Understanding mechanisms related to psychosis in Motor Neurone Disease

Abstract

Psychosis is a challenging feature of the syndromes of motor neurone disease (MND), frontotemporal dementia (FTD) and their overlap (FTD-MND). Clinically evident psychosis is not common, except in those with C9orf72+ expansions. However, subthreshold psychosis or pre-psychosis processes are common and provide the opportunity to study the mechanisms of psychosis in MND and FTD-MND.

My aim was to identify the prevalence and the cognitive and neural correlates of psychosis, and related processes, in MND. I used a tiered cohort study approach. Tier 1 introduced screening as standard in a regional MND clinic (N=111) using the Edinburgh Cognitive and Behavioural ALS Screen and Cambridge Behavioural Inventory-Revised (CBI-R). In Tier 2, 60 patients and 30 controls underwent neuropsychological assessment, including (i) evidence-based decision-making, to quantify jumping to conclusions (JTC), (ii) attentional control and associative learning, (iii) perceptual inference, and (iv) psychiatric screening with Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BRPS), and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Tier 3 included magnetic resonance imaging of 30 patients and 20 controls.

Carer reports in Tier 1 indicated that 10% of patients exhibited features suggestive of psychosis and 40% exhibited behavioural change. In Tier 2, many patients manifested abnormal behaviours (CBI-R 41%; NPI showed 19%; BPRS 24%), with 12-16% showing psychosis-specific symptoms (CBI-R and NPI psychosis index scores). In the jumping to conclusions task, patients made decisions based on less evidence than controls and were insensitive to negative feedback. Carer ratings of patient behaviour correlated with performance on the jumping to conclusions task when decisions were rewarded or costs fixed. Attentional shifting and perceptual inference were normal in MND. A principal component analysis (PCA) of questionnaires revealed two component scores, reflecting distinct patients’ and carers’ perspectives.

The imaging analyses focused on the correlates of jumping to conclusions and insensitivity to negative feedback, as a potential risk profile for psychosis, with exploratory analyses of the correlates of the CBI-R psychosis index, and carers’ ratings of behaviour from the PCA. Using a Freesurfer regions-of-interest approach, grey matter volume correlated inversely with CBI-R psychosis index in the caudate, amygdala, cingulate and hippocampus. Using tract-based spatial statistics, increased mean diffusivity (MD) of diffusion weighted imaging correlated with the CBI-R psychosis responses in inferior longitudinal and uncinate fasciculi. Cost sensitivity in the JTC task correlated with cingulate and cerebellar grey matter volumes. White matter correlates of cost sensitivity included reduced FA with increasing cost sensitivity in white matter connecting the inferior frontal lobe in controls and patients.

Although overt psychosis is uncommon in MND, many patients displayed abnormal behaviour or cognitive symptoms, including suboptimal reasoning biases and inferential impulsivity. Degeneration of cerebellar, cingulate and striatal grey matter, and adjacent major white matter tracts, may underlie these cognitive impairments and together represent a vulnerability to develop psychosis. Compromised reasoning and inference have implications for clinical management, including decisions around treatment options and management of well-being in MND.