Peter R. Martin

[18F]AV-1451 tau-PET and primary progressive aphasia: [18F]AV-1451 and PPA

To 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.

[18F] AV-1451 uptake in corticobasal syndrome: the influence of beta-amyloid and clinical presentation

Corticobasal syndrome (CBS) is a phenotypic manifestation of diverse pathologies, including Alzheimer’s disease and 4-repeat tauopathies. Predicting pathology in CBS is unreliable and, hence, molecular neuroimaging may prove to be useful. The aim of this study was to assess regional patterns of uptake on [18F] AV-1451 PET in CBS and determine whether patterns of uptake differ according to beta-amyloid deposition or differing clinical presentations. Fourteen patients meeting criteria for CBS underwent Pittsburgh Compound B (PiB) and [18F] AV-1451 PET. Seven patients presented as CBS and seven presented with apraxia of speech (AOS) and later evolved into CBS. A global PiB summary was calculated and used to classify patients as PiB (−) or PiB (+). AV-1451 uptake was calculated in fourteen regions-of-interest, with values divided by uptake in cerebellar crus grey matter to generate standard uptake value ratios. AV-1451 uptake was considered elevated if it fell above the 95th percentile from a group of 476 cognitively unimpaired normal controls. Six of the 14 CBS patients (43%) were PiB (+), with three of these patients showing strikingly elevated AV-1451 uptake across many cortical regions. Of the eight PiB (−) patients, only those with AOS showed elevated AV-1451 uptake in supplementary motor area and precentral cortex compared to controls. No region of elevated AV-1451 uptake were observed in PiB (−) typical CBS patients without AOS. These results suggest that regional [18F] AV-1451 is variable in CBS and depends on the presence of beta-amyloid as well as clinical presentation such as AOS. PiB (+) CBS does not necessarily reflect underlying Alzheimer’s disease; however, the possibility some of these patients will evolve into Alzheimer’s disease over time cannot be excluded.

Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [ 18F]AV-1451 PET in Atypical Alzheimer’s Disease

BACKGROUND Despite common pathology, Alzheimers disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. OBJECTIVE To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). METHODS Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. RESULTS Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. CONCLUSION Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

THE INFLUENCE OF AGE ON REGIONAL [18F]AV-1451 PET, PITTSBURGH COMPOUND B PET AND MRI ATROPHY IN ATYPICAL ALZHEIMER’S DISEASE

tionship between [18F]AV-1451 uptake and age. Figure 5. Correlated change in regional asymmetry. Note: Repeated measures correlations for regional changes in asymmetry between Ab and tau. Each dot represents one observation (colors reflect subjects), the shape of the symbol indicates the time point (circles for baseline and squares for the follow-up measures) and the lines represent the withinsubject repeated measure correlation fit (under the assumption of random intercept/same slope). Both regions show that EC (rrm1⁄40.28, p1⁄40.018 [0.022, 0.55]) and Temp pole PIB (rrm1⁄40.42, p1⁄40.0003 [0.060, 0.640]) change to a more left-warded asymmetry, which is correlated with the change in tau for these regions. For comparison, we also plotted the change in IT PIB vs tau asymmetry, showing no correlation: IT PIB showed a left-warded bias with time, whereas IT tau shows little change (rrm1⁄4-0.09, p1⁄40.46 [-0.361, 0.265]) Podium Presentations: Saturday, July 21, 2018 P6

REGION-LEVEL RELATIONSHIPS BETWEEN TAU, AMYLOID, HYPOMETABOLISM AND ATROPHY IN ATYPICAL ALZHEIMER’S DISEASE

Figure 2. First canonical dimensions from sparse canonical correlation analyses: tau SUVR versus FDG SUVR (a) and Ab SUVR (b). Colors represent the canonical weights found by SCCA for the ROI that contributed to the first canonical dimensions. ROI associated to weights equal to zero are left transparent. Irene Sintini, Christopher G. Schwarz, Peter R. Martin, Jonathan GraffRadford, Mary M. Machulda, Matthew L. Senjem, Anthony J. Spychalla, Daniel A. Drubach, Val J. Lowe, Clifford R. Jack, Jr., Keith A. Josephs, Jennifer L. Whitwell, Mayo Clinic, Rochester, MN, USA. Contact e-mail: Sintini.Irene@mayo.edu

