Ralf Reilmann

Introduction:Motor symptoms develop to varying degrees in neurodegenerative disorders. This study investigated differences in motor symptoms and associations between motor symptoms, cognition, and computerized MRI brain atrophy patterns, in patients with cognitive decline due to neurodegenerative and cerebrovascular disorders. Methods:Patients were prospectively included and underwent cognitive testing, MRI, clinical motor evaluation using the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and quantitative motor (Q-Motor) assessment, including grip lift, pronation/supination, and finger-tapping tasks. Statistical analyses included analysis of variance and covariance, and multiple linear regression.Results:We included 131 participants (Alzheimer's disease (AD, n = 49), cerebrovascular disease, including mixed cerebrovascular disease and AD (Vascular, n = 17), Parkinson's spectrum disorders (PSD, n = 12), subjective cognitive decline (SCD, n = 38), and healthy controls (HC, n = 15)). Compared with SCD and HC, the Vascular and PSD groups showed significant differences in motor symptoms, with predominantly poorer performances in both Q-Motor and UPDRS. No significant differences were found for AD compared to all other groups. More pronounced motor symptoms in the grip lift and pronation/supination tasks were associated with lower scores on the Mini-Mental State Examination and Addenbrooke’s Cognitive Examination, and with a larger volume of white matter hyperintensities. Conclusion:Our findings suggest that clinical motor scales, e.g., UPDRS, are relevant in detecting motor symptoms in neurodegenerative and cerebrovascular disorders in general, not exclusively PSD. Q-Motor may have limited value for differential diagnosis, but appears to be indicative of disease stage and global cognition.

: This analysis evaluates the feasibility and psychometric properties of daily digital cognitive assessments (DCAs) delivered on smartphones using data from the large, international Identifying Digital Endpoints to Assess FAtigue, Sleep and acTivities of daily living in Neurodegenerative disorders and Immune-mediated inflammatory diseases (IDEA-FAST) study. The data we analyse were collected from patients with neurodegenerative diseases (NDDs) and immune-mediated inflammatory diseases (IMIDs), and healthy controls (a subset who participated in all phases of the study, total N=1005) in their own homes. These data were obtained alongside data from other devices that monitored physiology, kinematics, and sleep quality. Following a baseline visit, participants were remotely monitored via three scheduled daily sessions for 6-7 days in each of 4 active assessment phases (APs). APs were separated by 6-week intervals. Daily schedules comprised a morning psychomotor vigilance task (PVT) with eDiary, afternoon session (eDiary only), and an evening digit symbol substitution task (DSST) with eDiary. We evaluated session coverage using logistic mixed effects, test-retest reliability using ICCs, disease impacts on performance using linear mixed effect ANCOVA, and familiarisation using linear mixed effects. Overall coverage was 66.7% for the PVT and 76.2% for the DSST, with no significant differences between the healthy volunteers and disease cohorts. Coverage varied significantly by time-of-day (Evening > Morning > Afternoon), and improved with age, with an interaction revealing session time-of-day affected older participants less, all p < .001. Coverage was highest in AP 1 and reduced in subsequent APs. AP-day effects on coverage interacted significantly with AP, with a modest decline over AP 1, and the pattern reversed in APs 2-4. Baseline reliability was good (> .70) for both PVT mean reaction time and DSST total correct across all cohorts, and the movement-based measure from the DSST ranged [.54, .82], with lower values in the Parkinson’s Disease and Primary Sjögren’s Syndrome cohorts. Both tasks showed significant cohort effects, with performance in IMID cohorts intermediate between healthy controls and NDD. Longitudinal analysis revealed significant familiarisation effects in DSST. This was greatest in healthy controls, with significant attenuation of these effects in disease cohorts. No effect of familiarisation was seen in the PVT. Collectively, these results support the usefulness of at-home cognitive assessment on smartphones. Brief measures of cognition can be captured remotely in disease as well as controls with good adherence and sensitivity to distinguish known patient groups from healthy controls.

