Conceptualizing cognition and behaviour across amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Cognitive and behavioral dysfunction in frontotemporal dementia (FTD) evolves along a clinical continuum from a clinically silent stage of disease, through a prodromal period, often referred to as mild cognitive impairment (MCI) and/or mild behavioral impairment (MBI), and into a clinically manifest stage recognized by the syndromes of behavioral variant FTD and primary progressive aphasia (PPA). Similar cognitive and behavioral manifestations of varying severity are also encountered in individuals with amyotrophic lateral sclerosis (ALS). Notwithstanding this phenotypic overlap as well as a degree of shared genetic risk and underlying pathology, the approach to phenotypic characterization and description meaningfully differs between the ALS and FTD communities. The problem is particularly evident within the ALS community when describing impairment in the prodromal vs. clinically manifest disease stages. Pertinent considerations include the nature of cognitive and behavioral assessments, the nosology used to describe symptoms identified including those encompassed by the terms ‘behavioral’ and ‘neuropsychiatric’, the operationalized criteria that define prodromal syndromes and clinically manifest disease, and the extent to which these criteria rely on longitudinal (vs. cross-sectional) data. A multi-stakeholder workshop, held in London, Ontario (May 12-14, 2025), brought together neurologists, psychiatrists, neuropsychologists, neuropathologists, neuroscientists, and neurogeneticists studying ALS and FTD, to promote inter-disciplinary dialogue and to define a research agenda that might be jointly tackled to address these critical issues. A new nosology for classifying frontotemporal-related behavioral and neuropsychiatric dysfunction, which could be used to support empirical evidence collection, is proposed alongside a list of cognitive, language, behavioral and neuropsychiatric symptoms to be considered in the evaluation of individuals with ALS. Research priorities for each of the ALS and FTD communities, as well as initiatives that should be undertaken jointly, are highlighted. The long-term goal is to harmonize approaches to phenotypic characterization, the nosology used to describe symptoms, and the criteria used to define landmark stages along the clinical continua of the motor neuron and frontotemporal axes irrespective of clinical stage.