Brain reserve and physical disability in secondary progressive multiple sclerosis.

Background: The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS. Methods: We conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression. Results: 383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0-6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW. Conclusion: Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS. Trail registration number: NCT01910259.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

Perceptions of digital technology use for monitoring health in people living with neurological disorders.

BACKGROUND: Digital technology offers individuals the opportunity to monitor their symptoms. Information gathered from apps, devices, and web platforms may be used to direct clinical care and to support research. AIM: Using this survey, we aim to explore the views of people attending the Anne Rowling Regenerative Neurology Clinic (ARRNC) and their relatives/caregivers regarding the use of digital health technologies to monitor health. METHOD: People attending the ARRNC were invited to complete a structured 18-item questionnaire evaluating their experience and attitudes to using technology for monitoring health. People with neurodegenerative disease (pwND) and their caregivers completed a mix of closed and open-ended questions. RESULTS: 249 people responded, 51 relatives/caregivers and 198 pwND. 67.1% (n= 167) of respondents do not use technology for monitoring their health, but 98.2% (n = 164) of these are interested in their future use. 29.7% (n = 74) respondents currently use a smartphone for health monitoring, 20.9% (n = 52) use a wearable device, and 13.3% (n = 33) use a tablet. 79.3% (n = 65) of users use their technology for monitoring physical activity, 37.8% (n = 31) use it for assisting with self-management, and 41.5% (n = 34) use it for tracking sleep. Factors which would encourage use of technology are ease of access to devices and ability to monitor health. Respondents reported data security concerns and difficulty using technology as potential barriers. CONCLUSION: People attending a neurology clinic, and their relatives/caregivers, support the use of digital technologies as an adjunct to routine care. There is a need for coordinated digital strategies for development and delivery of validated measures.

Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease.

Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Investigating Domain-Specific Cognitive Impairment Among Patients With Multiple Sclerosis Using Touchscreen Cognitive Testing in Routine Clinical Care.

Cognitive dysfunction is present in up to 70% of patients with multiple sclerosis (MS) and has been reported at all stages and in all subtypes of the disease. These deficits have been reported across a variety of cognitive domains, but are generally under-recognized and incompletely evaluated in routine clinical practice. The aim of this study was to investigate the spectrum of cognitive impairment in patients with MS presenting to a specialist MS clinic using the Cambridge Neuropsychological Test Automated Battery (CANTAB), administered on a touchscreen platform. Ninety MS patients completed computerized CANTAB tasks assessing working memory, executive function, processing speed, attention, and episodic memory. Scores were adjusted for age, sex, and level of education and classified as normal or impaired based on comparison with a large normative data pool. We also investigated the impact of clinical and demographic variables which could potentially influence cognitive performance including patient educational level (a proxy for cognitive reserve), disease status (duration, course, and severity of MS), and depression. CANTAB testing detected cognitive impairment in 40 patients (44% of the sample). The most frequently impaired domain was executive function, present in 55% of cognitively impaired individuals. Disease duration and severity were significantly associated with performance across various cognitive domains. Patients with depressive symptoms were also more likely to exhibit impaired processing speed. Results from this study confirm that cognitive impairment is common and occurs across a range of domains among MS patients attending routine clinical visits. CANTAB tasks provide a sensitive and practical approach to cognitive testing in MS patients as part of a holistic patient assessment.

A pilot study to assess if urine specific gravity and urine colour charts are useful indicators of dehydration in acute stroke patients.

AIM: The purpose of this pilot study was to examine whether urine specific gravity and urine colour could provide an early warning of dehydration in stroke patients compared with standard blood indicators of hydration status. BACKGROUND: Dehydration after stroke has been associated with increased blood viscosity, venous thrombo-embolism and stroke mortality at 3-months. Earlier identification of dehydration might allow us to intervene to prevent significant dehydration developing or reduce its duration to improve patient outcomes. METHODS: We recruited 20 stroke patients in 2007 and measured their urine specific gravity with urine test strips, a refractometer, and urine colour of specimens taken daily on 10 consecutive days and compared with the routine blood urea:creatinine ratios over the same period to look for trends and relationships over time. The agreement between the refractometer, test strips and urine colour were expressed as a percentage with 95% confidence intervals. RESULTS: Nine (45%) of the 20 stroke patients had clinical signs of dehydration and had a significantly higher admission median urea:creatinine ratio (P = 0·02, Mann-Whitney U-test). There were no obvious relationships between urine specific gravity and urine colour with the urea:creatinine ratio. Of the 174 urine samples collected, the refractometer agreed with 70/174 (40%) urine test strip urine specific gravity and 117/174 (67%) urine colour measurements. CONCLUSIONS: Our results do not support the use of the urine test strip urine specific gravity as an early indicator of dehydration. Further research is required to develop a practical tool for the early detection of dehydration in stroke patients.