Therapeutic Advances in Neurological Disorders最新文献

Background: People with rare diseases (RDs) often require intensive multidisciplinary care in disease-specific centers of excellence (CoE). However, access is limited for most patients living remotely. X-linked adrenoleukodystrophy (X-ALD) is a genetic RD leading to demyelination of the central and peripheral nervous system.

Objectives: This randomized-controlled trial tested the feasibility, acceptance, and effectiveness of a multidisciplinary online intervention provided by a CoE on the quality of life (QoL) and well-being of symptomatic women with X-ALD.

Design: Single-center, randomized-controlled clinical trial involving 68 German-speaking women with symptomatic X-ALD.

Methods: Participants were randomized into an experimental group (EG, n = 34) receiving 12-month online intervention SMART-ALD and a waiting-list control group (WL-CG, n = 34) receiving 6-month SMART-ALD after a 6-month waiting period. Within SMART-ALD, participants were offered regular web-based neurological, social, psychological, and nutritional counseling and fitness training provided by the Leukodystrophy Outpatient Clinic at Leipzig, Germany. Group, time, and interaction effects on primary (self-reported QoL) and secondary (physical and mental health) outcomes after 6-month SMART-ALD were tested by repeated measures ANOVAs.

Results: One WL-CG participant dropped out after the waiting period and was excluded from the final analysis. Significant QoL improvements in the EG versus WL-CG were found on self-reported mental health (mean difference (MD): 5.4, 95% confidence interval (CI) (2.8, 13.6), p = 0.020, η² = 0.08) and vitality (MD: 8.8, 95% CI (0.1, 17.4), p = 0.002, η² = 0.14). Further significant interaction effects emerged for improved knowledge about nutrition (MD: 0.4, 95% CI (-0.7, 1.4), p = 0.002, η² = 0.15), socio-medical benefits (MD: 1.8, 95% CI (0.5, 3.0), p = 0.033, η² = 0.07), and intense physical activity (MD: 2.2, 95% CI (-3.9, 8.4), p = 0.024, η² = 0.10).

Conclusion: The study shows that easily accessible, multidisciplinary online interventions provided by the CoE have the potential to improve the QoL in people with RDs by providing regular access to specialized care.

Trial registration: This study was registered on ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04687007).

Background: Sex differences in multiple sclerosis (MS) progression are poorly characterized, especially for disability worsening independent of relapses.

Objectives: To assess sex-specific risks of progression independent of relapse activity (PIRA), relapse and magnetic resonance imaging (MRI) activity (PIRMA), and relapse-associated worsening (RAW) in a real-world MS cohort, quantify each event's contribution to disability accumulation, and explore variation across clinical subgroups.

Design: Inverse probability-weighted analysis of adults with relapsing-remitting MS ambispectively enrolled in a local registry who had their first recorded neurological evaluation within 12 months of MS onset.

Methods: We used weighted conditional proportional hazard models for recurrent events, adjusted for visit/MRI frequency, to compare risks between sexes. We also tested the homogeneity of sex effects across prespecified subgroups: age at MS onset, symptom location at onset, presence of ⩾10 T2-hyperintense brain lesions, ⩾1 spinal T2 lesion, ⩾1 Gadolinium-enhancing brain lesion at baseline, initial MS treatment type, and percentage of follow-up time on disease-modifying therapy (DMT).

Results: We included 492 people with MS (median age 44.0 years, interquartile range (IQR) 35.0-53.6; 68.9% women), followed for a median of 5.1 years (IQR 3.1-7.2). In the weighted cohort, women had higher hazards of PIRA (hazard ratio (HR) 2.44, 95% confidence interval (CI) 1.56-3.70; p < 0.001) and PIRMA (HR 2.13, 95% CI 1.25-3.70; p < 0.001), mainly postmenopausal (56.6% and 52.4%). RAW risk was similar (HR 1.07, 95% CI 0.54-2.11; p = 0.843), despite higher relapse rates in women (0.13 ± 0.18 vs 0.06 ± 0.16; p < 0.001). Men had greater Expanded Disability Status Scale worsening per PIRA (+0.29 ± 0.71 vs +0.16 ± 0.53; p = 0.023) and PIRMA (+0.25 ± 0.71 vs +0.09 ± 0.38; p = 0.001). Age ⩾50 at onset increased PIRA/PIRMA risk without sex interaction. Significant sex interaction was seen for onset symptom location (p < 0.001 for both outcomes) and initial DMT (p = 0.013 for PIRA; p = 0.022 for PIRMA).

