Behavioral subtypes impact prognosis and survival in amyotrophic lateral sclerosis: a clustering-based approach.

Background: Behavioral impairments are well established in amyotrophic lateral sclerosis (ALS). A refined understanding of the contribution of delineated patterns of behavioral impairments to prognosis is vitally important.

Methods: Leveraging data-driven two-step cluster analysis, we first stratified a large cross-sectional cohort of 170 ALS patients into distinct phenotypic subtypes based on their baseline behavioral profiles, as determined by the well-validated and informant-rated Motor Neuron Disease Behavioral Instrument (MiND-B). Mixed-effects model and multivariate Cox regression analyses were performed to compare rate of functional decline as measured by the revised ALS functional rating scale (ALSFRS-R) over follow-up assessments in 121 participants, as well as survival duration (n = 130), between the behavioral subtypes. Results: Clustering analysis yielded three behavioral phenotypes characterized by 1) intact behavioral functioning (n = 125), 2) apathy alone (n = 20), and 3) concurrent disinhibition and stereotypical behavior (n = 25). Apathy was associated with both significantly shorter survival (p = .003) and most rapid functional decline across follow-up assessments (both p <.001). Importantly, this pervasive effect was not observed in other behavioral cluster groups.

Conclusions: Extending previous cross-sectional work, current findings offer delineation of the trajectory of clinical outcomes associated with classic behavioral phenotypes of ALS. Converging with past evidence of unique disease and progression profile in ALS patients with apathy, our work provides strong support for behavioral change and in particular apathy as a reliable indicator of poor prognosis across cross-sectional and longitudinal markers of clinical outcomes.