Traditional clinical assessments in Parkinson's disease (PD) trials are limited by subjectivity and inter‐rater variability. Digital health technologies (DHT) offer an objective continuous assessment of motor symptoms and are increasingly used in clinical research. This review evaluated the role of DHTs as outcome tools in pharmacological trials for PD. A systematic search of MEDLINE and Embase was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines, covering studies up to August 31, 2025. Eligible studies included randomized controlled trials, open‐label or crossover designs, and observational studies using DHTs to assess motor outcome variables in PD. Studies focusing only on technology development or with fewer than 10 participants were excluded. Data extracted included study design, DHT type, assessment setting, and motor parameters measured. Study quality was appraised using an eight‐criterion tool, and level of evidence was rated using the Oxford Centre for Evidence‐Based Medicine framework. A total of 42 studies were included, covering 26 distinct DHTs. These comprised 11 wearable sensors and 15 nonwearable systems such as motion capture platforms and force‐sensing assessments. DHTs were used to measure bradykinesia, tremor, gait, balance, and nocturnal motor symptoms in both supervised and unsupervised settings. Fifteen studies were rated as high quality, 14 moderate, and 13 low. Among currently available tools, only Opal reached the threshold of Level 1a evidence. Other validated tools included the Parkinson's Kinetigraph, Actiwatch, and Roche PD Mobile Application (Level 1b). DHTs offer valuable tools for objective assessment in PD trials, though broader adoption requires greater standardization and regulatory alignment. © 2025 International Parkinson and Movement Disorder Society.

Background: Huntington's disease is a rare, progressive, neurodegenerative disease. Capturing symptomatic progression and treatment effects reliably in clinical therapeutic trials has shown to be a challenging task, facing the problem of small cohorts and a variable phenotype. Hence, robust and sensitive outcome measures are needed, to assess efficacy and safety of novel therapies in clinical studies with small cohorts. Objective: Objectives of this study were to assess feasibility, discriminative potential, and correlation to clinical and imaging endpoints of the Q-Motor isometric force matching task with visual feedback. Furthermore, a statistical comparison with the Q-Motor grasping and lifting task should be assessed. Methods: 220 huntingtin gene expansion carriers (HGEC) and 110 non-huntingtin gene expansion carrier (Non-HGEC) participants of the observational TRACK-HD study completed the Q-Motor force matching assessment, along with a standard battery of clinical tests (UHDRS) and MRI assessments. During the Q-Motor force matching assessments, patients were reproducing a target force in precision grip with help of visual feedback. Q-Motor utilizes a highly sensitive force transducer to record force feedback. HGEC participants were categorized into four groups by a CAG- and age-based survival score. Results: Q-Motor force matching allowed for very good discrimination between HGEC and Non-HGEC participant groups (p < 0.001 for all but least affected HGEC group) and between different HGEC groups (all p < 0.05). Strong correlations with UHDRS scores (TMS = −0.708, TFC = −0.638), CAG-Age product scores (Survival Score = 0.626) and imaging outcomes (caudate volume = −0.609, striatum volume = −0.624) were observed. A statistical difference between correlation strength of Q-Motor force matching and Q-Motor grasping and lifting tasks could not be observed. Conclusions: Cross-sectional analysis of Q-Motor force matching showed promising results, outperforming clinical rating scales in sensitivity. Further efforts are required to assess longitudinal robustness of the task, and to further explore its potential of capturing cognitive effects by increasing cognitive load during the task.

Huntington’s disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington’s Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was −0.18 (95% confidence interval −0.49 to 0.14; P = 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was −0.11 (95% confidence interval −0.40 to 0.18; P = 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier: NCT04556656 .

