Pick Disease: Picking Away at the Pathology
By Joseph E. Safdieh, MD
Vice Chair and Associate Professor, Weill Cornell Medical College
Dr. Safdieh reports no financial relationships relevant to this field of study.
SYNOPSIS: The neuropathologic changes of Pick disease may sequentially progress through the brain in specified phases over time and may correlate with the progression of clinical symptoms.
SOURCE: Irwin DJ, et al. Deep clinical and neuropathological phenotyping of Pick disease. Ann Neurol 2015;79:272-287.
Pick disease was initially described in the late 19th century in a patient who suffered a progressive neurodegenerative syndrome manifested by behavioral and language changes with gross frontotemporal atrophy noted on pathologic examination. Pick disease is now categorized as pathologic variant of one of the frontotemporal lobar degenerations (FTLD). FTLD pathologic subtypes include FTLD-Tau, FTLD-TDP, and FTLD-FUS. Pick disease is categorized under the FTLD-Tau subtype and is specifically a 3-repeat tauopathy. Pick disease is diagnosed pathologically by the presence of Pick bodies, which are spherical intraneuronal tau inclusions composed predominately of tau isoforms containing three microtubule-binding domain (MTBD) repeats. Some older sources still use the umbrella term of Pick disease to describe the entire family of FTLDs, but this is incorrect. Pick disease is a specific subtype of FTLD-Tau.
The phenotypic presentation of Pick disease typically manifests with behavioral variant frontotemporal dementia, with progressive behavioral and personality changes. Less common phenotypic presentations include primary progressive aphasia or corticobasal syndrome. The clinical phenotype of frontotemporal lobar degeneration syndrome does not easily predict the pathologic subtype of FTLD. Unlike many other forms of FTLD syndromes, Pick disease does not have a clear genetic linkage and is considered sporadic.
In this study, the authors thoroughly investigated the neuropathologic changes, as well as neuroimaging and available clinical histories, of 21 patients with pathologically confirmed Pick disease from a brain bank at the University of Pennsylvania. Tissue samples were immunostained for multiple forms of tau including phospho-tau, 4R tau, 3R tau, tau associated with amyloid as well as ubiquitin, MAP2, and GFAP. Experienced neuropathologists evaluated the specimens for degree of tau inclusions and neuronal loss in multiple brain regions. Clinical histories were derived from chart review by behavioral neurologists. Antemortem MRI imaging was available for five of the 21 cases and was evaluated for gray matter density in various regions as well as white matter diffusivity. After detailed neuropathologic and immunohistochemical analysis of the specimens, the authors hypothesized the presence of four sequential phases of pathologic tau deposition in Pick disease, from mildest (phase I) to most severe (phase IV). Phase I changes involved frontotemporal limbic/paralimbic and neocortical regions. Phase II changes involved subcortical structures, including the basal ganglia, locus ceruleus, and raphe nuclei. Phase III changes involved primary motor cortex and precerebellar nuclei. Phase IV changes involved the visual cortex. Clinically, the mean age of disease onset was 57 years with mean age of death at 65 years. The vast majority of patients (18 of 21) presented with the behavioral variant of FTLD. The other patients presented with either corticobasal syndrome or primary progressive aphasia. All patients eventually manifested behavioral and personality changes. Importantly, pathological tau phases (I through IV) directly correlated with disease duration and inversely correlated with brain weight at autopsy. Imaging changes also correlated with pathologic tau phases. Similar to pathologically defined tau phase I, the authors noted early and severe MRI changes in limbic and paralimbic regions. Regional development of atrophy in follow-up imaging generally correlated with the phases of tau pathology.
COMMENTARY
This is an important paper in understanding Pick disease, which is a rare but important form of FTLD. Pick’s original description of this disease led to the earliest conceptual understanding of the phenotypic varieties of neurodegenerative illnesses manifesting with cognitive impairment. The concept of progressive, sequential, predictable neuropathologic changes has been well established in other neurodegenerative disorders, especially in Alzheimer’s disease and Parkinson’s disease. Understanding the pathologic progression of Pick disease may lead to a better understanding of the pathophysiologic underpinnings of this disorder. More work needs to be done to further validate these findings and to build on this work to determine what underlying pathophysiologic etiologies might explain the sequential progression of these pathologic changes. The major unanswered question in all sporadic neurodegenerative diseases is, “What is the cause of the pathologic changes?” Studies like this one help lay the groundwork for future studies that may answer this critical question.
The neuropathologic changes of Pick disease may sequentially progress through the brain in specified phases over time and may correlate with the progression of clinical symptoms.
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