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The Use of Digital Devices to Monitor Physical Behavior in Motor Neuron Disease: Systematic Review
Background Motor neuron disease (MND) is a progressive and incurable neurodegenerative disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the primary clinical tool for assessing disease severity and progression in MND. However, despite its widespread use, it does not adequately capture the extent of physical function decline. There is an urgent need for sensitive measures of disease progression that can be used to robustly evaluate new treatments. Measures of physical function derived from digital devices are beginning to be used to assess disease progression. There is value in establishing a consensus approach to standardizing the use of such devices. Objective We aimed to explore how digital devices are being used to quantify free-living physical behavior in MND. We evaluated the feasibility and assessed the implications for monitoring physical behavior for future clinical trials and clinical practice. Methods Systematic searches of 4 databases were performed in October 2023 and June 2024. Peer-reviewed English-language articles (including preprints) that examined how people living with MND used digital devices to assess their free-living physical behavior were included. Study reporting quality was assessed using a 22-item checklist (maximum possible score=44 points). Results In total, 12 articles met the inclusion criteria for data extraction. All studies were longitudinal and observational in design, but data collection, analysis, and reporting protocols varied. Quality assessment scores ranged between 19 and 40 points. Sample sizes ranged between 10 and 376 people living with MND at baseline, declining over the course of the study. Most studies used an accelerometer device worn on the wrist, chest, hip, or ankle. Participants were typically asked to continuously wear devices for 1 to 8 days at 1- to 4-month intervals, with studies running for 12 weeks to 24 months. Some studies asked participants to wear the device continuously for the full duration. Studies derived traditional end points focusing on duration, intensity, and frequency of physical activity or nontraditional end points focusing on features of an individual’s movement patterns. The correlation coefficients (r) between physical behavior end points and ALSFRS-R ranged from 0.31 to 0.78. Greater monitoring frequencies and improved end point sensitivity were shown to provide smaller sample size requirements and shorter durations for hypothetical clinical trials. People living with MND found using devices acceptable and reported a low burden. Adherence assessed in 8 (67%) studies was good, ranging from approximately 86% to 96%, with differences evident between wear locations. The perspectives of other end users and implications on clinical practice were not explored. Conclusions Remote monitoring of free-living physical behavior in MND is in its infancy but has the potential to quantify physical function. It is essential to develop a consensus statement, working toward agreed and standardized methods for data collection, analysis, and reporting.
Associations of postprandial ghrelin, liver‐expressed antimicrobial peptide 2 and leptin levels with body composition, disease progression and survival in patients with amyotrophic lateral sclerosis
AbstractBackground and purposeLoss of appetite contributes to weight loss and faster disease progression in amyotrophic lateral sclerosis (ALS). Impairment of appetite control in ALS may include altered production or action of orexigenic (i.e., ghrelin) and anorexigenic (i.e., liver‐expressed antimicrobial peptide 2 [LEAP2] and leptin) hormones. We aimed to determine if postprandial circulating ghrelin levels, LEAP2 levels, LEAP2:ghrelin molar ratio and leptin levels differ in ALS patients compared to non‐neurodegenerative disease controls, and whether they are associated with disease progression and body composition.MethodsIn this prospective natural history study, we assessed postprandial plasma levels of ghrelin, LEAP2 and leptin in patients with ALS (cases; n = 46) and controls (controls; n = 43). For cases, measures were compared to changes in body weight, body composition and clinical outcomes.ResultsPostprandial ghrelin level was decreased by 52% in cases compared to controls (p = 0.013). LEAP2:ghrelin molar ratio was increased by 249% (p = 0.009), suggesting greater ghrelin resistance. Patients with lower LEAP2:ghrelin tended to have better functional capacity at assessment, as inferred by the ALS Functional Rating Scale‐Revised (τ = −0.179, p = 0.086). Furthermore, ghrelin and LEAP2:ghrelin molar ratio correlated with diagnostic delay (ghrelin, τ = 0.223, p = 0.029; LEAP2:ghrelin, τ = −0.213, p = 0.037). Baseline ghrelin level, LEAP2 level, LEAP2:ghrelin ratio and leptin level were, however, not predictive of change in functional capacity during follow‐up. Also, patients with higher postprandial ghrelin levels (hazard ratio [HR] 1.375, p = 0.048), and lower LEAP2:ghelin ratios (HR 0.828, p = 0.051) had an increased risk of earlier death.ConclusionsReduced postprandial ghrelin levels, coupled with increased LEAP2:ghrelin molar ratios, suggests a loss of ghrelin action in patients with ALS. Given ghrelin's actions on appetite, metabolism and neuroprotection, reduced ghrelin and greater ghrelin resistance could contribute to impaired capacity to tolerate the physiological impact of disease. Comprehensive studies are needed to explain how ghrelin and LEAP2 contribute to body weight regulation and disease progression in ALS.