Background: Digital‐motor outcomes promise better responsiveness than clinician‐reported outcomes in ataxia trials. However, their patient meaningfulness and sensitivity to change remain to be demonstrated, particularly in the upper limb domain. Objectives: Validation of quantitative motor (Q‐Motor) assessment for upper limb ataxia against patient‐reported outcomes and regarding sensitivity to both longitudinal and treatment‐induced change, the latter in n‐of‐1 treatment settings. Methods: Single‐center longitudinal assessment of finger tapping, diadochokinesia, grip‐lift, spiral drawing, and target reaching in (1) 36 cross‐genotype ataxia patients and 20 controls, validating digital measures for correlations with patient‐reported outcome measure (PROM)‐ataxia, 2‐weeks test–retest reliability, and sensitivity to change within a trial‐relevant 1‐year follow‐up, anchored in Patient Global Impression of Change (PGI‐C); and (2) two patients with spinocerebellar ataxia type 27B (SCA27B) on versus off treatment with 4‐aminopyridine. Results: Twenty‐four digital measures correlated with the PROM‐ataxia upper‐limb composite (|ρ| = 0.4–0.7) and had excellent test–retest reliability (ICC = 0.91–0.99). Correlations to individual PROM‐ataxia items were specific for functional impairment the respective measure was hypothesized to capture. Speed of finger tapping and diadochokinesia, and smoothness of target reaching (spectral arc length of movement in three dimensions [SPARC _3D ]) captured 1‐year progression in ataxia patients (| r _prb | = 0.38–0.51), and specifically in patients with worsening PGI‐C. Estimated sample sizes to detect longitudinal change were lower for digital than clinical outcomes (SPARC _3D : n = 33, Scale for the Assessment and Rating of Ataxia (SARA): n = 79, nine‐hole peg‐test: n = 214). Speed of diadochokinesia, stability of grip‐lift, and variability of target reaching captured treatment responses to 4‐aminopyridine in SCA27B, exceeding minimal detectable and minimal important change. Conclusion: Digital upper limb measures capture patient‐meaningful 1‐year longitudinal and treatment‐induced change, and are therefore promising outcomes for upcoming ataxia trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Fatigue is a prevalent and debilitating symptom in many chronic conditions, including immune-mediated inflammatory diseases (IMIDs) and neurodegenerative diseases (NDDs). Fatigue often fluctuates significantly within and between days, yet traditional patient-reported outcomes (PROs) typically rely on recall periods of a week or more, potentially missing these short-term variations. The development of digital tools, such as electronic diaries (eDiaries), offers a unique opportunity to collect granular, real-time data. However, the feasibility, adherence, and comparability of eDiary-based assessments to established PROs require further investigation. Objective: This study aimed to evaluate the feasibility and acceptability of using a high-frequency eDiary to capture intraday variability in fatigue and to compare eDiary data with scores obtained from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), a validated weekly recall PRO. Methods: Data were collected from 159 participants enrolled in the IDEA-FAST (Identifying Digital Endpoints to Assess Fatigue, Sleep and Activities in Daily Living in Neurodegenerative Disorders and Immune-Mediated Inflammatory Diseases) feasibility study; a 4-week prospective observational study conducted at 4 European centers. Participants included individuals with NDDs (n=39), IMIDs (n=78), and healthy volunteers (n=42). Participants used an eDiary to report their physical and mental fatigue levels up to 4 times daily on a 7-point Likert scale (0=low and 6=high). Adherence was calculated as the proportion of completed eDiary entries relative to the total expected entries. Correlations between averaged eDiary scores and weekly FACIT-F scores were analyzed. Results: Adherence to the eDiary protocol was 5505/8880 (61.99%) overall, varying by cohort, with the highest adherence (1117/1200, 93.07%) observed in the primary Sjögren syndrome cohort and the lowest adherence in the Parkinson disease (410/960, 42.7%) and Huntington disease (320/720, 44.4%) cohorts. The average adherence was 430/1680 (43.45%) in the NDD cohorts and 3367/4560 (73.84%) in the IMID cohorts. Fatigue levels showed clear diurnal variation, with significantly higher fatigue reported in the evening compared to the morning (P<.001). A moderate correlation (Spearman=0.46, P<.001) was observed between eDiary fatigue scores and FACIT-F scores, with stronger cohort-specific associations for certain FACIT-F items. These results indicate that eDiaries provide complementary insights to weekly PROs by capturing intraday fluctuations in fatigue. Conclusions: This study demonstrates the feasibility, acceptability, and validity of using high-frequency eDiaries to assess fatigue in chronic conditions. By effectively detecting intra- and interday fatigue variations, eDiaries complement traditional PROs such as FACIT-F, offering a more nuanced understanding of fatigue patterns. Future research should explore optimized eDiary protocols to balance participant burden with data granularity.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Mobile health apps are useful tools for research and disease management. However, implementation of mHealth apps is lacking in many areas. While mHealth apps offer various advantages to researchers and patients, their effectiveness depends on its actual use by the intended population. Barriers to the adoption of mHealth apps often stem from human factors such as usability or technology acceptance. Objective: This study explores user perceptions of two mHealth apps in the setting of an observational technology evaluation study with the goal to investigate technology acceptance as a barrier to the implementation of mHealth apps in research. Methods: Patients with chronic diseases as well as healthy participants used a symptom and activity e-diary (SAD) and a Cognitive Test App (CTA) over the course of four weeks within the IDEA-FAST Feasibility study. Thereafter, 61 qualitative interviews were conducted, recorded and transcribed. A qualitative content analysis using the Unified Theory of Acceptance and Use of Technology (UTAUT) was performed. Results: As the apps did not directly impact the participants’ health, motivation and adherence to schedule were issues with actual use. Some users perceived the SAD as a burden, while others enjoyed tracking their symptoms. The three tests of the CTA differed in popularity. While one test was described as repetitive, another was perceived as too hard and frustrated users. An important aspect of motivation for participants was feedback on their data and performance. While using the apps was quick, the fixed periods of use were more problematic, as they could lead to conflicts with a user’s daily life. Participants preferred using their own phone. The support provided by written instructions and the study team was sufficient for most participants. Participants stressed the importance of good relations with the study team. Conclusions: In choosing suitable applications, one size will certainly not fit all. For medical research, pre-testing of all materials with the potential users is of utmost importance. When an app seemingly does not provide direct impact on the users’ health, other factors can motivate usage, e.g. feedback, gamification, adjustable functions, applicability on all smartphone operating systems and good relations to the study team.

