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Objective assessment of the neuropsychiatric symptoms in Huntington's Disease

McLauchlan, Duncan 2018. Objective assessment of the neuropsychiatric symptoms in Huntington's Disease. PhD Thesis, Cardiff University.
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Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder, caused by a repeat expansion in the HTT gene, carried on chromosome 4. HD causes motor symptoms (chorea, dystonia and an eye movement disorder), cognitive decline (impairments in social cognition, memory and executive function) and neuropsychiatric disorders. The commonest neuropsychiatric problems are apathy, depression and irritable behaviour, whilst disinhibited behaviour and perseveration are also frequently reported later in the disease course. The neuropsychiatric symptoms are common in HD and have signifcant, deleterious effects on quality of life and function, yet the underlying cognitive processes and neurobiology remain unclear. This study addresses the gap in knowledge: we have used a battery of established and novel tasks to delineate the specific cognitive processes leading to neuropsychiatric disorders in HD. 53 patients, with a confirmed genetic test for HD were recruited from the South Wales HD service, and 26 controls were recruited from both gene negative family members and local advertising. Subjects completed gold standard measures of europsychiatric symptoms in HD: Problem Behaviours Assessment- short form (PBA), Apathy Evaluation Scale (AES), Behavioural Inhibition Scale Behavioural Activation Scale (BISBAS), Urgency, Premeditation (lack of), Perseverance(lack of), Sensation Seeking, Positive Urgency, Impulsive Behaviour Scale (UPPSP), Barratt Impulsiveness Scale (BIS), Mini International Neuropsychiatric Interview (MINI); in addition to a battery of novel and established tasks measuring depressive cognition, planning, learning, reward value, reward-effort calculation, option generation, susceptibility to provocation, reactive aggression, delay discounting and response inhibition. We compared performance between groups and then used regression models, generalised linear models and generalised linear mixed models to study the cognitive processes underlying the neuropsychiatric symptoms in HD. We found that apathy in HD is predicted by a selective deficit in learning from aversive stimuli, in addition to impairments in executive dysfunction and option generation, whilst reward value and reward-effort calculations do not make major contributions to apathy in HD. Impulsivity in HD is associated with impairment on tasks measuring inhibition of pre-potent responses and cognitive impulsivity, with relative preservation of delay discounting and risk-taking. HD participants also had higher scores on some questionnaire measures of impulsive behaviour: the UPPS P Negative Urgency scale, Barratt Impulsiveness scale and the inhibitory subscale of the BISBAS. Irritability in HD is related to enhanced negative anticipatory emotional reactivity, but v not with measures of impulsive behaviour or reactive aggression. The data on mood disorders suggests that suicidal ideation is associated with executive dysfunction and over-estimate of performance. Reward and effort measures did not significantly contribute to mood symptoms in HD. This study has demonstrated an entirely novel cognitive mechanism leading to apathetic behaviour, and the finding of relatively preserved reward and effort in apathy and mood disorders is also novel. We have replicated previous findings of an executive function deficit leading to apathy. The data on impulsivity with regard to response inhibition and delay discounting is consistent with the known pattern of striatal degeneration in HD. Irritability in HD is not related to impulsive or reactive aggression, but to measures of negative mood induction. The data do not support anhedonia or negative cognitive bias as contributory mechanisms to mood disorders in HD, but executive dysfunction and over-estimate of performance are related to suicidal behaviour. This work demonstrates that the cognitive processes leading to neuropsychiatric symptoms in HD are consistent with the known degeneration in cortico-striatal circuits. The selective preferential degeneration in the indirect compared with the direct pathway is consistent with impaired learning from punishment, but not reward which we found in association with apathy in HD, whilst the dorso-ventral progression of striatal degeneration is consistent with the finding of preserved delay discounting, but impaired pre-potent response inhibition.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 3 May 2019
Last Modified: 03 May 2019 09:49
URI: http://orca.cf.ac.uk/id/eprint/122117

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