Amyotrophic lateral sclerosis & frontotemporal degeneration最新文献

Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.

Objectives: To describe participant, site personnel (SP) and sponsor perspectives regarding their experiences with a decentralized clinical trial (DCT).

Methods: COURAGE-ALS was a 48-week, double-blind, randomized, phase III, hybrid DCT of reldesemtiv versus placebo for ALS. Fifty participants completed semi-structured interviews at Week ∼22; the majority provided feedback on DCT features. Subsequently, a planned interim analysis led to termination of COURAGE-ALS for futility; 486 participants were randomized and dosed. SP completed an online survey focusing on operational aspects of the hybrid design.

Results: RVs influenced the decision to pursue the trial in 13/31 participants. Remotely performing forced vital capacity (FVC) was a concern for 17/43 (40%). Survey response rate for SP was 41% (141/344). The trial was viewed as less time/labour for the site versus a traditional design by 52/136 (38%) of SP. Twenty percent (25/125) agreed their participants liked doing remote FVC assessments; 6% (7/109) of SP reported no challenges in obtaining FVC remotely. Technological problems were commonly reported by SP (71/109, 65%). Biospecimen collection and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale done at in-clinic visits (ICVs) and return visits (RVs) had similar completion rates, FVCs were missed more often at RVs than ICVs (completion rates 82% vs. 96%, p < 0.001).

Conclusions and relevance: Participants and SP viewed RVs favorably, despite common technical challenges. RV FVC assessments were more likely to be missed. COURAGE-ALS demonstrated that an interventional hybrid DCT is feasible in ALS but limitations remain that will need to be considered when designing future DCTs.

Trial registration: ClinicalTrials.gov (NCT04944784).

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Background: Research on the link between Type 2 Diabetes mellitus (T2DM) and amyotrophic lateral sclerosis (ALS) has produced mixed results. The potential role of antidiabetic medications in ALS etiology is also unclear. To contribute to these discussions, we aimed to examine the connections between T2DM, antidiabetic medications, and ALS using data from a large Israeli health fund. Methods: A total of 504 ALS cases diagnosed in 2002-2018 and 42,873 matched controls were considered in this population-based nested case-control study. T2DM was ascertained using diagnosis codes, laboratory test results, and medication use history, employing a 3-year lag from initial ALS diagnosis date to minimize chances for reverse causation. Multivariable-adjusted odds ratios (OR) were estimated for the association between T2DM, antidiabetic medications, and ALS. Results: T2DM overall was not linked with ALS (multivariable-adjusted odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.72-1.23). However, T2DM with a history of insulin use showed a protective association with ALS (OR = 0.29; 95% CI = 0.09-0.92) compared to the non-T2DM group. A similar trend of protective associations with ALS was observed for T2DM with history of use of other antidiabetic medications, but none were statistically significant, and all associations were further attenuated after adjusting for insulin use. Conclusions: We observe a potential protective effect of T2DM-linked insulin use on risk of ALS. Although caution is necessary due to the limited number of ALS cases with insulin exposure, the observed protective association may suggest a biological pathway worth exploring for future therapeutic development.

Objective: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. Results: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (p > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. Conclusion: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.

Background: Epidemiological data on amyotrophic lateral sclerosis (ALS) in Spain have primarily been derived from small cohort studies, with limited information on survival and comorbidities. This study presents a 10-year follow-up of a large, well-phenotyped community-dwelling ALS cohort in Catalonia, Spain. Methods: This observational study utilized data from the Information System for the Development of Research in Primary Care (SIDIAP), which includes health records for 6,301,095 individuals from 2015 to 2020. We assessed ALS incidence, prevalence, comorbidities, territorial distribution, mortality, and survival times. Results: From 2015 to 2020, 1173 ALS cases were identified, with a median age at diagnosis of 68 years, and 50.4% of cases were female. Incidence and prevalence were estimated at 2.39 per 100,000 person-years and 7.98 cases per 100,000 persons. Dementia was present in 6.8% of cases before ALS diagnosis, while depression and/or anxiety affected 45.7%. Median survival from diagnosis was 2.19 years. Multivariate analysis identified older age at diagnosis (HR: 1.04, 95% CI: 1.04-1.05, p value < 0.001), alcohol abuse (HR: 1.56, 95% CI: 1.04-2.56, p value = 0.017), history of stroke (HR: 1.47, 95% CI: 1.07-2.04, p = 0.006), and dementia (HR: 1.57, 95% CI: 1.18-2.12, p value = 0.001) as independent predictors of mortality. Conclusions: ALS incidence and prevalence in Catalonia are higher than previously estimated for Spain and align closely with rates observed in other Western countries. Older age at diagnosis, alcohol abuse, stroke history, and dementia were all significantly associated with reduced survival. These findings underscore important risk factors affecting prognosis, offering valuable insights into ALS progression.