THE INFLUENCE OF BETA-AMYLOID ON THE PROGRESSION OF PROGRESSIVE APRAXIA OF SPEECH

Background:Fronto-temporal lobe degeneration with TDP-43 proteinopathy (FTLD-TDP) is a clinically heterogeneous entity usually presented with behavioral or language impairment. Corticobasal syndrome (CBS) is an unusual manifestation of FTLD-TDP at the beginning of the disease. On the other hand, CBS is usually associated with 4R-tau deposition in nearly half of the cases and its association with TDP-43 is very uncommon. We present a patient who started with a classic CBS which remained relatively unchanged for several years. TDP-43 deposition was observed in his brain at post-mortem necropsy. Methods:A 79year-old male presented withmild cognitive impairment and apathy in August 2010. Two years later started with progressive rigidity, bradykinesia and apraxia in his left limbs. He remained behavioral and cognitively stable for several years and no language impairment was observed. Three years later, the patient developed a progressive dystonic posture with flexion of left arm, dysarthria, dysphagia and gait impairment. There was no response to LDopa and no oculomotor impairment was observed. Finally in october 2014 after and aspiration-related pneumonia the patient died. Results: A brain MRI showed an asymmetrical atrophy of the frontal, temporal and parietal cortices, which were markedly more atrophic in the right side. A brain perfusion SPECT imaging oberved an intense hypoperfusion in the right frontal, temporal and parietal cortices and also in the right striatum nucleus. The patient was diagnosed in life with probable corticobasal degeneration based on the symptomatology and the imaging findings. The necropsic examination showed diffuse neuronal lose in fontal, parietal and temporal cortices with pathological aggregates of TDP-43 protein, predominantly of type A.Conclusions:FTLD-TDPmay present uncommonly as a CBS without prominent behavioral or language impairment

ADVANTAGES OF HIERARCHICAL MODELS FOR REGIONAL PET ANALYSES

Background: Tauopathies, including Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), display numerous pathologies beyond the neurofibrillary tangles that define this class of disease. Cortical and hippocampal atrophy, ventricular dilation, white matter degeneration, gliosis and frank neuronal loss occur concomitantly with tau pathology, culminating in cognitive deficits and behavioral changes. Although current models of tauopathy have replicated some of these features to varying degrees, there still persists a need for more advanced and comprehensive models that exhibit all these pathophysiological and behavioral phenotypes. Methods: We developed a rat model that overexpresses human 4R/2N tau carrying the FTDP-17 mutation, P301S, under the CaMKIIa neuronal promoter. This transgenic line, McGill-R-Tau-P301S, was characterized at multiple timepoints using various behavioral, biochemical, immunohistochemical and imaging techniques. Results: Disease-associated phosphorylation and conformation dependent tau immunoreactivity was observed throughout the hippocampus and neocortex from 3 months of age, and progressed in a temporospatial dependent manner. Neuronal loss, cortical thinning and extensive ventricular dilation were present by 18 months of age. In parallel, astrocytic activation and disorganization, as well as pervasive microglia proliferation were observed. Notably, microglia displayed both amoeboid and distinct rod-like microglia morphologies. Additionally, using electron microscopy, we observed axon and myelin degeneration and the occurrence of axonal ballooning. Cognitive decline was detected starting at 18 months of age: rats were impaired in novel object recognition memory, spatial learning and memory, contextual and cued fear conditioning, in the absence of motor deficits. Conclusions: The McGill-RTau-P301S rat is a novel model of tauopathy which recapitulates important pathophysiological and behavioral phenotypes associated with human tauopathies. Thus, this model represents a unique and very valuable tool for research in Alzheimer’s disease and other tauopathies.