Neuropathological background of phenotypical variability in frontotemporal dementia

Abstract

Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.

C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts

“…Neurology Frontotemporal dementia (FTD) refers to a heterogeneous group of diseases characterized by personality changes, behavioral or language deficits associated with progressive loss of neurons in the frontal and temporal regions of the brain, and a range of pathologies characterized by the accumulation of intraneuronal protein inclusions. [1][2][3] Evidence for the overlap between FTD and amyotrophic lateral sclerosis (ALS) has been strengthened by the recent finding of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function on chromosome 9p21, in Finnish and North American familial FTD and ALS cohorts. 4,5 It remains unclear, however, how common this repeat expansion is in different populations, and what clinical and pathologic phenotypes are associated with this mutation.…”

Pathology of frontotemporal dementia with limb girdle muscular dystrophy caused by a DNAJB6 mutation

“…However, neither TDP-43, Tau nor FUS reactivity were observed in the CNS. Therefore, this patient was diagnosed as "FTLD-other", or FTD with ubiquitin-positive aggregates and without tau, TDP, and FUS pathology [2]. Previous studies suggest that DNAJB6 facilitates ubiquitin-dependent degradation substrates.…”

“…FTLD is classified into three categories: frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA), and semantic dementia (SD) [2]. [2].…”

“…FTLD is classified into three categories: frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA), and semantic dementia (SD) [2]. [2]. These symptoms gradually progressed, and brain magnetic resonance images showed frontal atrophy with mild temporal atrophy (Fig.…”

Manifestaciones neuropsiquiátricas y cognitivas en demencia frontotemporal y esclerosis lateral amiotrófica: dos polos de una entidad común

“…Está presente en DFTvc, DFT-ELA y ocasionalmente ELA pura 121,122 . La DFT con FUS presenta cambios conductuales prominentes y síntomas psicóticos frecuentes 118,123 .…”