Clinicopathological correlates in frontotemporal dementia

TLDR

Frontotemporal dementia (FTD) comprises diverse clinical syndromes that do not reliably correspond to known pathological spectra. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). The authors classified 61 FTD cases into clinical subtypes—behavioral, language (semantic dementia and progressive nonfluent aphasia), and motor (corticobasal degeneration and motor neuron disease)—and pathological subtypes based on tau‑positive inclusions (with or without Pick bodies), ubiquitin‑positive inclusions, or non‑specific histology. Behavioral FTD cases sometimes presented with marked amnesia, and while behavioral symptoms and semantic dementia were linked to diverse pathologies, other phenotypes—motor neuron disease, parkinsonism/apraxia, and nonfluent aphasia—predicted specific pathologies (ubiquitin inclusions, corticobasal, and Pick bodies, respectively), allowing the pathological substrate to be predicted in a significant proportion of patients.

Abstract

The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). Clinical subtypes defined were behavioral variant FTD (n = 26), language variants (semantic dementia, n = 9; and progressive nonfluent aphasia, n = 8), and motor variants (corticobasal degeneration, n = 9; and motor neuron disease, n = 9), although most cases presented with a combination of behavioral and language problems. Unexpectedly, some behavioral cases (n = 5) had marked amnesia at presentation. The pathological subtypes were those with tau-immunopositive inclusions (with Pick bodies, n = 20; or without, n = 11), those with ubiquitin immunopositive inclusions (n = 16), and those lacking distinctive histology (n = 14). Behavioral symptoms and semantic dementia were associated with a range of pathologies. In contrast, other clinical phenotypes had relatively uniform underlying pathologies: motor neuron disease predicted ubiquitinated inclusions, parkinsonism and apraxia predicted corticobasal pathology, and nonfluent aphasia predicted Pick bodies. Therefore, the pathological substrate can be predicted in a significant proportion of FTD patients, which has important implications for studies targeting mechanistic treatments.