely aligned throughout their entire range, while a linear transformation does not. Additionally the NoDiM transform better matches true positive and false positive profiles across tracers.. The NoDiM transformation provides a useful alternative to the linear mapping advocated in the Centiloid project, and provides improved correspondence between measurements from different tracers across the range of observed values. This improved alignment enables disparate measures to be merged on to continuous scale, and better enables the use of uniform thresholds across tracers.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Brain; Datasets as Topic; Ethylene Glycols; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Models, Theoretical; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.. To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET).. This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET.. A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined.. The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07).. Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbolines; Contrast Media; Cross-Sectional Studies; Entorhinal Cortex; Ethylene Glycols; Female; Healthy Volunteers; Humans; Male; Middle Aged; Positron-Emission Tomography; Sex Factors; tau Proteins; Temporal Lobe; Thiazoles

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

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

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

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

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [

Topics: Aniline Compounds; Animals; Autoradiography; Brain Edema; Carbon Radioisotopes; Cerebral Ventricles; Corpus Callosum; Corpus Striatum; Demyelinating Diseases; Dilatation, Pathologic; Disease Models, Animal; Ethylene Glycols; False Positive Reactions; Fluorine Radioisotopes; Image Processing, Computer-Assisted; Injections; Lysophosphatidylcholines; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Myelin Sheath; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Thiazoles

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

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

The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies.. To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA).. This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA.. Clinical, cognitive, neuroimaging, and pathology results.. Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy.. Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.

Topics: Aged; Amyloid; Aniline Compounds; Aphasia, Primary Progressive; Brain; Ethylene Glycols; Female; Humans; Imaging, Three-Dimensional; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Severity of Illness Index; Thiazoles

Klunk et al. recently proposed a means of standardizing quantitation of amyloid burden from positron emission tomography scans to a common Centiloid scale, and we have applied that method to florbetapir.. Florbetapir and Pittsburgh compound B scans were acquired for 46 mixed clinical presentation subjects within 18 ± 20 days. Florbetapir and Pittsburgh compound B cortical standardized uptake value ratio (SUVr) values were well correlated for both standard Centiloid (R. The equation for conversion of florbetapir SUVr from Avid VOIs to the Centiloid scale was as follows: Florbetapir Centiloids = 183 × SUVr. These findings may allow improved tracer-independent amyloid quantitation.

Topics: Adult; Aged; Amyloid; Aniline Compounds; Brain; Cohort Studies; Ethylene Glycols; Female; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The centiloid scale was recently proposed to provide a standard framework for the quantification of β-amyloid PET images, so that amyloid burden can be expressed on a standard scale. While the framework prescribes SPM8 as the standard analysis method for PET quantification, non-standard methods can be calibrated to produce centiloid values. We have previously developed a PET-only quantification: CapAIBL. In this study, we show how CapAIBL can be calibrated to the centiloid scale.. Calibration images for. Using the calibration images, there was a very strong agreement, and very little bias between the centiloid values computed using CapAIBL and those computed using the standard method with R. The PET-only quantification method, CapAIBL, can produce reliable centiloid values. The bias observed in the AIBL dataset for 18F-NAV4694 and

Topics: Adult; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Calibration; Ethylene Glycols; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Thiazoles

Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer's disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood.. The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18F T807 (also known as 18F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults.. We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET).. Higher GDS was significantly associated with greater IT tau (partial r = 0.188, p = 0.050) and marginally associated with greater EC tau (partial r = 0.183, p = 0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p = 0.001).. Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Cross-Sectional Studies; Depression; Entorhinal Cortex; Ethylene Glycols; Female; Humans; Male; Middle Aged; Pilot Projects; Positron-Emission Tomography; Psychiatric Status Rating Scales; Temporal Lobe; 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

