Ubiquitinated Inclusions Link Amyotrophic Lateral Sclerosis with Frontotemporal Dementia

Abstract

Although amyotrophic lateral sclerosis (ALS) is often viewed as a motor systems disorder, evidence has surfaced indicating that ALS patients may develop cognitive losses. In particular, clinical and histopathological studies suggest a predominance of frontotemporal pathology in some ALS patients. Pick-like ubiquitinated inclusions have been described in hippocampal dentate granule cells and in small cortical neurons of the frontal and temporal cortices. However, these inclusions are distinctive from those of Pick’s disease because they do not contain tau protein and they lack argyrophilia. We report a case from a kindred with familial frontotemporal dementia (FTD) with identical ALS-like, ubiquitin-positive lesions. Tau-immuno-reactive Pick bodies and other specific pathological changes were absent. This case lacked clinical signs of ALS and showed few histopathological features of ALS. We review the literature describing the clinical and pathological link between ALS and FTD, and propose that tau-negative, ubiquitinated inclusions similar to those of ALS may be seen in familial forms of FTD, even in the absence of typical clinical or pathological features of ALS. These ubiquitinated inclusions may be a common biological link underlying dementia in some ALS and FTD cases.