Exploring the beneficial effects of cardiorespiratory fitness and exercise on cerebrovascular health in Huntington’s Disease: a cross-species approach

This thesis explores the benefits of physical activity on cerebrovascular health in healthy subjects and in Huntington’s Disease (HD), where cerebrovascular health is thought to be jeopardised. A cross-species approach was employed, to inform the relevance of MRI findings in humans, using histology and pre-clinical imaging. In Chapter 2, measurement of cerebrovascular markers using arterial spin labelling (ASL) MRI showed that arterial compliance and resting cerebral blood flow was lower in subjects with higher cardiorespiratory fitness, whilst differences in cerebrovascular reactivity (CVR) to a breath-hold task were not statistically significant. Measurements of vessel density in Chapter 3 showed that running mice had greater vessel density than non-running mice following a 6-week voluntary wheel running intervention, which may be attributed to a process of angiogenesis. Methods developed in healthy subjects were subsequently applied to investigate the cerebrovascular benefits of exercise in HD. In Chapter 4, pre-/early- symptomatic patients with HD were assessed for subtle differences in cerebrovascular health and whether this varied with cardiorespiratory fitness. Disease-related differences were observed in cognition, and ASL measures including resting CBF and CVR, but no clear relationship with fitness was observed. Preclinical imaging was used in Chapter 5 to measure longitudinal changes in resting CBF and CVR in a transgenic Q175 mouse model of HD, prior to behavioural deficits (preHD). Neither CBF or vessel density differed between preHD animals and controls, and did not appear altered by voluntary running

Glutamate, N-acetyl aspartate and psychotic symptoms in chronic ketamine users

Rationale: Ketamine, a non-competitive NMDA receptor antagonist, induces acute effects resembling the positive, negative and cognitive symptoms of schizophrenia. Chronic use has been suggested to lead to persistent schizophrenia-like neurobiological changes. Objectives: This study aims to test the hypothesis that chronic ketamine users have changes in brain neurochemistry and increased subthreshold psychotic symptoms compared to matched poly-drug users. Methods: Fifteen ketamine users and 13 poly-drug users were included in the study. Psychopathology was assessed using the Comprehensive Assessment of At-Risk Mental State. Creatine-scaled glutamate (Glu/Cr), glutamate + glutamine (Glu + Gln/Cr) and N-acetyl aspartate (NAA/Cr) were measured in three brain regions—anterior cingulate, left thalamus and left medial temporal cortex using proton magnetic resonance spectroscopy. Results: Chronic ketamine users had higher levels of subthreshold psychotic symptoms (p < 0.005, Cohen’s d = 1.48) and lower thalamic NAA/Cr (p < 0.01, d = 1.17) compared to non-users. There were no differences in medial temporal cortex or anterior cingulate NAA/Cr or in Glu/Cr or Glu + Gln/Cr in any brain region between the two groups. In chronic ketamine users, CAARMS severity of abnormal perceptions was directly correlated with anterior cingulate Glu/Cr (p < 0.05, r = 0.61—uncorrected), but NAA/Cr was not related to any measures of psychopathology. Conclusions: The finding of lower thalamic NAA/Cr in chronic ketamine users may be secondary to the effects of ketamine use compared to other drugs of abuse and resembles previous reports in individuals at genetic or clinical risk of schizophrenia

A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD)

Background Huntington’s disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD. Methods Thirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study. Results 26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion. Conclusions The CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD

Exploring computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD): protocol for a randomised feasibility study

Background Cognitive impairments, especially deficits of executive function, have been well documented as a core and early feature in Huntington’s disease (HD). Cognitive impairments represent considerable burden and can be devastating for people and families affected by HD. Computerised cognitive training interventions that focus on improving executive function present a possible non-pharmacological treatment option. We propose to determine the feasibility, acceptability, and appropriate outcome measures for use in a randomised controlled feasibility study. Methods/design Participants will be randomised into either a computerised cognitive training group or a control group. Those randomised to the training group will be asked to complete a cognitive training intervention based on the HappyNeuron Pro software tasks of executive function, for a minimum of 30 min, three times a week for the 12-week study duration. Participants in the control group will not receive computerised cognitive training but will receive a similar degree of social interaction via equivalent study and home visits. We will explore quantitative outcome measures, including measures of cognitive performance, motor function, questionnaires and semi-structured interviews, as well as magnetic resonance imaging (MRI) measures in a subset of participants. Feasibility will be determined through assessment of recruitment, retention, adherence and acceptability of the intervention. Discussion The results of this study will provide crucial guidance and information regarding the feasibility of conducting a randomised controlled study into computerised cognitive training in HD. This study is crucial for the development of larger definitive randomised controlled trials which are powered to determine efficacy and for the development of future cognitive training programmes for people affected by HD

