Journal of Neurology, Neurosurgery & Psychiatry

ImportanceElevated circulating low-density lipoprotein (LDL) cholesterol is associated with an increased risk of amyotrophic lateral sclerosis (ALS) onset. Previous studies have explored the relationship between statin use and ALS onset. However, findings have been inconsistent, potentially due to methodological limitations, such as confounding by indication, and failure to account for baseline differences in LDL cholesterol levels. ObjectiveTo compare the risk of ALS onset between new users of statins and ezetimibe among patients with hypercholesterolemia. DesignActive-comparator, new-user cohort study using inverse probability of treatment-weighted Cox proportional hazards models. The study period spanned April 2012 to February 2024. SettingTwo administrative claims databases in Japan. ParticipantsPatients with hypercholesterolemia who newly initiated statins or ezetimibe, and patients with dyslipidemia who newly initiated fibrates. All participants were required to have at least 365 days of baseline observation and no prior diagnosis of ALS. Exposure(s)Statin use compared with ezetimibe use. Fibrate use was assessed for benchmarking. Main Outcome(s) and Measure(s)The outcome was incident ALS, defined as a first definitive diagnosis of ALS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare ALS risk between statins and ezetimibe. ResultsThe study included 607,292 statin users (median [IQR] age, 61 [51-71] years; 51.4% male), 26,963 ezetimibe users (median [IQR] age, 59 [49-71] years; 50.1% male), and 114,871 fibrate users (median [IQR] age, 61 [51-71] years; 51.4% male). The incidence rate per 100,000 person-years of ALS was 6.8, 15.9, and 4.3, respectively. Statin use was associated with a lower hazard of ALS onset than ezetimibe use (adjusted HR [95% CI]: 0.42 [0.19-0.92]). The mean (SD) LDL cholesterol immediately prior to treatment initiation was 171.0 (28.6) mg/dL in the statin group and 162.8 (30.8) mg/dL in the ezetimibe group. After treatment, mean LDL cholesterol levels decreased to and stayed below 140 mg/dL in both groups. Conclusions and RelevanceThis study suggests that statins may lower the risk of ALS onset among patients with hypercholesterolemia. The mechanism underlying this association is not yet clear and may involve pathways beyond circulating LDL cholesterol reduction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes statin use lower the risk of amyotrophic lateral sclerosis (ALS) onset among patients with hypercholesterolemia? FindingsIn this active-comparator, new-user cohort study of 607,292 statin users and 26,963 ezetimibe users with hypercholesterolemia, statin use was associated with a lower hazard of ALS onset compared with ezetimibe use. Prior to treatment initiation, mean LDL cholesterol levels were similar between statin and ezetimibe users. MeaningThese findings suggest that statins may lower the risk of ALS among patients with hypercholesterolemia.

BackgroundMotivational symptoms such as apathy and anhedonia are common in Parkinsons disease, respond poorly to treatment, and have been hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in Parkinsons disease, but the association has never been examined longitudinally. We investigated whether the progression of dopaminergic neurodegeneration was associated with emergent apathy and anhedonia symptoms in Parkinsons disease. MethodsLongitudinal cohort study of 412 newly diagnosed Parkinsons disease patients followed over five years as part of the Parkinsons Progression Markers Initiative (PPMI) cohort. Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item geriatric depression scale (GDS-15) and part I of the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS). Dopaminergic neurodegeneration was measured using repeated ioflupane [123-I] single photon emission computed tomography imaging of striatal dopamine transporters (DAT). ResultsLinear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio(SBR) and apathy/anhedonia symptoms, which emerged as Parkinsons disease progressed (interaction: {beta}=-0.09, 95%CI[-0.15 -0.03], p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average two years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) ({beta}=-0.06, 95%CI[-0.13 0.01]) or motor symptoms indexed by the MDS-UPDRS part III ({beta}=0.20, 95%CI[-0.25 0.65]). ConclusionThe relationship between the progression of dopaminergic neurodegeneration and emergent apathy/anhedonia symptoms supports a central role for dopaminergic dysfunction in motivational symptoms in Parkinsons disease. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

