Persistent high levels of perceived fatigue are not associated with hypermetabolism in patients with amyotrophic lateral sclerosis.Amyotrophic lateral sclerosis & frontotemporal degeneration • March 01, 2025
Lauren Buckett, Cory Holdom, Stephanie Howe, Pamela Mccombe, Robert Henderson, Ammar Al Chalabi, Frederik Steyn, Shyuan 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.
Assessment of the "MND-Prism" smartphone application as a tool for self-management.Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration • June 06, 2025
Sally Neville, Laura Ziser, Anjali Henders, Jane Milne, Shyuan Ngo, Rebecca Packer, Frederik Steyn
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.
An Annotated Multi-Site and Multi-Contrast Magnetic Resonance Imaging Dataset for the study of the Human Tongue Musculature.Brain Communications • November 08, 2024
Ruben P Van Eijk, Frederik Steyn, Mark Janse Van Mantgem, Angela Schmidt, Myrte Meyjes, Sally Allen, Dara Daygon, Jean-philippe Loeffler, Ammar Al Chalabi, Leonard Van Den Berg, Robert Henderson, Shyuan Ngo
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.
Appetite loss in patients with motor neuron disease: impact on weight loss and neural correlates of visual food cues.Brain Communications • November 05, 2024
Jeryn Chang, Thomas Shaw, Pamela Mccombe, Robert Henderson, Diana Lucia, Christine Guo, Jinglei Lv, Kelly Garner, Saskia Bollmann, Shyuan Ngo, Frederik Steyn
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.
Identification of passive wrist-worn accelerometry outcomes for improved disease monitoring and trial design in motor neuron disease.EBioMedicine • Background: Motor neuron disease (MND) leads to progressive functional decline, making reliable measures of disease progression critical for patient care and clinical trials. Current clinical outcome measures lack the ability to continuously and objectively track functional decline in daily life of patients with MND. This study assessed and validated wrist-worn accelerometry outcome measures for continuous monitoring in MND, with the potential to refine clinical trial outcomes.
Methods: This longitudinal study included 95 patients with MND who wore an ActiGraph GT9X Link device on their non-dominant wrist for 8 days, with follow-up every 3-4 months. Accelerometer data were processed using ActiLife and GGIR. Joint models were used to simultaneously investigate the longitudinal change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and accelerometer-derived outcomes alongside their relationship with overall survival. Sample size estimates for clinical trials were generated using both accelerometer- and ALSFRS-R-based outcomes, and principal component analysis (PCA) explored outcome relationships.
Results: Accelerometer outcomes showed a slower rate of decline (-0.03 to -0.07 SD/month) compared to ALSFRS-R (-0.10 SD/month) and had stronger correlations with ALSFRS-R motor subdomains (partial r: 0.60-0.73). PCA revealed that longitudinal measures of accelerometry were distinct from the ALSFRS-R, highlighting the complementary nature of these measures. Peak 6-min activity predicted smaller clinical trial sample sizes for studies over 12 months. Accelerometer-derived outcomes were not significantly associated with survival.
Conclusions: Wrist-worn accelerometry offers a practical solution for continuous monitoring in MND, complementing ALSFRS-R. Measures of peak performance, and specifically peak 6-min activity shows promise, potentially reducing sample sizes and improving disease tracking over longer duration studies. Further refinement and validation are needed to adopt actigraphy measures as clinical assessment outcomes. Background: This study was supported by Wesley Medical Research (2016-32), the Honda Foundation, Motor Neurone Disease Research Australia, and FightMND. CJH received a Higher Degree Research Scholarship from UQ. STN received support from the Scott Sullivan Fellowship (MND and Me Foundation/RBWH Foundation), a FightMND Mid-Career Fellowship, and the AIBN.
Cory Holdom, Rakesh Pilkar, Christine Guo, Ruben P A Eijk, Nadia Sethi, Robert Henderson, Shyuan Ngo, Frederik Steyn
