Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

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.

Patterns of Language Impairment in Early Amyotrophic Lateral Sclerosis.

OBJECTIVE: To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing. METHODS: One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated. RESULTS: Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present. CONCLUSIONS: Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS.

Social cognition in cervical dystonia: A case-control study.

BACKGROUND: Although considered a motor disorder, adult onset isolated focal dystonia has many non-motor symptoms. There is a paucity of neuropsychological research on cognitive processing in adult onset focal dystonia. METHODS: We employed a battery of clinical and cognitive assessments, including basic and complex social cognition, and assessed 46 patients with adult-onset cervical dystonia, compared to 46 age-, sex-, education-, and premorbid IQ-matched healthy controls. RESULTS: Significant between-group differences were observed in relation to measures of memory encoding, recall and recognition, as well as multimodal measures of basic Social Cognition (emotion recognition: face and prosody), but not complex Social Cognition (mentalising). There were no deficits observed in multimodal measures of executive function. Controlling for mood did not affect performance. CONCLUSION: In this multi-dimensional assessment of cognition in cervical dystonia, we report deficits in memory encoding, and in social cognition. Further investigation of social cognitive processes, memory, and sustained attention are required. Longitudinal studies are also needed to further delineate the role of psychological distress on cognitive outcomes and document the cognitive profile over time.