Here we focus on PSP, a primary tauopathy characterised by the accumulation of 4-repeat tau in neuronal and glial cells, without the accumulation of beta-amyloid, as seen in Alzheimer’s disease, or alpha-synuclein, as seen in Parkinson’s disease. Such tau pathology is related to neuronal loss, grey matter atrophy and clinical severity. Hyperphosphorylated and misfolded aggregates of tau accumulate in common and rare neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, and Progressive Supranuclear Palsy (PSP). Understanding the severity and distribution of this protein pathology is key to investigate the aetiology, understand disease heterogeneity, model disease progression, and to design molecular-targeted disease-modifying therapies. Many neurodegenerative diseases are characterised by abnormal protein accumulation within neurons and glia. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. ![]() Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman’s rank correlation. ![]() The tau pipeline achieved high classification performance (F1-score > 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. We quantified 4 tau objects (‘neurofibrillary tangles’, ‘coiled bodies’, ‘tufted astrocytes’, and ‘tau fragments’) using a probabilistic random forest machine learning classifier. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function.
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