Amyotrophic lateral sclerosis and non-tau frontotemporal lobar degeneration

Abstract

Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. The characteristic aggregate-forming protein in non-tau FTLD is either TDP-43 or FUS. It has been known for several years that frontotemporal dementia (or less severe forms of cognitive impairment) may coexist with ALS. Recent discoveries in genetics (e.g., C9orf72 mutation) and the subsequent neuropathologic characterization have revealed remarkable overlap between ALS and non-tau FTLD also at a molecular level, indicating common molecular pathways in pathogenesis. After a historic overview we demonstrate and compare the macroscopic and microscopic appearances and molecular characteristics with emphasis on genetic background, neuroanatomic distribution, and morphology of abnormal protein aggregates and their possible association with specific mutations. The clinicopathologic classifications and correlations are also discussed.

Keywords: C9orf72; FUS; TDP-43; VCP; frontotemporal dementia; genetics; immunohistochemistry; motor neuron disease.