Conclusion: Women, especially postmenopausal, had higher PIRA/PIRMA risk, but disability worsening per event was greater in men, associations varied by onset phenotype and initial DMT strategy.

The development of novel therapy classes such as Bruton's tyrosine kinase (BTK) inhibitors, which target disability progression independent of relapses and largely independent of new lesion formation, requires a reappraisal of strategies in the treatment of multiple sclerosis (MS). We argue that this novel class of treatment further emphasizes the need for early and aggressive treatment with classical disease-modifying compounds for the prevention of both relapses and new MRI lesion formation and their associated disability accrual. This will extend the window to recognize early progressive disability accumulation independent of acute focal inflammatory activity, and for people with MS to benefit from novel therapies such as BTK inhibition, which target damaging pathophysiological processes independent of peripherally driven focal inflammation.

Cardiovascular symptoms are common in Parkinson's disease (PD), either as non-motor symptoms (NMS) of PD or as coexisting cardiovascular diseases (CVD), since both PD and CVD primarily affect the elderly population. Autonomic dysfunction in PD often involves blood pressure issues, including orthostatic hypotension, postprandial hypotension, and supine hypertension (SH). The combination of these NMS is particularly challenging to diagnose and treat. Other atherosclerotic vascular diseases, such as stroke or myocardial infarction, appear to be more common in PD patients. Prophylactic measures, such as statins or managing hypertension/SH, are essential for PD patients with an elevated risk of CVD, although PD patients usually undergo polypharmacy due to the short half-life of levodopa and the requirement of multiple drugs for CVD. This review presents studies in the literature on the current state-of-the-art therapy for CVD in PD.

Twenty years on from its initial approval as the first monoclonal antibody for the treatment of multiple sclerosis (MS), natalizumab remains a valuable high-efficacy treatment option for people with relapsing-remitting MS, with robust real-world evidence supporting its long-term efficacy and well-characterized safety profile, provided that the risk of progressive multifocal leukoencephalopathy (PML) is monitored and mitigated. This review explores the long-term clinical impact of natalizumab. It draws on two decades of experience to guide treatment strategies with natalizumab, including its use early in the disease course, switching to natalizumab, its use during vaccination, and PML risk management and exit strategies. Guidance on the use of natalizumab in pregnant and breastfeeding women with MS, children with MS, and people with comorbidities is discussed, along with reflections on what has been learned from 20 years with natalizumab, and what the future holds for this impactful treatment in MS and beyond.

Background: Cumulative research data indicate that migraine is characterized by a glutamatergic imbalance, particularly an excessive glutamatergic signal. Increases in glutamate levels in the brain and plasma of migraine patients have been reported, but less is known about the association between liver enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) that regulate blood glutamate levels and migraine.

Objectives: We evaluated associations between AST, ALT, and GGT levels across the quartiles and a history of probable/defined migraine in the Atherosclerosis Risk in Communities Study cohort.

Design: We included 11,718 participants with measured liver enzyme levels and self-reported data on migraine with and without aura. Multiple logistic regression models were used to assess associations of sex-specific quartiles of liver enzymes with probable/definite migraine.

Results: A total of 1626 probable/definite migraine events were reported in 1993-1995. After adjustment for age, race-center, and sex, higher levels of AST, ALT, and GGT were associated with a lower prevalence of migraine. The adjusted odds ratios (95% CIs) for migraine for Q1 versus Q4 levels of AST, ALT, and GGT were 1.24 (1.06-1.45), 1.17 (1.00-1.37) and 1.21 (1.03-1.41), respectively. Analysis by yes/no aura showed higher odds of migraine without aura for lower (Q1) compared with higher (Q4) levels of ALT (adjusted OR 1.38, 95% CI 1.05-1.82), while no significant association was observed between enzyme levels and prevalence of migraine with aura.

