Labuzan, Sydney A.

AbstractBackgroundSummarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both pathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and post‐mortem CVD evaluation. We used (1) Strozyk scale (Strozyk et. al. NBA 2010) which is based on presence and number of three macroscopic lesions (large infarctions, lacunar infarctions, and leukoencephalopathy) and (2) Kalaria scale (Deramecourt et. al. Neurology 2012) which summarizes detailed evaluation of vessel wall modifications (arteriolosclerosis, amyloid angiopathy), perivascular spaces, myelin loss, microinfarctions, and large infarctions.MethodWe identified n=51 individuals in Mayo Clinic Study of Aging (mean age of 83.8 years, 37% female) with MRI scans within 5 years of death. We computed CVD measures from DTI (fractional anisotropy of the genu of the corpus callosum [FAGCC] and fractional anisotropy of cingulum adjoining the hippocampus [FACGH]), FLAIR (white matter hyperintensities [WMH] and total number of infarctions), and T2* GRE (total number of microbleeds). We also computed our recently developed imaging CVD composite score which summarizes the variability in all individual CVD imaging measures described above. We computed the Strozyk and Kalaria scales on postmortem tissue. We used weighted linear regression models with adjustments for MRI scan time to death to evaluate the associations between the antemortem neuroimaging measures and pathology scales in those who had scans within 3 years of death (N=31) and 5 years of death (N=51) (tables 1 and 2).ResultOf all the neuroimaging measures, DTI measures were the best predictors of the Strozyk and Kalaria Scales (p<0.05). In sensitivity analyses of data in Table 1, FAGCC explained 44% and FACGH predicted only 5.5% variability in white matter sub‐component of the Strozyk scale. The CVD composite score was a poor surrogate of the composite pathological scales.ConclusionMicrostructural white matter injury measurement using DTI may be a good surrogate of pathological CVD scales and possibly captures diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

AbstractBackgroundUsing an objective mathematical algorithm to assess corticolimbic involvement of neurofibrillary tangle pathology, we identified three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Typical AD brains were representative of the expected patterns of hippocampal and cortical involvement as outlined by Braak tangle stage. In contrast, we discovered an extreme phenotype that exists outside of the Braakian‐concept of neurofibrillary tangle patterns. Hippocampal sparing AD cases demonstrate unexpected sparing of the hippocampus relative to severely involved association cortices and limbic predominant AD cases demonstrate inundation of the hippocampus relative to mildly involved association cortices. Using these AD subtypes, our objective was to leverage our understanding of disease spectrum to uncover transcriptomic changes that underlie selective vulnerability of the hippocampus in AD.MethodWe performed RNA‐sequencing in 40 neuropathologically diagnosed AD cases (10 HpSp, 20 Typical and 10 Limbic) and 15 controls to uncover gene expression changes associated with phenotype differences allowing us to prioritize 44 genes for further exploration. Validation with NanoString and quantification with digital pathology were performed in an expanded cohort of 158 AD cases (36 HpSp, 79 Typical and 35 Limbic) and 32 controls. We quantified digital pathology measures of early tangle pathology (CP13), mature tangle pathology (Ab39), amyloid‐β (33.1.1). In addition, we measured cellular markers for microglia (CD68), endothelia (CD34), and astroglia (GFAP). Deep learning based prediction models were employed, which nominated the SLC38A2 gene as a predictor of AD.ResultThe SLC38A2 gene was originally prioritized in our RNA‐sequencing data based upon differential expression between controls and typical AD. We observed upregulation of SLC38A2 in all AD subtypes. RNA‐seq gene expression measures validated well with NanoString for SLC38A2 (R=0.97, p<0.001). Regression analysis identified early tangle (p=0.011) and late tangle measures (p=0.026) as significant predictors of gene expression, but not amyloid measures (p=0.74). Microgliosis approached significance (p=0.052), but with no contribution from endothelial cell burden (p=0.17) or astrogliosis (p=0.58). Age approached significance (p=0.06), but not sex (p=0.88) or APOE‐ε4 status (p=0.10).ConclusionOur data supports consideration of intra‐disease divergence with regard to case stratification and may reveal genes previously masked by heterogeneity of cohorts.

ObjectiveTo examine associations between tau and amyloid β (Aβ) molecular positron emission tomography (PET) and both Alzheimer‐related pathology and 4‐repeat tau pathology in autopsy‐confirmed frontotemporal lobar degeneration (FTLD).MethodsTwenty‐four patients had [18F]‐flortaucipir–PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD‐TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)‐PET. Braak staging, Aβ plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta‐ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden.ResultsNine cases (37.5%) had Aβ plaques. Global PiB SUVR correlated with Aβ plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty‐one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta‐ROI SUVRs were not elevated in Braak IV or primary age‐related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions.InterpretationMolecular PET shows expected correlations with Alzheimer‐related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009–1022