Schwarz, Christopher G

ObjectivesTo assess [18F]AV‐1451 tau‐PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [18F]AV‐1451 independent of clinical diagnosis, and compare the diagnostic utility of [18F]AV‐1451, [18F]‐fluorodeoxygluclose (FDG)‐PET and MRI (magnetic resonance imaging) to differentiate the PPA variants.MethodsWe performed statistical parametric mapping of [18F]AV‐1451 across 40 PPA patients (logopenic‐PPA = 14, semantic‐PPA = 13, and agrammatic‐PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B–negative controls, age and gender matched 2:1. Principal component analysis of regional [18F]AV‐1451 tau‐PET standard uptake value ratio was performed to understand underlying patterns of [18F]AV‐1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility.ResultsLogopenic‐PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic‐PPA, and agrammatic‐PPA. Semantic‐PPA and agrammatic‐PPA showed milder patterns of focal [18F]AV‐1451 uptake. Semantic‐PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic‐PPA. Agrammatic‐PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic‐PPA. The principal component analysis of regional [18F]AV‐1451 indicated two primary dimensions, a severity dimension that distinguished logopenic‐PPA from agrammatic‐PPA and semantic‐PPA, and a frontal versus temporal contrast that distinguishes agrammatic‐PPA and semantic‐PPA cases. Diagnostic utility of [18F]AV‐1451was superior to MRI and at least equal to FDG‐PET.Interpretation[18F]AV‐1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [18F]AV‐1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [18F]AV‐1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599–611

ObjectiveTo use a cluster analysis of [18F]AV‐1451 tau‐PET data to determine how subjects with Alzheimer's disease (AD) vary in the relative involvement of the entorhinal cortex and neocortex, and determine whether relative involvement of these two regions can help explain variability in age and clinical phenotype in AD.MethodsWe calculated [18F]AV‐1451 uptake in entorhinal cortex and neocortex in 62 amyloid‐positive AD patients (39 typical and 23 atypical presentation). tau‐PET (positron emission tomography) values were normalized to the cerebellum to create standard uptake value ratios (SUVRs). tau‐PET SUVRs were log‐transformed and clustered blinded to clinical information into three groups using K‐median cluster analysis. Demographics, clinical phenotype, cognitive performance, and apolipoprotein e4 frequency were compared across clusters.ResultsThe cluster analysis identified a cluster with low entorhinal and cortical uptake (ELo/CLo), one with low entorhinal but high cortical uptake (ELo/CHi), and one with high cortical and entorhinal uptake (EHi/CHi). Clinical phenotype differed across clusters, with typical AD most commonly observed in the ELo/CLo and EHi/CHi clusters, and atypical AD most commonly observed in the ELo/CHi cluster. The ELo/CLo cluster had an older age at PET and onset than the other clusters. Apolipoprotein e4 frequency was lower in the ELo/CHi cluster. The EHi/CHi cluster had the worst memory impairment, whereas the ELo/CHi cluster had the worst impairment in nonmemory domains.InterpretationThis study demonstrates considerable variability in [18F]AV‐1451 tau‐PET uptake in AD, but shows that a straightforward clustering based on entorhinal and cortical uptake maps well onto age and clinical presentation in AD. Ann Neurol 2018 Ann Neurol 2018;83:248–257

AbstractQuantitative measurement of β‐amyloid from amyloid PET scans typically relies on localizing target and reference regions by image registration to MRI. In this work, we present a series of simulations where 50 small random perturbations of starting location and orientation were applied to each subject's PET scan, and rigid registration usingspm_coregwas performed between each perturbed PET scan and its corresponding MRI. We then measured variation in the output PET‐MRI registrations and how this variation affected the resulting SUVR measurements. We performed these experiments using scans of 1196 participants, half using 18F florbetapir and half using 11C PiB. From these experiments, we measured the magnitude of the imprecision in the rigid registration steps used to localize measurement regions, and how this contributes to the overall imprecision in SUVR measurements. Unexpectedly, we found for both tracers that the imprecision in these measurements depends on the degree of amyloid tracer uptake, and thus also indirectly on Alzheimer's disease clinical status. We then examined common choices of reference regions, and we show that SUVR measurements using supratentorial white matter references are relatively resistant to this source of error. We also show that the use of partial volume correction further magnifies the effects of registration imprecision on SUVR measurements. Together, these results suggest that this rigid registration step is an attractive target for future work in improving measurement techniques.Hum Brain Mapp 38:3323–3336, 2017. ©2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

