The author offers an updated article of dementia associated with amyotrophic lateral sclerosis, including discussion of the consensus criteria for frontotemporal cognitive and behavioral syndromes in amyotrophic lateral sclerosis as well as updated information on the considerable neuropathological overlap between amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Additional updates highlight genetic and protein associations more recently described, including TDP-43, FUS, UBQLN2, and C9orf72, as well as avenues for clinical investigations and potential therapies to be pursued in light of these advances.
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• The prevalence of dementia in amyotrophic lateral sclerosis is much higher than historically reported, with some evidence of cognitive or behavioral impairments not meeting criteria for the diagnosis of dementia in the majority of amyotrophic lateral sclerosis patients.
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• The convergence of neuropathological and genetic evidence suggests that amyotrophic lateral sclerosis and frontotemporal dementia may represent a continuum of the same neurodegenerative process in many cases.
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• A growing understanding of the protein neuropathology of both amyotrophic lateral sclerosis and frontotemporal dementia provides exciting opportunities for the development of disease-modifying therapies for this spectrum of neurodegenerative illnesses.
Historical note and terminology
Nineteenth-century neurologists regarded dementia in patients with amyotrophic lateral sclerosis as either a second, independent neurologic process or an atypical presentation of amyotrophic lateral sclerosis (20). Two centuries later, it remains uncertain why only some amyotrophic lateral sclerosis patients become demented. Cognitive deficits in amyotrophic lateral sclerosis represent a wide spectrum from relatively mild frontal lobe dysfunction to fully manifested frontal lobe dementia (105). Although many names have been applied to this condition (50), this review will continue to refer to it as "dementia associated with amyotrophic lateral sclerosis," while also acknowledging contemporary classification schemes for clinical and molecular diagnosis.
Dementia and amyotrophic lateral sclerosis can present within other disorders. Guamanian amyotrophic lateral sclerosis associated with dementia seems to differ from dementia associated with sporadic or familial types of amyotrophic lateral sclerosis in etiology and pathology. In addition, clinical presentations of dementia associated with amyotrophic lateral sclerosis and the motor neuron variant of frontotemporal dementia overlap considerably. The motor neuron variant of frontotemporal dementia is classified as a pathological subtype of clinical frontal lobe dementia with its own diagnostic criteria (18; 49), whereas an international research conference on amyotrophic lateral sclerosis and frontotemporal dementia held in London, Canada in 2007 resulted in the publication of consensus criteria for the diagnosis of frontotemporal cognitive and behavioral syndromes in amyotrophic lateral sclerosis (102).