Deep clinical and neuropathological phenotyping of P ick disease
Year: 2015
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease. METHODS: Detailed neuropathological examination using 70μm and traditional 6μm 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 gray 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 precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 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 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.
Source: Annals of Neurology
DOI: 10.1002/ana.24559
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1659106019, G234895681, Age, Hearing Loss, and Sentence Comprehension: Neural Correlates, G3361226164, G3438298939, G3815257936, G3841832043, Parkinson's Disease and Dementia, Alzheimer's Disease Core Center, G4325234025, Conceptual Processing in Alzheimer's Disease, Frontotemporal Dementias: Genotypes and Phenotypes, G4875909425, G502624863, G5152921967, G6303712181, G6433178756, Multimodal Biomarkers in Frontotemporal Lobar Degeneration, G6492025387, G7036089480, Identification of Endophenotypes in the Behavioral-Variant of Frontotemporal Deme, G7247542487, G7527168623, G8061420933, G8714196310, TDP-43 Proteinopathies in ALS-Dementia, Neural Basis of Generalized Quantifiers, G9000030004, G9000033698, Frontotemporal Dementia: Genes, Images, and Emotions, New Approaches to Dementia Heterogeneity
OpenAlex ID: W2176830446