ObjectiveTo characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome.MethodsSeventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [¹⁸F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [¹⁸F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine β-amyloid positivity.ResultsThe bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was β-amyloid–positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter.ConclusionPatterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.