Objective: To systematically evaluate the efficacy and safety of Deep Brain Stimulation (DBS) for the management of disabling tremor in patients with Multiple Sclerosis (MS) by synthesizing data from available clinical studies. Methods: This systematic review and meta analysis followed PRISMA 2020 guidelines and was registered with PROSPERO (CRD420261347426). A comprehensive search of PubMed, Scopus, Web of Science, and Embase was performed from database inception until December 2025 with no time or language limitation. A pre-post meta analysis design was used to estimate the pooled effect size using the Standardized Mean Change (SMC) between baseline and follow up tremor severity. Because most included studies were single arm cohorts and clinical heterogeneity was anticipated, a random effects model using the Restricted Maximum Likelihood (REML) estimator with the Hartung-Knapp adjustment was applied. Safety outcomes including hardware complications and postoperative infections were pooled using random effects meta analysis of proportions. Results: Thirteen studies including 131 patients met the eligibility criteria. Eight studies with adequate outcome data were included in the pooled efficacy analysis. DBS was associated with a significant reduction in tremor severity with an overall pooled SMC of 1.42 (95% CI 1.07 to 1.77). Statistical heterogeneity was minimal (I2 = 0.0%, p = 0.6300), although this finding should be interpreted cautiously given the limited number of studies and clinical variability in surgical targets, most commonly the ventral intermediate nucleus (VIM), and follow up duration ranging from months to more than 20 years. The pooled incidence of postoperative infection was approximately 7% with substantial heterogeneity across studies (I2 = 74.1%). The most frequently reported adverse events were stimulation related effects such as dysarthria and disequilibrium, which were generally reversible after adjustment of stimulation parameters. Overall methodological quality of included studies was predominantly moderate. Conclusion: Deep brain stimulation may provide meaningful tremor reduction in selected patients with disabling and medication refractory MS tremor, with a large pooled treatment effect (SMC = 1.42). Although complications such as postoperative infection (approximately 7%) and transient stimulation related adverse effects can occur, these events appear manageable in most cases. However, the current evidence base remains limited by small sample sizes, heterogeneous study designs, and variability in surgical targets and outcome reporting. Larger prospective studies with standardized tremor outcome measures and consistent reporting of safety outcomes are needed to better define the long term efficacy and optimal clinical role of DBS in patients with MS related tremor.

ImportanceSeveral preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objectiveto describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. DesignThe ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. ResultsOut of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevanceWe found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations. Questionwhat are the phenotypes of encephalitis associated to SARS-CoV-2 infection? Findings25 cases of encephalitis in SARS-CoV-2 infection were included in a prospective observational multi-centre study. Encephalitis cases in COVID-19 exhibited a wide heterogeneity in terms of clinical features, CSF, MRI findings, response to treatment and outcomes with 13 cases with normal MRI, 7 with heterogeneous MRI alterations and rarer ADEM/limbic encephalitis cases. Meaningheterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms

BackgroundAdvanced cell therapeutics are emerging as potentially effective treatments for chronic neurological diseases, including secondary progressive multiple sclerosis (SPMS). Here we report the results of a phase I trial in which good manufacturing practice-grade foetal allogeneic human neural stem cells (hNSCs) were implanted via intracerebroventricular (ICV) injection in 15 individuals with active and non-active SPMS. MethodsThis is a phase I, open-label, multicentre, dose-escalation, international study. The primary objective was to assess the feasibility, safety, and tolerability of ICV injections of allogeneic hNSCs in patients affected by SPMS over a study follow up of 12 months. We also evaluated the number and type of adverse events (AEs) leading to a maximum tolerated dose, the general health status, and mortality. The secondary objectives were the therapeutic benefit of allogeneic hNSCs using assessment scales, magnetic resonance imaging (MRI), and laboratory and neurophysiologic parameters. FindingsFifteen unrelated SPMS patients were enrolled and treated between 2018 and 2020. The participants had a median age of 49.8 years. Their mean extended disability status scale (EDSS) at enrolment was 7.6, the mean disease duration was 22 years, and mean time from diagnosis to progression was 10.1 years. Neither treatment-related deaths nor serious AEs were reported during the study (1 year follow up after treatment). All the other AEs were classified as non-serious and were associated to non-study concomitant therapy or other medical conditions not connected to the experimental treatment. During the study, none of the participants worsened in the progression of their SPMS as shown by the evaluation scales implemented to assess their progress. Laboratory and neurophysiologic parameters showed no clinically significant variations. MRI follow-up showed non-clinically significant type 1, 2, and 3 changes. InterpretationThe intracerebroventricular injection of foetal allogeneic hNSCs in people with SPMS is feasible, tolerated and safe. Study participants displayed a substantial clinical stability during the 12-month follow-up. The absence of relevant adverse reactions (Ars) arising from the transplantation of hNSCs indicates a short-term neutral balance between benefits and risks and suggests a concrete, though perspective therapeutic possibility for SPMS patients. Further studies are needed to confirm and extend the findings herein and evaluate the actual therapeutic potential of advanced cell therapeutics for a condition where the lack of effective disease modifying therapies is a major unmet clinical need.

BackgroundThe glucagon-like-peptide-1 (GLP-1) hormone exerts metabolic effects leading to delayed gastric emptying, decreased appetite, and lower blood glucose levels. GLP-1 receptor activators (GLP-1RACT) are increasingly used to treat diabetes mellitus (DM) and obesity. However, their impact on the progression of amyotrophic lateral sclerosis (ALS) is unknown. ObjectiveWe examined the relationship between GLP-1RACT treatment and disease progression among people with ALS and DM. MethodsAn electronic health record search was conducted to identify consecutive patients seen at a single institution from July/2020 to February/2024 with ALS and DM diagnostic codes. All charts were reviewed for demographics, disease history, medication use, and tracheostomy/survival. Patients who did not meet Awaji ALS diagnostic criteria, lacked a documented history of DM, or had insufficient records were excluded. Those who were treated with GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors were grouped with GLP-1RACT. The others were grouped with No-GLP-1RACT. Tracheostomy-free survival was compared between the GLP-1RACT and No-GLP-1RACT groups using Kaplan-Meier survival curves and Cox-proportional hazard models adjusted for age, sex, bulbar onset, body mass index (BMI) at diagnosis, and riluzole use. ResultsAmong the 1,310 ALS patients screened, 85 had confirmed ALS and DM diagnosis, 36 (42%) of whom were treated with GLP-1RACT. Sixty (71%) of the cohort died during follow-up. Diagnostic delay was shorter in GLP-1RACT compared to the No-GLP-1RACT group (371 vs 561 days, p=0.01). Other baseline characteristics were not significantly different between groups. Tracheostomy-free survival from symptom onset was significantly shorter in the GLP-1RACT group (median survival 31 vs 45 months, p=0.007). After adjusting for covariates, the GLP-1RACT group was associated with increased mortality compared to the No-GLP-1RACT group (hazard ratio 3.1, 95% confidence interval [1.6, 6.0], p<0.001). ConclusionsTreatment with GLP-1RACT is associated with shorter tracheostomy-free survival in people with ALS and comorbid DM.

