Pick Disease: Navigating the Frontotemporal Dementia Diagnosis

The clinical diagnosis of Pick disease can be one of the most difficult facing the neurologist. Those patients found to have lobar atrophy usually present clinically with bouts of irrational behavior, bulimia, marked reductions in speech, abulia, and apathy. In contrast with Alzheimer disease (AD), Pick disease generally is not associated with symptoms of memory loss or disorientation in regard to time and space. Aphasia is a prominent feature. Psychiatric features that often accompany Pick disease but are not seen in AD include obsessive-compulsive disorder, delusions, and paranoia. Common noncognitive features of AD, such as blindness, sensory loss, and weakness, are not usually encountered in Pick disease.1 DIFFERENTIAL DIAGNOSIS Pick disease is characterized by frontotemporal lobar degeneration (FTLD). It can take on a variety of clinical presentations that make a differential diagnosis difficult. With the advent of specialized immunohistochemical staining techniques and insights gleaned from molecular genetics, researchers have found that FTLD is closely related to and often overlaps with other neurodegenerative disorders, such as motor neuron disease, progressive supranuclear palsy, and corticobasal ganglionic degeneration. Because the pathogenesis of FTLD has been associated with the tau protein—which plays a central role in microtubule-associated neuronal destruction—FTLD has become classified as a tauopathy.2 Tau proteins have been associated with the formation of intraneuronal, neurofibrillary, filamentous lesions that are found in a number of neurological diseases.3 "If you consider Pick disease as a postmortem neuronal pathology demonstrating cytoplasmic inclusion bodies [ie, Pick bodies], that's one thing," commented Howard Crystal, MD, professor of neurology and pathology at the State University of New York Downstate Medical College in Brooklyn. "For the clinician, the question arises about whether patients presenting with progressive frontal lobe dysfunction with anterior temporal lobe dysfunction have FTLD or whether they are just presenting with a kind of primary aphasia." BASIC PATHOLOGY The postmortem appearance of the brain of patients with classic FTLD is unique. Notable is its highly demarcated reduction in cortical mass, which is often so severe that it has been given the name "knife-blade" atrophy. This remarkable atrophy, generally confined to the frontal and temporal lobes, has led to the widespread use of the alternative term, "frontotemporal lobe atrophy," as another name for Pick disease. When compared with the conspicuous general atrophy noticed in the brains of patients with AD, most cases of Pick disease demonstrate a marked sparing of the parietal lobe, the occipital lobe, the temporal gyrus, and the posterior two thirds of the superior temporal gyrus. However, there are cases in which the characteristics of both AD and Pick disease are present in the same brain.4 TAU PROTEIN AND GENES Tau proteins have been studied extensively. Advanced techniques in molecular biology have produced a more complete understanding of their involvement in the pathogenesis and histopathology of FTLD.5,6 The tau protein is located on chromosome 17q21, and mutations in this tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). An autosomal dominant inherited syndrome that expresses the clinical features of FTLD develops in patients carrying the mutated tau gene. Mutations of the tau gene responsible for the clinical syndrome of Pick disease are clustered around exon 10.7