We hypothesized that florbetapir, a Food and Drug Administration-approved PET tracer, could distinguish cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH).. We prospectively enrolled survivors of primary ICH related to probable CAA (per Boston Criteria, n = 10) and HTN-ICH (n = 9) without dementia. All patients underwent florbetapir-PET and multimodal MRI, and patients with CAA had additional Pittsburgh compound B (PiB) PET. Amyloid burden was assessed quantitatively (standard uptake value ratio [SUVR]) and visually classified as positive or negative.. The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex, and leukoaraiosis volumes (31 vs 30 mL, all p > 0.8). Florbetapir uptake and PiB retention strongly correlated in patients with CAA both globally within cerebral cortex (r = 0.96, p < 0.001) and regionally in lobar cortices (all r > 0.8, all p ≤ 0.01). Mean global cortical florbetapir uptake was substantially higher in CAA than HTN-ICH (SUVR: 1.41 ± 0.17 vs 1.15 ± 0.08, p = 0.001), as was mean occipital SUVR (1.44 ± 0.12 vs 1.17 ± 0.08, p < 0.001), even after correcting for global SUVR (p = 0.03). Visual rating for positive/negative florbetapir demonstrated perfect interrater agreement (k = 1) and was positive for all 10 patients with CAA vs 1 of 9 HTN-ICH patients (sensitivity 100%, specificity 89%).. Florbetapir appears to label vascular amyloid in patients with CAA-related ICH. The approved florbetapir binary visual reading method can have diagnostic value in appropriate clinical settings.. This study provides Class II evidence that florbetapir-PET provides a sensitivity of 100% (95% confidence interval [CI] 66%-100%) and specificity of 89% (95% CI 51%-99%) for determination of probable CAA among cognitively normal patients.

Topics: Aged; Aniline Compounds; Cerebral Amyloid Angiopathy; Cohort Studies; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

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

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

The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD).. The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands.. Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology.. CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity.. CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Australia; Benzothiazoles; Ethylene Glycols; Female; Humans; Life Style; Longitudinal Studies; Male; Mental Status Schedule; Peptide Fragments; Positron-Emission Tomography; ROC Curve; tau Proteins; Thiazoles

Radioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer's Disease. We therefore aimed to visualize the pathological deposition of fibrillar amyloid-β and neuronal dysfunction in aged double transgenic mice.. Using non-invasive positron emission tomography (PET) we assessed brain glucose utilization with [(18)F]FDG and fibrillar amyloidosis with [(11)C]PiB and [(18)F]AV45 in 12 month old APPPS1-21 (n = 10) mice and their age-matched wild-type controls (n = 15). PET scans were analyzed with statistical parametric mapping (SPM) to detect significant differences in tracer uptake between genotypes. After imaging, mice were sacrificed and ex vivo measures of amyloid-β burden with immunohistochemistry as well as glucose utilization with [(14)C]-2DG autoradiography were obtained as gold standards.. Voxel-wise SPM analysis revealed significantly decreased [(18)F]FDG uptake in aged APPPS1-21 mice in comparison to WT with the thalamus (96.96 %, maxT = 3.35) and striatum (61.21 %, maxT = 3.29) demonstrating the most widespread reductions at the threshold of p < 0.01. [(11)C]PiB binding was significantly increased in APPPS1-21 mice, most notably in the hippocampus (87.84 %, maxT = 7.15) and cortex (69.08 %, maxT = 7.95), as detected by SPM voxel-wise analysis at the threshold of p < 0.01. Using the same threshold [(18)F]AV45 uptake was comparably lower with less significant differences. Compared to their respective ex vivo equivalents [(18)F]FDG demonstrated significant positive correlation to [(14)C]2-DG autoradiography (r = 0.67, p <0.0001) while [(11)C]PiB and [(18)F]AV45 binding did not correlate to ex vivo immunohistochemistry for amyloid-β (r = 0.25, p = 0.07 and r = 0.17, p = 0.26 respectively). Lastly no correlation was observed between regions of high amyloid burden and those with decreased glucose utilization (r = 0.001, p = 0.99).. Our findings support that fibrillar amyloid-β deposition and reduced glucose utilization can be visualized and quantified with in vivo μPET imaging in aged APPPS1-21 mice. Therefore, the combined use of [(18)F]FDG and amyloid μPET imaging can shed light on the underlying relationship between fibrillar amyloid-β pathology and neuronal dysfunction.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Autoradiography; Brain; Brain Mapping; Carbon Radioisotopes; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Glucose; Humans; Immunohistochemistry; Mice, Inbred C57BL; Mice, Transgenic; Phenanthrolines; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

(11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer's Disease Neuroimaging Initiative (ADNI).. From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.. There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86-0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96-0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59-0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB-florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.. PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan-rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Carbon Radioisotopes; Cerebral Cortex; Ethylene Glycols; Female; Humans; Image Processing, Computer-Assisted; Male; Neuroimaging; Positron-Emission Tomography; Radioactive Tracers; Reference Standards; Retrospective Studies; Thiazoles; Time Factors

Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's disease (AD). The positron emission tomography (PET) ligand, Pittsburgh Compound-B (PiB-C11), is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with postmortem Aβ histopathology, but has not been directly compared with PiB-C11.. Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28-day period.. Both ligands displayed highly significant group discrimination and correlation of regional uptake.. These data support the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Case-Control Studies; Ethylene Glycols; Female; Humans; Male; Neuroimaging; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

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