Neuropsychiatric disorders in motor neurone disease kindreds: clinical and subclinical symptoms and their relationship with cognition and behaviour

Abstract

BACKGROUND: Motor neurone disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common, and frontotemporal dementia (FTD) occur on a spectrum, overlapping clinically, pathologically and genetically. Family members of ALS patients show an increased risk or schizophrenia, suicide, autism and alcoholism and there is a genetic correlation between schizophrenia and ALS suggesting that neuropsychiatric disorders may also occur on this spectrum. However, studies to-date capture only diagnosed neuropsychiatric disorders and focus on depression and anxiety. Furthermore, their relationship with cognitive and behaviour changes in MND is largely unexplored. Overall, this PhD thesis aimed to explore whether a shared predisposition between neuropsychiatric disorders and MND exists by examining the full spectrum of neuropsychiatric symptoms in both MND patients and their family and how they relate to cognitive and/or behaviour change.

AIMS: More specifically, this PhD thesis aimed to determine whether: 1) MND patients and their family members experienced higher clinical and subclinical symptoms of neuropsychiatric disorders compared to controls and 2) MND patient and/or family members rates and symptoms of neuropsychiatric disorders were associated with patient cognition and behaviour changes. These aims were investigated in: a) a cohort study which examined the spectrum of neuropsychiatric symptoms (clinical and subclinical) and b) a population-based study using anonymised data from the Scottish Clinical Audit Research Evaluation for MND (CARE-MND) register.

METHODS: MND patients (n=119) and their family members (n=171), and healthy controls (n=131 and 17 family members) were recruited in Scotland and Ireland. In addition, population-based controls were included from the UK Biobank (n=157,389). Clinical and subclinical symptoms of neuropsychiatric disorders at both the time of assessment and/or across the life-span were assessed using self-report questionnaires (depression, mania, anxiety, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), alcohol and drug use, psychosis, suicidal ideation and/or behaviour, autism, attention-deficit-hyperactivity disorder (ADHD), apathy and impulsivity). Patient and family history of neuropsychiatric disorders (collected using self-reported diagnosis and medical-note review) was obtain from the CARE-MND register (n=305). All patient cognition and behaviour were assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

RESULTS: Symptoms of current depression and anxiety were common in MND patients while other symptoms were generally low. In addition to higher rates of depression and anxiety, MND family members reported higher rates of anxiety across the lifespan, problematic alcohol use, self-harming behaviour and symptoms of psychosis. Some associations between neuropsychiatric symptoms and cognition and behaviour were identified such that patients with at least one family member with a mood or neurotic disorder (clinical and subclinical) had poorer cognition and increased behavioural changes, including increased odds of MND-FTD.

DISCUSSION: This study is the first to provide an in-depth examination of clinical and subclinical neuropsychiatric symptoms in MND kindreds and their associations with cognition and behaviour. Depression was common in MND and some neuropsychiatric symptoms appeared to be elevated in their family members. Neuropsychiatric symptoms, particularly in MND family members, showed some association with patient’s cognition and behaviour. These findings provide further evidence that neuropsychiatric disorders may contribute to the MND-FTD spectrum, however this may be specific to certain categories of neuropsychiatric disorders.