ObjectiveSeizure following immunization, especially in persons with epilepsy (PwE), has long been a concern, and seizure aggravation followed by Coronavirus Disease 2019 (COVID-19) vaccines is a serious issue for PwE. The immunization rate in PwE has been lower compared to same-age controls due to vaccine hesitancy and concerns about seizure control. Herein, we systematically reviewed the seizure activity-related events in PwE following COVID-19 vaccination. MethodsFour search engines were searched from inception until January 31, 2023, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed. Random- and fixed-effect models using the logit transformation method were used for meta-analysis. The quality of the studies was evaluated by the Newcastle-Ottawa scale. Outcomes of interest included (a) pooled proportion of increased seizure frequency and (b) pooled incidence proportion of status epilepticus (SE) in PwE receiving COVID-19 vaccines. ResultsOf the 2207 studies identified, 18 met eligibility criteria, of which 16 entered the meta-analysis. The pooled proportion of increased seizure frequency (16 studies-4197 PwE) was 5% (95CI: 3%-6%, I2 =57%), further subcategorized into viral vector (3%, 95CI: 2%-7%, I2 =0%), mRNA (5%, 95CI: 4%-7%, I2 =48%), and inactivated (4%, 95CI: 2%-8%, I2 =77%) vaccines. The pooled incidence proportion of SE (15 studies-2480 PwE) was 0.08% (95CI: 0.02%-0.32%, I2 =0%), further subcategorized into the viral vector (0.00%, 95CI: 0.00%-1.00%, I2 =0%), mRNA (0.09%, 95CI: 0.01%-0.62%, I2 =0%), and inactivated (0.00%, 95CI: 0.00%-1.00%, I2 =0%) vaccines. No significant difference was observed between mRNA and viral vector vaccines (5 studies, 1122 vs. 198 PwE, respectively) regarding increased seizure frequency (OR: 1.10, 95CI: 0.49-2.50, p-value=0.81, I2 =0%). SignificanceThe meta-analysis proposed a 5% increased seizure frequency following COVID-19 vaccination in PwE, with no difference between mRNA and viral vector vaccines. Furthermore, we found a 0.08% incidence proportion for SE. While this safety evidence is noteworthy, this cost should be weighed against vaccination benefits.

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

IntroductionAnti-amyloid immunotherapies are approved by the United States Food and Drug Administration (FDA) for the treatment of Alzheimers disease. The adoption and safety profile of these medications in routine clinical practice have not been described. MethodsWe performed a retrospective observational cohort study using nationwide electronic health record data from Epic Cosmos. The principal objective was to describe the baseline characteristics of patients prescribed anti-amyloid immunotherapy in routine clinical practice. Secondarily, we wished to determine whether prescription of anti-amyloid immunotherapy (with or without an acetylcholinesterase inhibitor [AChEI] or memantine) was associated with an increased risk of key safety end points when compared to an AChEI or memantine alone. We used a target trial emulation framework to identify and mitigate sources of bias. The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Secondary end points included other cardiovascular conditions (ischemic stroke (IS), myocardial infarction (MI), and a composite of ICH, IS, or MI), headache, diarrhea and overall healthcare utilization. Exploratory end points included adverse events linked to other immunotherapies. We used propensity score overlap weighting to balance baseline demographic and clinical characteristics across treatment groups. ResultsBetween July 1, 2023 and January 1, 2025, 2,616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9 % female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety end points. Compared with AChEI/memantine, prescription of anti-amyloid immunotherapy was not associated with increased hazard of ICH after adjustment (owHR 0.73 [95% CI 0.11-5.46]). Anti-amyloid immunotherapy prescription was associated with a higher risk of headache (owHR 2.16 [95% CI 1.12-4.16]) and respiratory infection (owHR 1.57 [95% CI 1.04-2.37]) but was not associated with other immune-related safety endpoints. ConclusionAnti-amyloid immunotherapy has been principally adopted by patients who are younger and medically healthier than patients receiving AChEI/memantine alone. Prescription of anti-amyloid immunotherapy was not associated with an increased risk of ICH.