Conclusion: Our findings suggest that higher AST, ALT, and GGT levels are associated with a lower prevalence of migraine. Although the exact mechanisms linking lower blood levels of AST, ALT, and GGT to migraines remain unclear, their association may be explained by inefficient plasma glutamate regulation, which could play a role in migraine pathology. This finding is important for patients as it sheds light on potential metabolic contributions to migraines, supporting the hypothesis that factors beyond traditional neurovascular theories are involved.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as potential neuroprotective agents for Parkinson's disease (PD). However, evidence regarding their efficacy remains inconclusive.

Objective: To assess the therapeutic effects and safety profile of GLP-1 RAs in patients with mild-to-moderate PD. We aim to conduct an updated systematic review to evaluate the effects of GLP-1 RAs in patients with mild-to-moderate PD.

Design: Systematic review and meta-analysis of randomized controlled trials (RCTs) with trial sequential analysis (TSA) and Grading of Recommendations, Assessment, Development, and Evaluations certainty assessment.

Data sources: PubMed, Embase, and the Cochrane Library were searched through April 14, 2025.

Methods: We conducted a systematic review and meta-analysis of RCTs with TSA comparing GLP-1 RAs to placebo in patients with mild-to-moderate PD. The primary outcome was change in the Movement Disorder Society-unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores.

Results: Five RCTs involving a total of 708 nondiabetic patients with mild-to-moderate PD were included. GLP-1 RAs significantly attenuated motor symptom progression, as evidenced by a mean difference in MDS-UPDRS Part III (off medication) of -2.06 (95% confidence interval (CI): -4.09; -0.03; I ² = 56%), with conclusive evidence supported by TSA. No statistically significant improvements were observed in other MDS-UPDRS domains, levodopa equivalent daily dose reduction, or functional scales (Parkinson's Disease Questionnaire-39, Non-Motor Symptoms Scale for Parkinson's Disease, UDysRS). A nonsignificant trend toward increased serious adverse events or treatment discontinuation was observed (odds ratio = 1.52; 95% CI: 0.66; 3.50), with low heterogeneity. TSA for secondary outcomes indicated that additional trials are required.

Conclusion: GLP-1 RAs may provide a modest benefit in slowing motor progression in PD. However, their effects on nonmotor symptoms, medication use, and long-term safety remain uncertain due to the limited number of available trials. Further large-scale, long-duration trials are warranted.

Trial registration: INPLASY2024110119.

Background: Multiple sclerosis (MS) manifests clinically as relapsing disease (relapsing-remitting MS (RRMS)), progressive disease, or as combination of these phenotypes. The underlying pathology for relapses and focal inflammatory activity is driven by adaptive immune cells, whereas brain-compartmentalized pathology promoted by innate immune cell activation likely contributes to progression.

Objectives: To explore the usability of various imaging and soluble biomarkers in predicting change in clinical phenotype from RRMS to secondary progressive MS (SPMS).

Design: Prospective longitudinal study.

Methods: Twenty-three RRMS patients aged 40-50 years had clinical evaluation, brain MR imaging, serum neurofilament light and glial fibrillary acidic protein (GFAP) measurements, and brain positron emission tomography with translocator protein (TSPO)-binding radioligand [¹¹C](R)-PK11195 at baseline. Patients were followed for 5 years and assessed for signs of conversion to SPMS at the end of follow-up. Evolution to SPMS was determined based on an increased Expanded Disability Status Score and significant accrual of clinical symptoms.

Results: After 5 years, 8/23 (35%) patients had converted to SPMS. At baseline, they had increased TSPO-binding in the normal appearing white matter, thalamus, and perilesional area compared to patients who did not convert to SPMS. The proportion and number of TSPO-rim-active lesions were higher among patients developing SPMS. Higher concentration of GFAP and more pronounced thalamic atrophy were also observed among the SPMS convertors.

Conclusion: The results suggest that imaging and serum biomarkers reporting on compartmentalized central nervous system inflammation support identification of MS patients at risk of SPMS conversion. Evaluation of thalamic atrophy and measurement of soluble biomarkers can be implemented in the assessment of individual patients' progression risk in daily clinical practice. This can help in identifying patients who are at greatest need of smoldering pathology-targeting therapy. Larger studies are needed to validate these results.

Trial registration: NCT3134716 role of microglia in the pathogenesis of progressive multiple sclerosis, https://clinicaltrials.gov/study/NCT03134716.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options and significant variability in care. Racial and ethnic disparities in ALS management and outcomes have been reported, but findings remain inconsistent.

