Kouri, Naomi

AbstractBackgroundThe coarse‐grained plaque (CGP) is a divergent plaque‐type recently described in Alzheimer’s disease (AD)1. In the current study, we studied the CGPs distribution over the brain, and its association with APOE, p‐tau, and neuroinflammation.MethodThe cohort (N = 60) was selected from the Mayo Clinic brain bank in Jacksonville, USA. Brain tissue from the frontal ‐, parietal ‐, temporal cortex, and the hippocampus was immunohistochemically stained for Aβ (6F/3D), p‐tau (AT8), CD68, and GFAP. The CGP and classic cored plaque (CCP) were scored as previously described1. Total plaque burden was expressed as the sum of all cortical regions.ResultThe CGP was predominantly located in the neocortex and present in ∼60% of AD cases, who were younger at onset (p<0.05) and had a lower brain weight (p<0.05) than CGP negative cases. When stratified for APOE Ɛ4+ and Ɛ4‐, CGP burden was only in Ɛ4+ positively correlated with p‐tau, Aβ, and GFAP burden in the frontal and parietal cortex (Table 1). CGP burden was not correlated with CD68. The CCP was negatively correlated with p‐tau, and not with GFAP, Aβ or CD68 (Table 1). In APOE Ɛ4+ cases, the burden of CGPs was negatively correlated with the burden of CCPs (Fig.1).ConclusionThe neocortical CGP is correlated with increased p‐tau burden and astrogliosis in APOE Ɛ4+. The CGP is inversely correlated with the common CCP, suggesting an opposite effect of Aβ‐induced tau‐toxicity for the CGP versus the CCP. 1Boon et al., Acta Neuropathologica, 2020

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.MethodWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.ResultsVascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.ConclusionOur findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.

AbstractBackgroundWe recently discovered a novel tau binding partner, SERPINA5, to be upregulated in Alzheimer’s disease (AD) and co‐localize with corticolimbic tau distribution. As tau pathology is also observed in primary tauopathies, we hypothesized that SERPINA5 burden would mirror tau burden in these diseases. Thus, we sought to define the relationship between SERPINA5 and tau in primary tauopathies and compare this relationship to AD.MethodImmunohistochemistry was performed on the hippocampus or cingulate in 4 groups (n=6 per disease group): 1) AD, 2) 3R+4R primary age‐related tauopathy, 3) 4R tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grains disease), and 4) 3R tauopathy (Pick’s disease). Burden analyses for SERPINA5 and a phospho‐tau marker (AT8) were performed on digitized whole slide images.ResultVisual interpretation of SERPINA5 immunostaining identified both neuronal and glial inclusions that are commonly AT8‐positive in primary tauopathies. There were exceptions to this pattern such as SERPINA5‐positive Pick bodies being rarely observed. However, some pathologic structures, like ballooned neurons, were preferentially stained by SERPINA5. Quantitative analyses confirmed this observation with AT8 and SERPINA5 burden correlating in both the cingulate (R2=0.47, p<0.0001, Figure 1a) and hippocampus (R2=0.74, p<0.0001, Figure 1d). Nonparametric rank sum tests revealed majority of the primary tauopathies had less AT8 and SERPINA5 burden compared to AD in both the cingulate and hippocampus (Figure1b‐c, e‐f; Table 1).ConclusionSERPINA5 immunostaining patterns in primary tauopathies reflect tau immunostaining patterns. Our data suggests the SERPINA5‐tau interaction may not be specific for AD, which may implicate the role of SERPINA5 more broadly across tauopathies.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

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.

AbstractMutations in microtubule‐associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17). Here, we describe a patient with FTDP‐17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40‐year‐old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP‐17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP‐17 due to p.E372G were similar to those of p.G389R, including tau‐immunoreactive Pick body‐like neuronal inclusions and swollen, tapering thread‐like processes in white matter immunoreactive for 3‐repeat and 4‐repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP‐17 similar to p.G389R.