BackgroundNon-invasive mechanical ventilation (NIMV) improves Amyotrophic Lateral Sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. ObjectiveTo test whether NIMV use changed the rate of functional decline among ALS patients. MethodsIn this retrospective observational study, we included 465 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation when adjusting for covariates. Functional decline was based on the non-respiratory items of the ALS Functional Rating Score - Revised (ALSFRS-R). ResultsA slower progression of functional decline followed NIMV initiation (mean improvement 0.13, 95%CI 0.11 to 0.16, p<0.001) regardless of sex, age at diagnosis, and disease duration prior to NIMV initiation. Indeed, the disease stage at NIMV initiation (early or advanced) did not influence the results. Respiratory support exerts its slowing effect mainly on the progression of spinal motor function. ConclusionsWe proved that NIMV influences the rate of motor progression in ALS. This result was not a consequence of the ALSFRS-R floor effect. The functional decline slowed after starting NIMV independently of the site of disease onset. Our results reinforce the importance of not delaying NIMV initiation in all ALS patients. NIMV-induced slowing of disease progression should also be accounted for when evaluating clinical trial outcomes.

BackgroundAmyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder causing motor neuron degeneration, muscle paralysis, and death within 3-5 years, with a rising global prevalence. While thyroid dysfunction is implicated in the pathology of other neurodegenerative diseases, its role in ALS remains unclear due to conflicting reports from observational studies. To address this, we aimed to investigate the causal relationship between thyroid function and ALS using two-sample Mendelian Randomization (MR). MethodWe performed a two-sample MR study to evaluate the bidirectional causal relationship between thyroid function traits (TSH, FT4, autoimmune hyperthyroidism, autoimmune hypothyroidism) and ALS. We used SNPs from GWAS data (TSH and FT4: n=271,040; autoimmune hyperthyroidism: n=1,828 cases/279,855 controls; autoimmune hypothyroidism: n=40,926 cases/274,069 controls; ALS: n=27,205 cases/110,881 controls). We applied the inverse-variance weighted (IVW) method as the primary analysis, with sensitivity analyses (MR-Egger, weighted median, weighted mode, MR-PRESSO) to assess pleiotropy and heterogeneity. ResultsWe identified a causal effect of autoimmune hyperthyroidism on reducing ALS risk (IVW OR = 0.96; 95% CI: 0.93-0.99; P = 0.03), but no associations for TSH (IVW OR = 0.99; 95% CI: 0.94-1.04; P = 0.71), FT4 (IVW OR = 1.03; 95% CI: 0.96-1.12; P = 0.36), or autoimmune hypothyroidism (IVW OR = 1.01; 95% CI: 0.98-1.05; P = 0.39) with ALS. Bidirectional analysis of genetic liability to ALS showed no causal effect on TSH (IVW OR = 0.98; 95% CI: 0.96-1.01; P = 0.65), FT4 (IVW OR = 0.98; 95% CI: 0.94-1.02; P = 0.46), autoimmune hypothyroidism (IVW OR = 0.93; 95% CI: 0.76-1.13; P = 0.59), or autoimmune hyperthyroidism (IVW OR = 1.01; 95% CI: 0.76-1.33; P = 0.78). ConclusionWe found that genetic predisposition to autoimmune hyperthyroidism may reduce ALS risk. Our findings expand the knowledge of its genetic underpinnings and lay a foundation for future research into therapeutic strategies targeting thyroid function to mitigate ALS risk.

The human nervous system evolved to optimise its interactions with the natural world. However, as civilisations over recent millennia have developed, the human brain has become steadily disconnected from these natural stimuli. Consequently, detrimental effects on individual health are increasingly recognised. Strategies that promote reconnection with Nature have yielded significant gains when it comes to psychological and general physical health, although much less is known about their direct impact on neurological health. In this systematic review, we identified 17 studies that assessed at least one Nature-based intervention to treat any neurological disease. The predominant study design was quasi-experimental (n=9). Interventions included horticultural therapy, petal arranging and farm visits. The majority of studies had a moderate risk of bias. While 88% (n=15) of studies reported improvements in measures such as quality of life, mood, agitation, apathy or cognitive function, there was such an overrepresentation of studies recruiting patients with dementia (94%; n=16) that for many common neurological disorders, including epilepsy, migraine and multiple sclerosis, the current literature leaves us none the wiser. Considering the extensive crosstalk that exists between physical and psychological disease, we argue that the potential benefit of formal Nature Prescriptions as an accessible, cheap and harmless endorsement of Mother Natures healing hand warrants greater attention in neurology. Indeed, this aligns with the wider societal and environmental need for humans to reconnect with the natural world.

BackgroundDepression in Parkinsons disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. AimsWe hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses. MethodsWe analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinsons Progression Markers Initiative cohort. Medication state for individual classes of Parkinsons medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. ResultsLinear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: {beta}=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years ({beta}=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: {beta}=-0.24, 95%CI [-0.43,-0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures. ConclusionsWe identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.

Parkinsons disease is a progressive neurodegenerative disorder characterised by motor dysfunction and cognitive disruption among other non-motor symptoms. No cure for Parkinsons disease exists. Deep Brain Stimulation of the Subthalamic Nucleus (DBS STN) has been utilised for control of motor symptoms. However, cognitive deficits are commonly reported after implantation, and few exhaustive analyses exist to quantify and explain them. Our systematic review, meta-analyses, and metaregressions examine within-subjects change across thirteen cognitive domains, from 70 studies and 3000 participants at baseline measurements. Improvement was not observed in any domain, but substantial decline at 12 months was observed for phonemic and categorical fluency, which appeared to stabilise 24 to 36 months. Meta-regression suggests that few study characteristics are predictive of longitudinal outcomes, and we propose that further research into specific surgical or placement effects is necessary to mitigate short-term cognitive change after DBS STN in Parkinsons disease.

ObjectiveTo provide a timely, rigorous and continuously updated summary of the available evidence on the effectiveness of deep brain stimulation (DBS) in people with severe and refractory obsessive-compulsive disorder (OCD). MethodsWe conducted a systematic literature review of intervention, as the baseline synthesis report of a living evidence approach. We followed the methodological framework by Elliot et al. 2014. The L.OVE platform from Epistemonikos was used for identification, screening and pre-selection of studies. Systematic reviews (SR) and randomized clinical trials (RCT) evaluating the use of DBS in patients with severe and refractory OCD were included. Data extraction and risk of bias assessment were performed in duplicate using appropriate instruments. Primary outcomes were symptom severity (efficacy) and adverse events (safety), secondary outcomes were quality of life, functionality, effect on cognitive function, patient perception and values. Evidence certainty was assessed with the GRADE approach. ResultsThe searches identified 45 references for full text review, finally, 16 SRs and 12 crossover RCT (112 patients) were included. The pooled estimates suggested a favorable effect of DBS on reducing symptoms measured by Y-BOCS score in the short term (MD=7.3 points, 95%CI: 3.9-10.6, p <0.0001) and the long term (MD=14.8 (95% CI: 12.1 - 17.5) (p <0 . 0001), with high and moderate certainty evidence, respectively. The estimated pooled incidence of permanent serious adverse events (SAE) was 6% (95% CI: 0%-19%), and surgical SAE was 9% (95% CI: 2%-18%); both with very low certainty due to serious imprecision. Non-pooled results from individual studies also suggested benefits of the interventions on quality of life and cognitive function. ConclusionsDeep brain stimulation of proposed targets for refractory obsessive-compulsive disorder has a large beneficial effect on reducing symptoms severity in the short and long term. Implantation has a low incidence of adverse events, and a high incidence of non-serious adverse events during the stimulation calibration period. Benefit to harm balance should consider uncertainty on the risk of adverse events related to the surgical procedure and to the device, and appears favorable given its large effects on symptom reduction.

BackgroundAutoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). MethodsClinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. ResultsOf the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0% vs 34.9%, p = 0.008), whereas involuntary movements were significantly less prevalent (31.3% vs 69.8%, p = 0.007), among anti-gAChR antibody-positive compared with - negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. ConclusionsAn autoimmune mechanism mediated by anti-gAChR antibodies may be involved in the etiology of FNSD/CD in a subgroup of patients.