Objectives: This study aimed to evaluate racial and ethnic disparities in ALS care, specifically differences in healthcare utilization, treatment patterns, and survival, within a large healthcare system.

Design: This retrospective cohort study analyzed electronic health records from a large healthcare system in Texas for patients diagnosed with ALS between 2013 and 2023, examining racial and ethnic differences in treatment and outcomes.

Methods: Patients were identified using International Classification of Diseases (ICD) codes. Baseline characteristics, including race/ethnicity and socioeconomic factors, were collected. Primary outcomes included the use of noninvasive ventilation (NIV), tracheostomy, gastrostomy, mobility aids, and ALS medications; secondary outcomes included time to diagnosis and survival. Racial and ethnic disparities were assessed using generalized linear regression and Cox proportional hazards models, adjusting for demographic and socioeconomic factors.

Results: A total of 636 patients were included (74.5% Non-Hispanic White, 5.3% Non-Hispanic Black, 7.4% Hispanic, and 12.7% Other). Non-Hispanic Black patients had significantly higher tracheostomy rates than Non-Hispanic White patients (35.3% vs 8.7%; adjusted odds ratio (OR), 6.20; 95% confidence interval (CI), 2.43-15.84). Hispanic patients had lower odds of receiving riluzole (42.6% vs 61.8%; adjusted OR, 0.36; 95% CI, 0.18-0.71) and higher rates of emergency department visits (adjusted OR, 2.00; 95% CI, 1.09-3.65) and hospitalizations (adjusted OR, 2.57; 95% CI, 1.37-4.81). No significant racial or ethnic differences were observed in time to diagnosis or survival after adjustment.

Conclusion: Significant racial and ethnic disparities exist in ALS care, particularly in tracheostomy utilization, medication prescribing, and healthcare access. These findings underscore the need for targeted interventions to promote equitable ALS management, including provider education and improved healthcare accessibility.

Background: Rescue stenting (RS) is a bailout strategy for failed thrombectomy. Optimal platelet inhibition strategy after RS remains unclear.

Objectives: We aimed to describe and compare different platelet inhibition strategies during/after RS.

Design: Retrospective cohort study across 34 international centers.

Methods: Patients with large vessel occlusion and RS after failed thrombectomy (2019-2023) were included. Periprocedural and postprocedural platelet inhibition strategies were described and compared, focusing on glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, single antiplatelet therapy (SAPT), and dual antiplatelet therapy (DAPT). We assessed the effects of platelet inhibition strategy and potentially covariates on the primary outcome of 90-day modified Rankin Scale (mRS) using ordinal shift analysis with proportional odds models.

Results: RS was performed in 589 patients (mean age 67.9 years, 60.8% male). Numerous combinations of platelet inhibitors were administered. Periprocedural GPIIb/IIIa inhibitors were used in 61.5% of patients. Postprocedural DAPT was administered to 80.5% and SAPT to 13.3%. Functional independence (mRS 0-2) was achieved in 40.7%, while 26.3% died within 90 days. Stent occlusion occurred in 20.5%, with 67.6% of these occlusions within 24 h. Postprocedural stent-occlusion was independently associated with worse functional outcome at 90 days (OR 4.1, 95% CI 2.3-7.2, p < 0.001). No significant association between periprocedural GPIIb/IIIa inhibitors, and 90-day mRS or stent occlusion was found. Postprocedural SAPT was associated with worse functional outcomes (adjusted odds ratio (aOR) 2.4, 95% CI 1.1-5.0, p = 0.02), higher mortality (aOR 2.1, 95% CI 1.05-4.0, p = 0.03), and increased stent occlusion rates (aOR 4.8, 95% CI 2.3-9.7, p < 0.001) compared to postprocedural DAPT. Symptomatic intracranial hemorrhage occurred in 6.8% of patients, with no significant difference between antiplatelet regimens.

Conclusion: Extensive heterogeneity exists in platelet inhibition strategies following RS. Stent occlusion is associated with worse clinical outcomes, and the first 24 h post-RS are critical for stent patency. Compared to SAPT, DAPT was associated with better functional outcome, lower mortality, and lower stent occlusion rates.