Shyuan T. Ngo

Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.

Motor Neurone Disease (MND) is a progressive neurodegenerative disease requiring complex, multidisciplinary care. Digital tools, including smartphone applications, offer innovative solutions to streamline self-management and care coordination for patients and caregivers. Here we evaluate the usability and value of the MND-Prism smartphone application as a tool for addressing the self-management and organizational needs of people living with MND (plwMND). A mixed-methods approach was used to assess MND-Prism within an Australian cohort (n = 31) of plwMND, and their informal and professional carers. Quantitative data included deidentified usage statistics and Mobile Application Rating Scale (uMARS) survey results. Semi-structured interviews (n = 11) provided qualitative insights into user experiences and perspectives. Usage data highlighted varying engagement with MND-Prism functions. uMARS evaluations show above-average satisfaction across engagement, functionality, information, and esthetics, though customization and accessibility scored lower. Five themes were generated from semi-structured interviews with MND-Prism users: Purpose and value, functionality, future needs and monitoring progression, access, and information. MND-Prism shows potential as a self-management tool for MND, addressing critical organizational challenges in care. Participants identified both positive aspects and areas for improvement, particularly in accessibility, customization, and carer integration. These findings provide a foundation for further development and evaluation, ensuring that applications like MND-Prism are responsive to the diverse and evolving needs of the MND community. Future research should validate these findings in larger, more diverse populations and assess the long-term role of digital tools in care coordination and support.

Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.

Motor Neuron Disease (MND) is associated with significant non-motor symptoms, including the loss of appetite. Loss of appetite has emerged as a dominant feature of the disease that may contribute to negative energy balance, faster disease progression and earlier death. We examined the prevalence and impact of appetite loss and analysed neural correlates of visual food stimuli with prandial status and appetite in people living with MND (plwMND). 157 plwMND and 120 non-neurodegenerative controls (NND Controls) were assessed for anthropometric, metabolic, appetite and clinical measures. Of these, 35 plwMND and 23 NND Controls underwent further functional MRI assessment of fasting and post-prandial responses to visual food cues. plwMND presented with reduced appetite (P < 0.001), with loss of appetite being more prevalent in plwMND than NND controls [OR = 2.59 (95% CI: = 1.46-4.61)]. Loss of appetite was not associated with hypermetabolism; however, was associated with fat mass loss (P < 0.05). Imaging assessment revealed no overall difference in response between plwMND and NND controls when viewing non-food and food images. In contrast, we found no prandial response in the temporal pole of plwMND compared with NND controls, and decreased activity in the cerebellum relative to appetite in plwMND. Loss of appetite, not hypermetabolism, contributes to negative energy balance in MND. Alterations in the temporal pole and cerebellum could contribute to altered appetite responses in some plwMND-brain regions not widely considered in appetite control-providing additional evidence to support widespread involvement of non-motor areas in the disease.