BackgroundImpulse control disorders (ICD) in Parkinsons disease (PD) patients mainly occur as adverse effects of dopamine replacement therapy. Despite several known risk factors associated with ICD development, this cannot yet be accurately predicted at PD diagnosis. ObjectivesWe aimed to investigate the predictability of incident ICD by baseline measures of demographic, clinical, dopamine transporter single photon emission computed tomography (DAT-SPECT), and genetic variables. MethodsWe used demographic and clinical data of medication-free PD patients from two longitudinal datasets; Parkinsons Progression Markers Initiative (PPMI) (n=311) and Amsterdam UMC (n=72). We extracted radiomic and latent features from DAT-SPECT. We used single nucleotic polymorphisms (SNPs) from PPMIs NeuroX and Exome sequencing data. Four machine learning classifiers were trained on combinations of the input feature sets, to predict incident ICD at any follow-up assessment. Classification performance was measured with 10x5-fold cross-validation. ResultsICD prevalence at any follow-up was 0.32. The highest performance in predicting incident ICD (AUC=0.66) was achieved by the models trained on clinical features only. Anxiety severity and age of PD onset were identified as the most important features. Performance did not improve with adding features from DAT-SPECT or SNPs. We observed significantly higher performance (AUC=0.74) when classifying patients who developed ICD within four years from diagnosis compared with those tested negative for seven or more years. ConclusionsPrediction accuracy for later ICD development, at the time of PD diagnosis, is limited; however, it increases for shorter time-to-event predictions. Neither DAT-SPECT nor genetic data improve the predictability obtained using demographic and clinical variables alone.

BackgroundDefinitive diagnosis of amyotrophic lateral sclerosis (ALS) is only possible through a postmortem examination. Extracellular vesicles (EVs) have emerged as promising minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. MethodsFollowing PRISMA guidelines, we searched PubMed and EMBASE from inception to October 15, 2025. Thirty-nine studies met inclusion criteria. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. ResultsEV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in ALS vs. controls (SMD = 1.30) with high heterogeneity (I{superscript 2} = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. ConclusionsEV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. Standardized protocols, transparent data sharing, and independent validation are needed.

ImportanceMultiple sclerosis (MS) is an immune-mediated neurological disorder that affects 2.4 million people world-wide, and up to 60% experience anxiety. ObjectiveWe investigated how anxiety in MS is associated with white matter lesion burden in the uncinate fasciculus (UF). DesignRetrospective case-control study of participants who received research-quality 3-tesla (3T) neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from June 1st to September 30th, 2024. SettingSingle-center academic medical specialty MS clinic. ParticipantsParticipants were identified from the electronic medical record. All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 372 were stratified into three groups which were balanced for age and sex: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). ExposureAnxiety diagnosis and anxiolytic medication. Main Outcome and MeasureWe first evaluated whether MS+severeA patients had greater lesion burden in the UF than MS+noA. Next, we examined whether increasing anxiety severity was associated with greater UF lesion burden. Generalized additive models were employed, with the burden of lesions (e.g. proportion of fascicle impacted) within the UF as the outcome measure and sex and spline of age as covariates. ResultsUF burden was higher in MS+severeA as compared to MS+noA (T=2.02, P=0.045, Cohens f2=0.19). A dose-response effect was also found, where higher mean UF burden was associated with higher anxiety severity (T=2.08, P=0.038, Cohens f2=0.10). Conclusions and RelevanceWe demonstrate that overall lesion burden in UF was associated with the presence and severity of anxiety in patients with MS. Future studies linking white matter lesion burden in UF with treatment prognosis are warranted. KEY POINTSO_ST_ABSQuestionC_ST_ABSAre white matter lesions that impact the uncinate fasciculus (UF) associated with anxiety in patients with multiple sclerosis (MS)? FindingsThis retrospective, case-control study of 372 patients with MS included 3 anxiety severity groups: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). We identified associations between anxiety and UF lesion burden. Specifically, we showed that MS+severeA had higher UF lesion burden than MS+noA, and worsening anxiety severity increased with greater UF burden. MeaningLesion burden in the UF may contribute to anxiety comorbidity in MS.