BACKGROUND Mobile health apps are useful tools for research and disease management. However, implementation of mHealth apps is lacking in many areas. While mHealth apps offer various advantages to researchers and patients, their effectiveness depends on its actual use by the intended population. Barriers to the adoption of mHealth apps often stem from human factors such as usability or technology acceptance. OBJECTIVE This study explores user perceptions of two mHealth apps in the setting of an observational technology evaluation study with the goal to investigate technology acceptance as a barrier to the implementation of mHealth apps in research. METHODS Patients with chronic diseases as well as healthy participants used a symptom and activity e-diary (SAD) and a Cognitive Test App (CTA) over the course of four weeks within the IDEA-FAST Feasibility study. Thereafter, 61 qualitative interviews were conducted, recorded and transcribed. A qualitative content analysis using the Unified Theory of Acceptance and Use of Technology (UTAUT) was performed. RESULTS As the apps did not directly impact the participants’ health, motivation and adherence to schedule were issues with actual use. Some users perceived the SAD as a burden, while others enjoyed tracking their symptoms. The three tests of the CTA differed in popularity. While one test was described as repetitive, another was perceived as too hard and frustrated users. An important aspect of motivation for participants was feedback on their data and performance. While using the apps was quick, the fixed periods of use were more problematic, as they could lead to conflicts with a user’s daily life. Participants preferred using their own phone. The support provided by written instructions and the study team was sufficient for most participants. Participants stressed the importance of good relations with the study team. CONCLUSIONS In choosing suitable applications, one size will certainly not fit all. For medical research, pre-testing of all materials with the potential users is of utmost importance. When an app seemingly does not provide direct impact on the users’ health, other factors can motivate usage, e.g. feedback, gamification, adjustable functions, applicability on all smartphone operating systems and good relations to the study team.

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved.