Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathological heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.

Fig. 1

Clinical, pathologic and genetic spectrum of frontotemporal lobar degeneration (FTLD). Clinical syndromes (top row), pathologic subtypes (middle row) and common gene mutations (bottom row) in FTLD are shown. Arrows represent links between clinical syndromes, genes and underlying histopathology, with thicker arrows corresponding to stronger relationships. bvFTD = behavioural-variant frontotemporal dementia; CBD = corticobasal degeneration; FTLD-ALS = FTLD with amyotrophic lateral sclerosis; FTLD-TAU = FTLD with tau-positive inclusions; FTLD-FUS = FTLD with fused in sarcoma (FUS)-positive inclusions; FTLD-TDP = FTLD with TAR DNA-binding protein 43 (TDP-43)-positive inclusions; MAPT = microtubule-associated protein tau; PGRN = progranulin; PNFA = progressive nonfluent aphasia; PSP = progressive supranuclear palsy; SD = semantic dementia.

Fig. 2

MRI findings in frontotemporal lobar degeneration (FTLD). T1-weighted images from representative patients with behavioural-variant frontotemporal dementia (bvFTD) [a and b], semantic dementia (SD) [c] and progressive nonfluent aphasia (PNFA) [d] are displayed in neurologic orientation. (a and b) bvFTD patient shows marked atrophy throughout the medial and lateral frontal cortex and the temporal poles, with striking relative preservation of the posterior brain regions on a sagittal view. (c) Patient with SD shows asymmetric degeneration of the temporal poles (left greater than right). (d) PNFA patient shows atrophy in the left inferolateral and dorsomedial frontal cortex and anterior insula.

Fig. 3

Frontotemporal lobar degeneration (FTLD) pathology. (a) Typical FTLD features circumscribed atrophy affecting anterior cortical and subcortical regions, as seen in this patient with progressive nonfluent aphasia due to underlying corticobasal degeneration. Scale bar = 5 cm. (b) Regardless of the associated disease protein, affected regions show neuronal loss, gliosis and microvacuolation, especially in superficial cortical layers. Hematoxylin and eosin stain. Scale bar = 200 microns. (c) Pick’s disease, a tau-positive form of FTLD, shows cytoplasmic hyperphosphorylated tau inclusions within neurons (Pick bodies) and in ramified astroglial processes (arrowheads). CP-13 antibody, courtesy of P. Davies. (d) In FTLD due to TAR DNA-binding protein 43 (TDP-43) proteinopathy, affected neurons like these dentate gyrus granule cells show cytoplasmic TDP-43 inclusions and clearing of TDP-43 from its normal nuclear location (arrows). TDP-43 antibody. Scale bars in c and d = 25 microns. Figure provided by W.W. Seeley, University of California, San Francisco.