Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis

Abstract

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Keywords: amyotrophic lateral sclerosis; cognition; endophenotype.

Graphical abstract

Figure 1

Verbal fluency performance in relatives of people with familial ALS, sporadic ALS and controls. (A) Violin plot of distribution of FAS verbal fluency Z-scores (each dot representing an individual data point) in FALS relatives (green), SALS relatives (blue) and controls (magenta). Significant one-way ANOVA main effect, F(2198) = 12.51, P = 0.0000077. Post hoc Tukey’s test significant between FALS relatives and controls, P = 0.000008, and between SALS relatives and FALS relatives, P = 0.005. (B) FAS verbal fluency Z-score data points in C9orf72 gene carrier (red) and non-C9orf72 carrier (black) relatives of people with FALS. FALS = familial amyotrophic lateral sclerosis; SALS = sporadic amyotrophic lateral sclerosis.

Figure 2

Autism quotient attention to detail traits and Ten-Item Personality Inventory conscientiousness and openness to experience traits in FALS relatives, SALS relatives and controls. Violin plots of (A) AQ attention to detail traits and TIPI; (B) conscientiousness and (C) openness to experience traits in FALS relatives (green), SALS relatives (blue) and controls (red). Each dot represents an individual data point from that group. Significant one-way ANOVA main effect on AQ attention to detail, F(2223) = 5.44, P = 0.0044. Tukey’s post hoc tests significant between FALS relatives and controls, P = 0.04, and between SALS relatives and controls, P = 0.004. Significant one-way ANOVA main effect on TIPI conscientiousness, F(2220) = 5.16, P = 0.0085. Tukey’s post hoc tests significant between FALS relatives and controls, P = 0.007, and between SALS relatives and controls, P = 0.03. Significant one-way ANOVA main effect on TIPI openness to experience, F(2220) = 5.82, P = 0.0034. Tukey’s post hoc tests significant between FALS relatives and controls, P = 0.002. FALS = familial amyotrophic lateral sclerosis; SALS = sporadic amyotrophic lateral sclerosis; AQ = autism quotient; TIPI = Ten-Item Personality Inventory.