The frontotemporal syndromes of ALS. Clinicopathological correlates

Abstract

Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a syndromic disorder in which the degeneration of motor neurons is frequently accompanied by a range of syndromes reflective of frontotemporal dysfunction, including a behavioural or cognitive syndrome, a dysexecutive syndrome or a frontotemporal dementia. Both sporadic and familial variants of ALS can be affected. The anatomic substrate of each is a frontotemporal lobar degeneration (FTLD) characterized by superficial linear spongiosus, atrophy and neuronal loss, and both astrocytic and neuronal deposition of TDP-43 as pathological inclusions. Largely unrecognized however is the extent of alterations in tau protein metabolism, particularly in cognitively impaired patients (ALSci). This includes hyper-phosphorylation (pThr(175)) and tau phosphatase resistance, increased fibril formation ex vivo of tau isolated from ALSci and tau immunoreactive aggregates in neurons, dystrophic neurites and astrocytes. In this article, we will review the contemporary clinical, genetic and neuropathological characteristics of the frontotemporal syndromes of ALS and propose that as opposed to being a FTLD in which TDP-43 is the primary disease protein (FTLD-TDP) and that the frontotemporal syndromes of ALS represent a hybrid of both TDP-43 and tau pathology.