Use of hip- versus wrist-based actigraphy for assessing functional decline and disease progression in patients with motor neuron disease
Abstract Background Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND. Methods In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97; hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline. Results Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12; variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16). Conclusions Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.
Lower hypothalamic volume with lower body mass index is associated with shorter survival in patients with amyotrophic lateral sclerosis
AbstractBackground and purposeWeight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS.MethodsWe compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non‐neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes.ResultsLower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07).ConclusionThese observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.
Patient perspectives on digital healthcare technology in care and clinical trials for motor neuron disease: an international survey
AbstractIntroductionTo capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology.MethodsWe performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use.ResultsIn total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements; reporting concerns about the burden and distress of home-monitoring, privacy and data security.ConclusionMost patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care.
Venous creatinine as a biomarker for loss of fat‐free mass and disease progression in patients with amyotrophic lateral sclerosis
AbstractBackground and purposeTo establish the utility of venous creatinine as a biomarker to monitor loss of fat‐free mass in patients with amyotrophic lateral sclerosis (ALS).MethodsIn this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow‐up were determined in a cohort of patients with ALS from Australia (n = 69) and the Netherlands (n = 38).ResultsThe mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat‐free mass was similar between all groups (r = 0.36, p < 0.001). Within patients, fat‐free mass declined by 0.31 (95% confidence interval [CI]: 0.22–0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38–0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35–0.76, p < 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90–0.98, p = 0.007).ConclusionsVenous creatinine is decreased in ALS and declines alongside a decline in fat‐free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat‐free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat‐free mass and disease progression in ALS.
Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations.
Post-mortem studies have shown that patients dying from severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection frequently have pathological changes in their CNS, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized coronavirus disease 2019 (COVID-19) patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on MRI is inconclusive. We therefore used ultra-high field (7 T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7 T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-dimer and platelet levels), functional recovery (modified Rankin scale), depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7). In COVID-19 survivors, the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. This study contributes to understanding the long-term effects of COVID-19 and recovery. Using non-invasive ultra-high field 7 T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors.
SNR‐efficient whole‐brain pseudo‐continuous arterial spin labeling perfusion imaging at 7 T
AbstractPurposeTo optimize pseudo‐continuous arterial spin labeling (PCASL) parameters to maximize SNR efficiency for RF power constrained whole brain perfusion imaging at 7 T.MethodsWe used Bloch simulations of pulsatile laminar flow to optimize the PCASL parameters for maximum SNR efficiency, balancing labeling efficiency and total RF power. The optimization included adjusting the inter‐RF pulse spacing (TRPCASL), mean B1+ (B1+ave), slice‐selective gradient amplitude (Gmax), and mean gradient amplitude (Gave). In vivo data were acquired from six volunteers at 7 T to validate the optimized parameters. Dynamic B0‐shimming and flip angle adjustments were used to avoid needing to make the PCASL parameters robust to B0/B1+ variations.ResultsThe optimized PCASL parameters achieved a significant (3.3×) reduction in RF power while maintaining high labeling efficiency. This allowed for longer label durations and minimized deadtime, resulting in a 118% improvement in SNR efficiency in vivo compared to a previously proposed protocol. Additionally, the static tissue response was improved, reducing the required distance between labeling plane and imaging volume.ConclusionThese optimized PCASL parameters provide a robust and efficient approach for whole brain perfusion imaging at 7 T, with significant improvements in SNR efficiency and reduced specific absorption rate burden.
