Frontotemporal dementia: clinicopathological correlations.

Frontotemporal lobar degeneration (FTLD) is characterized clinically by progressive changes in social, behavioral, and/or language function.1-3 In the frontal or social/dysexecutive variant of FTLD, there is an early change in social comportment and personality often associated with disinhibition, apathy, and lack of insight. In contrast, the aphasic variant of FTLD is further classified as either progressive nonfluent aphasia, characterized by effortful speech and phonemic errors,4 or semantic dementia, manifested by severe problems with naming and understanding word and object meaning.5 In both the social/dysexecutive and aphasic variants, there is relative preservation of memory, especially in early stages. In addition, some patients with FTLD manifest a motor disorder such as parkinsonism or motor neuron disease (MND).6,7 Multiple neuropathological abnormalities are associated with FTLD,3,8 and this pathological heterogeneity is reflected in a recent classification scheme from an frontotemporal dementia (FTD) work group that was the first to incorporate both immunohistochemical and biochemical data in the diagnostic algorithm (Fig 1).3 Two broad pathological subdivisions of FTD are recognized: brains with tau-positive pathology (tauopathies), and brains free of tau pathology (see Fig 1). The tauopathies are subdivided into several distinct entities, including Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease, tangle-predominant senile dementia, and patients with MAPT gene mutations collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17, or FTDP-17. In contrast, brains from the remaining patients lack tau-positive inclusions and are further categorized by the presence or absence of ubiquitin-positive inclusions, designated frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U)9-11 and dementia lacking distinctive histopathology (DLDH), respectively.12-14 A new pathological entity recently was described in FTLD-U patients, designated neuronal intermediate filament inclusion disease, that is characterized by neuronal intermediate filament-positive aggregates in neurons of affected brain regions.15-18 It also should be emphasized that both Alzheimer’s disease (AD) pathology and cortical Lewy bodies formed by filamentous α-synuclein aggregates (dementia with Lewy bodies) may present with clinical features indistinguishable from the FTLD syndromes described earlier (see Fig 1).12,19,20 Fig 1 Algorithm for the neuropathological diagnosis of patients with frontotemporal lobar degeneration (FTLD). This algorithm represents an oversimplification of the scheme used to diagnose FTLD patients and does not reflect the complexity of the cases or the ... FTLD clinical syndromes have been associated with specific neuropathological disorders by some researchers,7 although this association is controversial.3 With the development of therapies that target the underlying pathology and cell biology of specific diseases, classification of patients with various pathological entities will become increasingly important. The clinical and pathological features have been described, but few studies have performed detailed clinicopathological correlations of large series of FTLD patients. In this study, we sought to determine the clinical and/or neuropsychological features that correlate with the underlying pathology in a large series of subjects with a neuropathological diagnosis of FTD who were evaluated over a 10-year period.