Amygdala vulnerability in Pick disease with discrete frontotemporal dementia syndromes

Frontotemporal lobar degeneration with tauopathy (FTLD‐tau) typically manifests as either behavioral variant frontotemporal dementia (bvFTD) or primary progressive aphasia (PPA). Tau pathology in FTLD‐tau is characterized by predominantly three‐repeat (3R) tau, as in Pick disease (PiD), or four‐repeat (4R) tau species of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). FTLD‐tau preferentially targets frontal and anterior temporal lobes, including the amygdala, contributing to severe neuropsychiatric symptoms. This study investigated whether bvFTD and PPA due to FTLD‐tau exhibit distinct amygdalar histopathology and whether these patterns reflect their initially distinct clinical phenotypes, particularly in PiD. We examined 47 autopsy‐confirmed FTLD‐tau cases from the Northwestern Alzheimer's Disease Research Center Brain Bank using postmortem digital pathology analysis to quantify tau phosphorylation and HLA‐DR immunoreactivity in the amygdala. In a subset of 19 PiD cases (10 bvFTD‐PiD, 9 PPA‐PiD), we assessed neuropsychiatric symptoms, tracked longitudinally using the Neuropsychiatric Inventory–Questionnaire (NPI‐Q), and quantified neuronal and Pick body densities via unbiased stereology and neuronal sizes via digital pathology analysis. Across the FTLD‐tau cohort, bvFTD exhibited greater amygdalar neuroinflammation than PPA, despite comparable tau burden. Interestingly, 3R cases also demonstrated higher levels of phosphorylated tau and MHC‐II‐positive microglia than 4R cases. In PiD, neuropsychiatric symptoms converged over time, with PPA cases evolving to show bvFTD‐like symptoms with disease progression. BvFTD‐PiD showed a trend toward greater MHC‐II‐positive microglia than PPA‐PiD, despite similar neuronal size/density and Pick body burden. Increased HLA‐DR immunoreactivity correlated positively with Pick body pathology. Neurons containing tau pathology (Pick cells) were notably larger than unaffected neurons, suggesting that early tau accumulation precedes overt neuronal degeneration. These findings underscore the potential role of neuroinflammation in shaping clinical phenotypes in FTLD and highlight the role of the amygdala in complex clinicopathologic relationships. Targeting neuroinflammatory processes may represent a viable therapeutic avenue for managing neuropsychiatric symptoms in tauopathies.