A survey of perioperative medicine services with a focus on provision for older surgical patients in the UK and Republic of Ireland: SNAP-3.
BACKGROUND: Perioperative medicine aims to improve care for high-risk patients, and is endorsed by national guidelines in the UK and Republic of Ireland (ROI). However, comprehensive perioperative medicine services are not yet uniformly available. This survey addressed the current state of perioperative medicine services for older surgical patients in the UK and ROI and how these services align with current national guidance. METHODS: A survey was distributed electronically to all publicly administered UK and ROI hospitals performing surgical procedures. The survey examined perioperative care against national recommendations regarding service organisation and conduct. RESULTS: Of 339 eligible hospitals, 54.9% (186/339) responded. A hospital frailty lead was appointed in 54% (101/186) of hospitals, and 9% (16/186) had a designated anaesthetist for cognitive impairment. Hospital anaesthetic services outside the theatre were focused on preoperative assessment clinics (146/172), with few reporting routine postoperative involvement (17/166). Nurse-led preoperative assessments of frailty, cognition, and delirium risk were conducted in 49.5% (90/182), 44.3% (78/176), and 13.7% (24/175) of hospitals, respectively. The Clinical Frailty Scale was used in 87.0% (147/169) of hospitals for frailty screening. The 4 'A's Test (45.7% [85/186]) and Abbreviated Mental Test (43.0% [80/186]) were the preferred cognitive assessment tools. CONCLUSIONS: The survey highlights the variation in perioperative medicine services that exist for older surgical patients despite national guidelines advocating their widespread implementation. Opportunity exists to develop interspecialty perioperative services further and promote identification of frailty, cognitive impairment, and delirium, all of which negatively impact postoperative outcomes for older surgical patients.
Comorbidities Are Associated With Unfavorable Outcome in Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Exploratory Study From the CROCTINO Cohort.
BACKGROUND: Comorbidities occur in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and double seronegative NMOSD (DN-NMOSD), potentially contributing to a less favorable disease course. OBJECTIVES: To characterize comorbidities in AQP4-NMOSD, MOGAD, and DN-NMOSD and assess their association with optic neuritis (ON) outcomes by optical coherence tomography (OCT) in AQP4-NMOSD. METHODS: Four hundred and forty-two participants from the CROCTINO cohort were evaluated for comorbidities. RESULTS: In AQP4-NMOSD patients (n = 360), 43.5% (n = 161) had comorbidities, equally divided between single and multiple. In MOGAD (n = 49), 40.8% had comorbidities, with 75% (n = 15) single and 25% (n = 5) multiple. In DN-NMOSD (n = 33), 36.4% (n = 12) had comorbidities equally split. AQP4-NMOSD patients had more multiple comorbidities (50%, n = 81/161) than MOGAD (25%, n = 5/20, p = 0.03) and more autoimmune disorders (AID) (40.4%, n = 65) than MOGAD (20%, n = 4, p = 0.09) and DN-NMOSD (none, p = 0.004). Cardiovascular comorbidities and related risk factors (CVC/RF) occurred in 34.8% (n = 56) of AQP4-NMOSD, 50% (n = 10) of MOGAD, and 33.3% (n = 4) of DN-NMOSD. Expanded Disability Status Scale was higher in MOGAD (3.0 vs. 2.0, p = 0.006) and DN-NMOSD (5.0 vs. 2.0, p = 0.008) with comorbidities. AQP4-NMOSD patients with CVC/RF had higher ON relapse rates than those with AID (1.06 ± 3.33 vs. 0.49 ± 0.98, p