AbstractIntroductionTau‐positron emission tomography (PET) imaging with AV1451 is sensitive to Alzheimer disease (AD)–related tau deposition in the brain. We (1) examined regional variation of average tau‐PET standardized uptake value ratios (SUVRs) in a young normal population (30–49 years) and corrected for the regional variability and (2) tested if the standardized values (z‐scores) scaled appropriately to capture regional Alzheimer‐specific (i.e., amyloid sensitive) tau‐PET changes in individuals aged 50+ years.MethodsWe identified 490 individuals (70 between 30–49 years as a reference group and 420 cognitively normal between 50–95 years of age) with tau‐PET and amyloid PET scans from the Mayo Clinic Study of Aging.ResultsThere was intrinsic regional variability in average tau‐PET SUVR with uptakes higher in some regions than others, even in the younger individuals who would have minimal or no neurofibrillary tangles. We corrected for this using region of interest–specific z‐scores based on the reference group. Amyloid and tau‐PET uptake were associated throughout the brain after adjusting for age, with the highest correlations in the medial temporal regions.DiscussionRegions with high‐average SUVR are not necessarily those with the greatest tau pathology. Standardization is therefore recommended. Standardization of the data “realigns” the data such that the regional tau z‐scores are informative of the disease process, that is, regions with high z‐scores now coincide with regions correlated with amyloid deposition. Medial temporal structures, specifically entorhinal cortex–tau, may be useful as an AD‐specific tau‐PET signature due to its sensitivity to amyloid.

ABSTRACTBackgroundThe [18F]AV‐1451 positron emission tomography ligand allows the in vivo assessment of tau proteins in the brain. It shows strong binding in Alzheimer's dementia, but little is known about how it performs in progressive supranuclear palsy, a primary 4R tauopathy.ObjectivesThe objectives of this study were to determine whether [18F]AV‐1451 uptake can be observed in progressive supranuclear palsy and to characterize the regional distribution when compared with controls and Alzheimer's dementia.Methods[18F]AV‐1451 positron emission tomography was performed in 10 patients with probable progressive supranuclear palsy. These patients were age‐ and gender‐matched to 50 controls and 10 Alzheimer's dementia patients who had undergone identical [18F]AV‐1451 imaging. Regional comparisons of [18F]AV‐1451 uptake were performed across the whole brain using region‐of‐interest and voxel‐level analyses, and correlations between regional [18F]AV‐1451 and the progressive supranuclear palsy rating scale were assessed.ResultsAn elevated [18F]AV‐1451 signal was observed in progressive supranuclear palsy when compared with controls in the pallidum, midbrain, dentate nucleus of the cerebellum, thalamus, caudate nucleus, and frontal regions. Signal in the cerebellar dentate and pallidum were also greater in progressive supranuclear palsy when compared with Alzheimer's dementia. Conversely, the [18F]AV‐1451 signal across the cortex was higher in Alzheimer's dementia when compared with progressive supranuclear palsy. The [18F]AV‐1451 signal in a number of regions correlated with the progressive supranuclear palsy rating scale.ConclusionsProgressive supranuclear palsy is associated with an elevated [18F]AV‐1451 signal in a characteristic and distinct regional pattern that correlates with disease severity and differs from the patterns observed in Alzheimer's dementia. © 2016 International Parkinson and Movement Disorder Society.

AbstractIntroductionCerebrovascular lesions on MRI are common in Alzheimer's disease (AD) dementia, but less is known about their frequency and impact on dementia with Lewy bodies (DLB).MethodsWhite‐matter hyperintensities (WMHs) and infarcts on MRI were assessed in consecutive DLB (n = 81) and AD dementia (n = 240) patients and compared to age‐matched and sex‐matched cognitively normal subjects (CN) from a population‐based cohort.ResultsDLB had higher WMH volume compared to CN, and WMH volume was higher in the occipital and posterior periventricular regions in DLB compared to AD. Higher WMH volume was associated with history of cardiovascular disease and diabetes but not with clinical disease severity in DLB. Frequency of infarcts in DLB was not different from CN and AD dementia.DiscussionIn DLB, WMH volume is higher than AD and CN and appears to be primarily associated with history of vascular disease.

ABSTRACTBACKGROUND AND PURPOSEPathologic diagnosis is the gold standard in evaluating imaging measures developed as biomarkers for pathologically defined disorders. A brain MRI atlas representing autopsy‐sampled tissue can be used to directly compare imaging and pathology findings. Our objective was to develop a brain MRI atlas representing the cortical regions that are routinely sampled at autopsy for the diagnosis of Alzheimer's disease (AD).METHODSSubjects (n = 22; ages at death = 70‐95) with a range of pathologies and antemortem 3T MRI were included. Histology slides from 8 cortical regions sampled from the left hemisphere at autopsy guided the localization of the atlas regions of interest (ROIs) on each subject's antemortem 3D T1‐weighted MRI. These ROIs were then registered to a common template and combined to form one ROI representing the volume of tissue that was sampled by the pathologists. A subset of the subjects (n = 4; ages at death = 79‐95) had amyloid PET imaging. Density of β‐amyloid immunostain was quantified from the autopsy‐sampled regions in the 4 subjects using a custom‐designed ImageScope algorithm. Median uptake values were calculated in each ROI on the amyloid‐PET images.RESULTSWe found an association between β‐amyloid plaque density in 8 ROIs of the 4 subjects (total ROI n = 32) and median PiB SUVR (r2 = .64; P < .0001).CONCLUSIONSIn an atlas developed for imaging and pathologic correlation studies, we demonstrated that antemortem amyloid burden measured in the atlas ROIs on amyloid PET is strongly correlated with β‐amyloid density measured on histology. This atlas can be used in imaging and pathologic correlation studies.

Background: Different clinical syndromes can arise from Alzheimer’s disease (AD) neuropathology, including dementia of the Alzheimer’s type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.