Andreas Lazaris

Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations

Objective: To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation. Methods: MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging. Results: We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the probands mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the probands clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET. Conclusion: Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimers Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between 18F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.

Plasma BDNF levels associate with Pittsburgh Compound B binding in the brain

Brain‐derived neurotrophic factor (BDNF) plays an important role in Alzheimers disease (AD) and other neurodegenerative disorders. BDNF function is adversely affected by amyloid beta in AD. BDNF levels in brain and peripheral tissues are lower in patients with AD and mild cognitive impairment (MCI) than in controls. Here we examined the association between plasma levels of BDNF and amyloid deposition in the brain measured with Pittsburgh Compound B (PiB).

Rates of amyloid imaging positivity in patients with primary progressive aphasia

Importance The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants 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. Main Outcomes and Measures Clinical, cognitive, neuroimaging, and pathology results. 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. Conclusions and Relevance 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.

Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding

Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimers Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

Distinct [18F]AV1451 retention patterns in clinical variants of Alzheimer’s disease

N 5 4 3 19 Age 64 63 68 79 Sex (m/f) 2/3 1/3 0/3 6/13 MMSE 23 20 22 29 [F]AV1451 SUYr (Tau) Occipital 2.21 1.71 1.65 1.06 Parietal 2.41 2.26 2.20 1.11 Temporal 2.04 2.36 2.12 1.15 Frontal 1.56 1.79 1.36 1.10 MTL 1.47 1.30 1.67 1.18 [E]FDG SUYc (Glucose metabolism) Occipital 1.31 1.89 1.78 1.59 Parietal 1.18 1.43 1.41 1.55 Temporal 1.13 1.25 1.24 1.35 Frontal 1.43 1.53 1.58 1.50 MTL 1.03 1.11 1.09 1.11 [C]PIB DVR (Amyloid) Occipital 1.49 1.65 1.38 1.09 Parietal 1.80 2.17 1.84 1.19 Temporal 1.61 2.02 1.63 1.08 Frontal 1.79 2.28 1.82 1.13 MTL 1.12 1.34 1.21 1.05

TAU-PET PATTERNS OVERLAP AND EXCEED HYPOMETABOLISM IN ALZHEIMER'S DISEASE

latent variables as follows: (1) AgeEduct, denoted for Age and Education variables; (2) Brain, denoted, for ventricular, intracranial, whole brain, midtemporal, fusiform, entorhinal, and hippocampal volumes; and (3) TestN, denoted , for Functional assessment questionnaire (FAQ), ADAS, CDR and MMSE test results. The SEM model with the lowest root mean square error with respect to absolute values was when our outcome variable of interest, Brain, was predicted by AgeEduct and TestN, on top of measured volumes. We then used this model to compare APOEe4 status in the ADNI population. Results: Descriptive statistics for the measured variables according to APOEe4 status are shown in Table 1. Path diagrams for the SEM model according to APOEe4 status are shown in Figures 1 and 2. Results of the SEM model fit by APOEe4 groups are shown in Table 2. For the selected SEM model, we obtain similar results whether or not one takes into account APOEe4 status. Conclusions:We have selected the best SEM model, taking into consideration brain volumes, age, education and neuropsychological test results. This model is not influenced by APOEe4 status in the ADNI population.

AD RISK GENE MINOR ALLELES MODULATE RELATIONSHIP BETWEEN PLASMA APOE AND PIB BINDING IN THE BRAIN

IC-P-090 AD RISK GENE MINOR ALLELES MODULATE RELATIONSHIP BETWEEN PLASMA APOE AND PIB BINDING IN THE BRAIN Andreas Lazaris, Andreas Lazaris, Kristy Hwang, Jennifer Ann Eastman, Paul Thompson, Karen Gylys, Greg M. Cole, Liana Apostolova, Sophie Sokolow, UC Berkeley, Berkeley, California, United States; UCLA, Los Angeles, California, United States; University of California Los Angeles, Los Angeles, California, United States; USC, Los Angeles, California, United States; UCLA School of Nursing, Los Angeles, California, United States. Contact e-mail: alazaris@berkeley.edu