Deep clinical and neuropathological phenotyping of Pick disease

Abstract

Objective To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick’s disease. Methods Detailed neuropathological examination using 70 μm and traditional 6 μm sections was performed using Thioflavin-S staining and immunohistochemistry for phosphorylated-tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n=5) converging evidence was obtained using antemortem neuroimaging measures of grey and white matter integrity. Results Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (Phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus and raphe nuclei (Phase II), followed by primary motor cortex and pre-cerebellar nuclei (Phase III) and finally visual cortex in the most severe (Phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18/21) but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease-duration and inversely correlated with brain-weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. Interpretation Pick’s disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

Mapping Neurodegenerative Disease Onset and Progression

“…For less common diseases, like FTLD, determining early neuronal subtype selectivity has been even more difficult because of the diversity of FTD syndromes and the scarcity of postmortem materials from patients with asymptomatic or prodromal disease. The few laudable attempts to derive distinct stages using cross-sectional materials have not been able to include individuals with presymptomatic disease (Brettschneider et al 2014;Irwin et al 2016 ) that anchor distinct networks gives rise to three different clinicoanatomical presentations. Network depictions follow Figure 3.…”

Astrogliopathy in Tauopathies

“…The localization of tau-containing astrocytes does not always match that of tau-containing neurons in tauopathies [14,19,28,76,[88][89][90][91][92]. Curiously, tufted astrocytes and astrocytic plaques are often located near the blood vessels [93], and perivascular distribution is overwhelming in a rare familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy [87].…”

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

“…To date, more than 55 mutations have been identified in the MAPT gene causing autosomal dominant forms of FTD and parkinsonism, with a wide clinical heterogeneity mainly consistent of typical bvFTD (Ghetti et al, 2015; Irwin et al, 2016). Despite having some risk associations with MAPT variants (Jung et al, 2012; Rossi et al 2008; Wischik et al, 2015) pathogenic MAPT mutations are an unusual cause of CBS thus making it hard to define a clear genotype-phenotype correlation.…”