A qualitative and quantitative exploration of sedentary behaviour, physical activity and exercise in people with multiple sclerosis

Multiple sclerosis (MS) is a chronic neurological disease affecting motor and sensory nerve function and leading to a range of symptoms. Physically, gait, balance and vision can be impaired, with fatigue and depression being common mental health symptoms. People with MS have high levels of sedentary behaviour and low levels of physical activity. Despite the well-researched benefits of exercise for the symptoms of MS, uptake and participation in exercise programmes is low, particularly in those with higher disability. This thesis investigated a number of research questions relating to activity behaviours in people with MS using both qualitative and quantitative methodologies. Qualitative studies explored the measurement of sedentary behaviour, and perspectives of people with MS and health professionals around barriers and facilitators to exercise. This provided recommendations for exercise programmes. Communication was a key aspect, which included communication to the person with MS tailored to their individual circumstances and acceptance of MS, as well as communication within the multidisciplinary team. Appropriate knowledge of health professionals about exercise for people with MS was essential as well as suitable behavioural support for exercise. This support should be individualised to the patient, depending on their stage of acceptance of the disease. Cross-sectional analyses of associations between subjective and objective assessments of behaviour, physical function, and wellbeing revealed differences, such as objective but not subjective sedentary behaviour being associated with depression. Greater self-reported but not objective physical activity was associated with higher fitness. This highlighted the need to assess activity and function both subjectively and objectively. Subsequently, the effects of a twelve-week home exercise programme which included balance, strengthening and aerobic exercise, on physical activity, sedentary behaviour, functional ability, and wellbeing were explored. The outcomes of those with higher and lower disability from their MS were compared, as well as an internet group with access to web-based resources to support their programme, and a control group without these online resources. The exercise programme achieved good self-reported adherence. However, there were no significant changes in physical activity, function, wellbeing or behavioural measures, which suggests that more intensive behavioural support might be needed to ensure that participants exercise at the right intensity. Future research could investigate the effectiveness of different ways to provide additional support to encourage exercise in people with MS

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Illustration of training target placement for O-VCT (a) symmetry, (b) adaptability, (c) & turning and T-VCT (d) symmetry, (e) adaptability & (f) turning.

<p>Illustration of training target placement for O-VCT (a) symmetry, (b) adaptability, (c) & turning and T-VCT (d) symmetry, (e) adaptability & (f) turning.</p

Secondary outcomes summary.

<p>Secondary outcomes summary.</p

CONSORT study flowchart.

<p>* Other reasons for non-completion include: complex social issues preventing participation (n = 2 TVCT, n = 2 UC), fall at home (n = 1 TVCT), new diagnosis (n = 1 TVCT), therapist decision (n = 2 OVCT), no longer eligible for rehabilitation within the NHS (n = 2 OVCT). Reasons for withdrawal of consent include: unable to attend treatment 2X/week (n = 1 TVCT, n = 1 OVCT), too fatigued after exercise (n = 1 OVCT), difficulty travelling for treatment (n = 1 TVCT), comorbid health problems (n = 1 TVCT), unknown reasons (n = 1 UC).</p

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589