Cardiorespiratory fitness is associated with increased middle cerebral arterial compliance and decreased cerebral blood flow in young healthy adults: a pulsed ASL MRI study

Cardiorespiratory fitness is thought to have beneficial effects on systemic vascular health, in part, by decreasing arterial stiffness. However, in the absence of non-invasive methods, it remains unknown whether this effect extends to the cerebrovasculature. The present study uses a novel pulsed arterial spin labelling (pASL) technique to explore the relationship between cardiorespiratory fitness and arterial compliance of the middle cerebral arteries (MCAC). Other markers of cerebrovascular health, including resting cerebral blood flow (CBF) and cerebrovascular reactivity to CO2 (CVRCO2) were also investigated. Eleven healthy males aged 21 ± 2 years with varying levels of cardiorespiratory fitness (maximal oxygen uptake

Natural History and Burden of Huntington's Disease in the UK: A Population-Based Cohort Study

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population. METHODS: This cohort study utilised data from general practitioner (GP) medical records to estimate the prevalence and incidence of HD between Jan 2000 and Dec 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis. RESULTS: Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis. CONCLUSIONS: This study demonstrates the significant and progressive clinical burden in individuals up to 18 years after first recorded diagnosis

Using 3T MRI to explore myelin break-down in pre-symptomatic huntington’s disease

Background Aberrant myelination may contribute or even precede neurodegeneration. White matter (WM) abnormalities have been widely reported in Huntington’s disease (HD), and are detectable in the pre-manifest stage, prior to symptom onset, using diffusion-weighted (DW) MRI. However, standard DW MRI metrics (e.g. fractional anisotropy (FA)) are non-specific indices of underlying biological changes. Quantitative magnetization transfer (qMT) imaging is a more sensitive measure of myelin content in white matter, as indexed by the macromolecular proton fraction (MPF). MPF is lower in early-stage HD and is related to WM abnormalities measured with DW MRI (Bourbon-Teles et al, 2017). Aims To assess whether myelin breakdown can be detected in pre-manifest HD gene carriers using qMT and DW MRI. Methods/techniques MRI was performed on a Siemens PRISMA 3T MRI Scanner at Cardiff University Brain Research Imaging Centre (CUBRIC). Eight pre-HD participants (Disease burden score; 229–299), and eight matched controls were recruited and scanned. A 3D MT-weighted fast spoiled gradient recalled-echo (SPGR) sequence was used to obtain qMT data for estimation of myelin. DW MRI was acquired and manual tractography of the cortico-spinal tract (CST), corpus callosum (CC), anterior thalamic radiation (ATR) and SMA-putamen was performed in Explore-DTI v 4.8.3. Results/outcome We will present a group-wise comparison between MPF and FA, radial and axial diffusivity (RD and AD) across all WM tracts, in line with the methods of (Bourbon-Teles et al, 2017). Planned analysis to assess group differences in diffusion metrics will be used to infer microstructural differences in WM properties including myelin content, white matter integrity and axonal damage in pre-manifest participants. Conclusions This is the first study to apply qMT MRI to measure myelin content in a pre-manifest cohort. Reduced myelination in this cohort could help inform the development of new drug treatments that aim to tackle HD in the earliest stages. Further analysis will combine this with volumetric data, to probe the early relationship between myelination and grey matter atrophy

Comorbidities and clinical outcomes in adult- and juvenile-onset Huntington’s disease : a study of linked Swedish National Registries (2002–2019)

Background: Huntington’s disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families. Objective: To describe the clinical burden and natural history of HD. Methods: This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations. Results: The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive–compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis. Conclusions: This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD