Journal of Neurology, Neurosurgery & Psychiatry

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.

T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF sCD27+ and 15% blood sCD27+, compared to patients with MS where 88% were CSF sCD27+ and 22% were blood sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

Background: Depression is associated with an increased risk of subsequent Parkinson's disease. Neuroimaging studies suggest a neurobiological overlap in mechanisms underlying Parkinson's disease and psychomotor retardation in depression. Our aim was to investigate whether, among individuals with depression, the presence of psychomotor retardation was associated with the development of subsequent Parkinson's disease. Methods: In a retrospective cohort study, electronic healthcare records from individuals diagnosed with depression at age 40 or over in a large mental health service in London, UK were examined for the presence of psychomotor retardation. Linkage to general hospital records was used to ascertain diagnoses of Parkinson's disease between 2007 and 2023. Cox regression was used to compare the hazard of Parkinson's disease in individuals with depression with and without psychomotor retardation. Results: Among 6327 patients with depression, 2402 (38.0%) had psychomotor retardation. The adjusted hazard ratio for development of Parkinson's in those with psychomotor retardation was 1.43 (95% CI 1.02 - 2.01, p = 0.04). Secondary analyses demonstrated a significant difference in psychomotor retardation incidence at least 10 years before Parkinson's diagnosis. Conclusions: Psychomotor retardation in later-life depression is associated with increased risk of subsequent Parkinson's diagnosis over an extended period of time, suggesting that the relationship cannot solely be explained by misdiagnosis. Psychomotor retardation may therefore serve as a marker of prodromal Parkinson's disease.

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim light conditions at six predefined time points around habitual sleep onset (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.

Disability worsening is the critical long-term outcome in multiple sclerosis, yet the Expanded Disability Status Scale incompletely captures neurological deterioration and has limited sensitivity in the short time windows of clinical trials. Composite endpoints incorporating functional measures have been proposed to address these limitations, but whether they reliably improve detection of treatment effects has not been established across trials. We conducted a post-hoc analysis of individual patient data from ten phase III randomised controlled trials (ASCEND, BRAVO, CONFIRM, DEFINE, EXPAND, INFORMS, OLYMPUS, OPERA I/II, and ORATORIO; n = 9,369), spanning relapsing-remitting and progressive multiple sclerosis. Confirmed disability worsening was defined using harmonised criteria with the msprog package and confirmed at 24 weeks. Treatment effects were estimated using Cox proportional hazards models and combined across trials in a one-stage individual patient data framework. Composite endpoints were constructed from the Expanded Disability Status Scale, the timed 25-foot walk test, and the nine-hole peg test using logical unions (OR-type), intersections (AND-type), and majority-vote structures. Sensitivity to treatment effect was quantified using Z-scores (the ratio of the pooled log-hazard ratio to its standard error) and compared to the Expanded Disability Status Scale reference using interaction tests. Event rates varied across components: the timed walk test generated the highest rates (up to 46.8%) while the nine-hole peg test generated the lowest (as low as 2.1%). OR-type composite endpoints showed weaker treatment effects than the Expanded Disability Status Scale alone, with the largest reductions in sensitivity observed for endpoints incorporating the timed walk test ({Delta}Z up to +2.26; interaction p = 0.004). These findings were confirmed across disease subtypes and were pronounced in relapsing-remitting trials, where no composite endpoint outperformed the Expanded Disability Status Scale. In progressive multiple sclerosis, the combination of the Expanded Disability Status Scale and the nine-hole peg test showed numerically stronger treatment effects ({Delta}Z = -1.65), though interaction tests did not reach statistical significance (p = 0.051). Composite endpoints do not systematically improve treatment effect detection in multiple sclerosis trials. Increased event capture driven by the timed walk test introduces noise that dilutes the treatment signal rather than amplifying it, highlighting that event rate and endpoint quality are not interchangeable. Upper limb function assessed by the nine-hole peg test provides complementary and specific information, particularly in progressive disease. The combination of global disability and upper limb measures represents a promising direction for future endpoint development in progressive multiple sclerosis trials, warranting validation.

ObjectiveTo examine whether menopausal women who initiate systemic menopausal hormone therapy (MHT) around menopause (45-60 years old) have a different risk of developing dementia than those not taking MHT. DesignSystematic review and meta-analysis of randomised controlled trials and longitudinal observational studies. Risk of bias was assessed using ROB-2 and ROBINS I-V2. Data sourcesMEDLINE, Web of Science, EMBASE, and Cochrane Library to 27 March 2026. Eligibility criteria for selecting studiesStudies which measured dementia or cognitive decline in women who initiated systemic MHT between ages 45-60 or within 5 years of menopause, compared with placebo or no MHT. Authors contacted for additional details if needed. Main outcome measuresDementia, Alzheimers disease (AD), cognitive decline. Results10 studies totalling 213,678 participants (189,525 in studies with the primary population). There was no significant increased risk in women with a uterus for all cause dementia (pooled hazard ratio (HR): 1.12; 95% CI 0.91-1.31, N=78,613, I2 = 96.9%), but increased AD risk (HR: 1.14; 95% CI 1.02, 1.29, N=134,865, I2 = 35.6%). Results were similar in sensitivity analyses including women with or without a uterus. Results for cognitive decline were variable. ConclusionsMHT initiated around the age of menopause should not be prescribed for cognition or dementia prevention. It is not protective against dementia and may increase risk slightly. The magnitude of risk was similar in AD and dementia, but the latter with larger confidence intervals. Studies which followed up individuals rather than on health records lost people to follow up. This may account for difference in cognitive decline outcomes between studies, as people with cognitive impairment and dementia are more likely not to attend. MHT prescribing should balance benefits against risks, including evidence of a small increased dementia risk. There are few high-quality studies, so further research would inform recommendations. Systematic review registration Prospero CRD420251010663 What is already known on this topic?O_LIMenopausal hormone therapy (MHT) is effective for alleviating vasomotor symptoms. Contemporary guidelines recommend treatment should be initiated for such symptoms under age 60 and or within 10 years of menopause onset. C_LIO_LIA large randomised trial on the topic found increased risk of dementia in women initiating MHT after the age of 65. C_LIO_LIIt is unknown whether initiating MHT around the age of menopause impacts the risk of dementia or cognitive decline. C_LI What this study addsO_LIThere was no evidence that taking MHT around the time of menopause decreases the risk of dementia or cognitive impairment. C_LIO_LIThey should not be prescribed for these indications. C_LIO_LIWe were able to find more studies which examine this question by contacting authors for additional data. C_LIO_LIInitiating MHT in women with a uterus around the age of menopause increased the risk of Alzheimers disease slightly, by over 10%, and there is a similar but not significant effect in the fewer studies of all cause dementia. Women with or without a uterus show similar results. C_LIO_LIWe found no significant difference shown in cognitive decline, possibly due to loss to follow up. This may be because most studies of cognitive decline follow up C_LI

Background: Most trials of Parkinson's disease (PD) measure progression over a short to medium time-period using continuous rating scales that may be hard to interpret and less meaningful for patients. There is a lack of evidence connecting changes in these scales to changes in outcomes important to patients. Objectives: We present causal modelling to translate the causal, short-term disease-modifying treatment effects on functional rating scales to the 10-year risk of serious clinical progression milestones. Methods: We selected four important clinical milestones of disease progression from the Oxford Parkinson's Disease Centre "Discovery" cohort: dementia, any falls, frequent falls, and mortality. We proposed a causal framework for our research objectives so we could model the potential impact of a 30% reduction in disease progression slopes ("treatment effect") using the summation of parts I and II of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS12). This outcome was regressed on time to milestone using flexible parametric survival models. Marginal predictions of survival and survival difference at year 10 were then calculated for the Discovery cohort, and a counterfactual cohort applying the treatment effect to estimate the relative and absolute reductions for the four clinical milestones. Results: The model increase in risk for each unit change in the UPDRS12 were as follows: dementia hazard ratio (HR)=1.52 (95% Confidence Interval (CI) 1.36-1.70), any falls HR=1.37 (95% CI 1.29-1.46), frequent falls HR=1.68 (95% CI 1.49-1.89), mortality=1.29 (95% CI 1.17-1.42). These models led to marginal predictions of absolute reductions, when the progression was reduced by 30%, between 4.0% (mortality) and 7.5% (frequent falls) at 10 years follow up. Conclusions: We have demonstrated how a treatment effect in a trial specified in terms of a progression change of a rating scale can be contextualised into a long-term reduction in the probability of clinically relevant milestones. Whilst we have used PD as our exemplar, we believe this methodological approach is generalisable to other chronic progressive diseases where trials are often limited to a relatively short follow-up period and use some scalar measure of progression, but significant clinical milestones usually take longer to be observed. Keywords: Clinical trials; disease modifying therapies; causal estimation; prediction models

Background Deep brain stimulation (DBS) targeting the ventral intermediate nucleus (Vim) of the thalamus is an established surgical therapy for medically refractory tremor, particularly essential tremor. Accurate localization of the Vim remains challenging because the nucleus is not directly visible on conventional MRI. Consequently, multiple targeting approaches have been developed, including atlas-based stereotactic coordinates, microelectrode recording (MER), advanced MRI visualization techniques, and diffusion-based tractography. This systematic review and meta-analysis evaluated current Vim targeting strategies and synthesized tremor outcomes following intervention. Methods This systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines and registered in PROSPERO. PubMed/MEDLINE, Scopus, Web of Science, and Embase were searched from inception to January 29, 2026. Studies investigating Vim-targeted tremor surgery and reporting targeting strategies or tremor outcomes were eligible. Data extraction and risk of bias assessment were performed independently by two reviewers using JBI and QUADAS-2 tools. Random-effects meta-analysis using standardized mean differences (Hedges g) was performed to evaluate pre- to postoperative tremor improvement. Results A total of 2,398 records were identified, and 25 studies met inclusion criteria for the systematic review. Across these studies, 211 patients undergoing Vim-targeted tremor surgery were analyzed. Considerable heterogeneity was observed in study design, patient populations, imaging protocols, and targeting approaches, including atlas-based targeting, MER-guided localization, advanced MRI visualization, and diffusion tractography of tremor-related pathways such as the dentato-rubro-thalamic tract. Six studies comprising seven independent cohorts provided sufficient data for meta-analysis. Pooled analysis demonstrated substantial tremor improvement following intervention (SMD -3.91, 95% CI -4.81 to -3.01; p < 0.0001). Although between-study heterogeneity was moderate to substantial (Q = 18.12, p = 0.0059; I2 = 66.9%), all cohorts showed consistent reductions in tremor severity. Sensitivity analyses confirmed the stability of the pooled effect, and funnel plot and trim-and-fill analyses did not indicate significant publication bias. Conclusions Despite substantial heterogeneity in Vim targeting methodologies, surgical intervention consistently produces marked tremor reduction. Across anatomical, electrophysiological, and imaging-based targeting approaches, clinical outcomes remained robust. Future prospective studies with standardized outcome reporting and direct comparisons of targeting techniques are needed to determine whether emerging imaging-guided strategies provide measurable clinical advantages.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

ObjectiveVagus nerve stimulation (VNS) is an established neuromodulation therapy used in the management of drug-resistant epilepsy (DRE), or when other intracranial surgical modalities have not reduced seizure burden. We evaluated whether prior intracranial surgery for epilepsy influences safety and effectiveness outcomes with adjunctive VNS, using real-world data from the CORE-VNS study. MethodsCORE-VNS (NCT03529045), a prospective, multicenter, international observational study, was designed to collect data on seizure and non-seizure outcomes in patients with DRE treated with VNS. Participants were identified as having or not having undergone prior intracranial brain surgery for epilepsy (ICSE) and received an initial VNS implant. Baseline seizure frequency data and patient-reported outcome measures were collected at 3, 6, 12, 24, and 36 months. This analysis compared the baseline data for VNS therapy and safety outcomes at 36 months. ResultsAmong 531 participants implanted with VNS, prior ICSE was performed in 84. Median percentage seizure reductions at 36 months for all seizures (76.6% and 76.3%), all focal seizures (83.3% and 71.8%), and all generalized seizures (77.8% and 76.2%) were found to be similar between those without and with a history of ICSE, respectively. The 50% responder rate for all seizures reported at baseline was similar, 64.8% and 61.8%, in both groups and complete seizure freedom was reported by 17.9% and 8.8%, respectively. Implant-related adverse events (AE) and serious AE rates were similar between groups. ConclusionVNS was associated with clinically meaningful seizure reductions and showed a consistent safety profile irrespective of the history of ICSE. Prior ICSE should not be a contraindication to the consideration of VNS.

Background Chronic pain and depression are leading causes of disability and frequently co-occur. Depression presents with diverse symptoms, but despite this variability, the prevalence of individual depressive symptoms in chronic pain and the genetic and causal associations linking these traits remain poorly characterised. Methods Using data from 142,688 age- and sex-matched UK Biobank participants, we compared depressive symptom severity levels and item-level Patient Health Questionnaire-9 (PHQ-9) prevalences, spanning affective, cognitive and somatic domains, between participants with and without chronic pain. Using genome-wide association study (GWAS) summary statistics of multisite chronic pain (MCP), major depressive disorder (MDD), and individual symptoms of depression, genetic correlations and bidirectional causal effects between MCP and depressive phenotypes (MDD and individual symptoms) were estimated via linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomisation (MR), respectively. Results Depression (at every severity level) was more common in the chronic pain group compared to controls, with the largest between-group difference for severe symptoms (7.50-fold increase). All individual depressive symptoms were at least 2.79 times as prevalent in chronic pain. Additionally, chronic pain had a significant and positive genetic correlation with MDD (rg = 0.59) and all depressive symptoms (rg = [0.24, 0.55]). MR supported a bidirectional causal association between MCP and MDD (MCP[-&gt;]MDD: OR = 1.85, pFDR < 0.001, MDD[-&gt;]MCP: {beta} = 0.17, pFDR < 0.001). At the symptom level, MR indicated bidirectional effects between MCP and anhedonia (MCP[-&gt;]anhedonia: OR = 1.60, pFDR < 0.001, anhedonia[-&gt;]MCP: {beta} = 0.08, pFDR = 0.005), and unidirectional effects of MCP on appetite/weight gain (OR = 1.90, pFDR = 0.022) and appetite/weight loss (OR = 1.63, pFDR = 0.005), concentration problems (OR = 1.63, pFDR = 0.044), and suicidal thoughts (OR = 1.46, pFDR = 0.021). Additionally, genetic liability to concentration problems was associated with a lower risk of MCP ({beta} = -0.04, pFDR = 0.022). Conclusion Chronic pain is associated with a marked depressive burden spanning all symptom domains. Shared genetic architecture and symptom-specific causal pathways, particularly involving anhedonia, highlight potential targets for improved treatment of comorbid chronic pain and depression.

Background: Historically, OFF burden in Parkinsons disease has been primarily attributed to motor features. Recent studies highlight that non motor symptoms, and the predictability of OFF episodes also drive functional impairment, yet they are rarely measured in clinical practice. Objective: To identify which clinical features are most closely associated with OFF time and OFF impact, and to quantify the added explanatory value of temporal predictability, non-motor, and behavioural domains beyond a core motor model. Methods: We analysed 1,252 OFF only visits from 430 PPMI participants. Outcomes were MDS UPDRS IV 4.3 (OFF time) and 4.4 (OFF impact). Linear mixed effects models with a participant random intercept were fitted. The core motor model included OFF state motor severity, freezing, tremor, levodopa responsiveness, and dyskinesia, plus covariates. Predictability (IV; 4.5), non motor (mood, fatigue/sleep, autonomic/GI), and behavioural (impulse control behaviours) domains were then added to assess added influence beyond motor. Analyses were stratified by time since diagnosis (Pooled; [&le;] 4y; [&ge;] 6y). Results: Clinical features explained more variance in OFF impact than OFF time (25.9% vs 8.1%). OFF time was primarily linked to OFF state motor severity/freezing, with levodopa responsiveness important early. For OFF impact, predictability produced the largest increment in marginal R squared beyond the core motor model (pooled and Late). Within the core motor model, tremor was the largest contributor to OFF impact. Conclusions: Predictability is a prominent correlate of OFF impact. Asking about predictability may help tailor therapy, from timing optimisation to on demand rescue for unpredictable episodes.

Background: Concomitant gabapentinoid and dihydropyridine calcium channel blocker (DHP-CCB) use amplifies dementia risk, an interaction proposed to involve dual neuronal calcium channel blockade. Whether this risk depends on the sequence of drug initiation - and is therefore preventable by prescribing order - remains unknown. Methods: Using the Rutgers Clinical Research Data Warehouse (2015-2024), we conducted three complementary analyses. The primary analysis (Population 4) compared gabapentin versus pregabalin in 4,451 patients on chronic DHP-CCB therapy who newly initiated a gabapentinoid (55 dementia events; IPTW Cox model). The asymmetry confirmatory analysis (Population 3) compared DHP-CCB versus ACE/ARB initiation in 1,740 patients on chronic gabapentinoid therapy (29 dementia events). A sensitivity analysis replicated prior findings in a broader CCB-first cohort (N=9,383). A dementia acceleration analysis examined outcomes in 273 patients with established dementia initiating gabapentinoid. Results: In Population 4, gabapentinoid initiation on a background of chronic CCB therapy was associated with a 2.23-fold elevated dementia risk compared to pregabalin (IPTW HR 2.23, 95% CI 1.43-3.48, p=0.0004). The Population 3 asymmetry test yielded a null result: adding DHP-CCB to chronic gabapentinoid therapy carried no differential dementia risk versus adding ACE/ARB (IPTW HR 0.995, 95% CI 0.595-1.664, p=0.98). This directional asymmetry - elevated risk only when gabapentinoid is added to pre-existing CCB therapy, not the reverse - is the central finding. Lagged analyses showed HRs increasing monotonically from 2.23 to 2.87 across 0- to 180-day lag windows, reducing concern for protopathic bias. In the dementia acceleration cohort, DHP-CCB use at gabapentinoid initiation was associated with encephalopathy (IPTW HR 2.09, 95% CI 1.19-3.67, p=0.010); zero encephalopathy events occurred among non-DHP CCB users (N=16), consistent with DHP subtype specificity. Conclusions: The gabapentinoid-CCB cognitive interaction is directionally asymmetric: risk concentrates in patients adding gabapentinoid to pre-existing CCB therapy, not the reverse. This pattern is mechanistically consistent with impaired homeostatic synaptic plasticity in neurons compensating for chronic L-type calcium channel blockade. For patients already on CCB therapy requiring neuropathic pain management, pregabalin may be preferable to gabapentin, pending external validation. The asymmetry also implies that initiating a CCB in a patient already on gabapentin may not carry equivalent risk.

BackgroundPhenoconversion to Parkinsons disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. MethodsWe analyzed Parkinso[n]s Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimers disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [&ge;]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS) staging was applied. ResultsAmong 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15/47 (31.9%) iRBDs and 7/38 (18.4%) hyposmics were already NSD-ISS stage [&ge;]4 at time of phenoconversion. ConclusionsClinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.

BackgroundSubthalamic deep brain stimulation (STN-DBS) represents an established therapeutic intervention for advanced Parkinsons disease (PD), alleviating motor and non-motor symptoms. However, impulse control disorders (ICDs) present a complex challenge, with some patients experiencing postoperative improvements while others develop treatment induced impulsive-compulsive behaviours (ICB). The mechanisms determining these variable outcomes remain poorly understood, highlighting the need to predict postoperative ICB outcomes. MethodsThis prospective open-label study aimed to identify microstructural markers associated with postoperative changes in impulsive-compulsive behaviour following STN-DBS. Thirty-five patients underwent diffusion MRI and clinical evaluations preoperatively and six months postoperatively. A whole-brain voxel-wise analysis utilising diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) was conducted to explore associations between microstructural metrics and changes in the Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease-Rating Scale (QUIP-RS). ResultsIntact microstructure in frontolimbic WM tracts, including the cingulum, insular cortex connections, and major association fibres, was associated with greater postoperative reductions in impulsive-compulsive symptoms. Conversely, intact microstructure in specific grey matter areas including paracingulate gyrus, insular cortex, and precentral gyrus were associated with lower reductions or increases in postoperative ICB. ConclusionThese findings demonstrate that preoperative microstructural integrity within frontolimbic circuits and executive control networks associates with susceptibility to treatment-emergent impulsive-compulsive behaviours following STN-DBS. The convergent evidence from multiple diffusion metrics suggests that diffusion MRI may serve as a valuable tool for identifying patients at risk for developing ICB, potentially enhancing preoperative counselling and enabling targeted behavioural monitoring strategies.

Background: Clinical evidence on the contemporary management and functional outcomes of patients with Wernicke encephalopathy remains limited. This study aimed to clarify the nationwide patterns of thiamine administration and functional outcomes at discharge. Methods: Using the Japanese nationwide inpatient Diagnosis Procedure Combination database, we identified patients hospitalized with Wernicke encephalopathy between July 2010 and March 2024. Initial intravenous thiamine doses were categorized as low ([&le;]300 mg/day), medium (301-900 mg/day), or high (>900 mg/day). Outcomes included in-hospital mortality and functional status (Barthel Index) at discharge. Results: We identified 7856 patients with Wernicke encephalopathy. Over the 13-year study period, the proportion of patients receiving initial high-dose thiamine increased markedly from 5.4% to 49.0%, while the frequency of low-dose therapy decreased from 83.0% to 37.9%. Despite prompt intervention [median time to initial administration: 0 days (interquartile range, 0 to 0 days)], 56.1% of patients were discharged with impaired activities of daily living (Barthel Index <90), and the in-hospital mortality rate was 3.8%. Conclusions: High-dose thiamine treatment is increasingly implemented for Wernicke encephalopathy in Japan. Although in-hospital mortality was relatively low, the high prevalence of functional impairment at discharge, despite early treatment initiation, indicates substantial burden of Wernicke encephalopathy. Given the limited clinical evidence, further research investigating the optimal thiamine dose and develop effective primary prevention strategies for Wernicke encephalopathy is needed.

Nighttime agitation (NA) is a prevalent and challenging phenomenon affecting people with dementia (PwD), often resulting in premature institutionalization. Yet, informal caregivers' perspectives on this phenomenon remain underexplored. We conducted 15 in-depth interviews with informal caregivers to gain insight into their experiences and reactions to NA. Thematic analysis identified seven sub-themes related to carers' experience and eight sub-themes concerning their reactions. These themes emerged across three levels, namely, PwD, informal caregiver and the environment. Most phenomena occurred at a dyadic level between PwD and informal caregiver, highlighting the potential of interventions targeting dyadic coping. Informal caregivers feel insufficiently supported when sleep disturbances co-occur with NA. They primarily rely on self-initiated strategies and learn by experience. Caregivers mention the need for more advanced knowledge and skills in reacting to co-occurrence of sleep disturbances with NA or systemic support in terms of dealing with emergencies. Caregivers also reflect extensively on the impact of challenging behaviors during the night on their mental and physical well-being. Notably, no non-pharmacological interventions for NA adequately address the themes identified in this study, highlighting the urgent need for integrative approaches and recognition of caregiver wellbeing as a core outcome, not a secondary consideration in interventions.

Background Chronic pain and depression are prevalent and burdensome conditions that frequently co-occur. Separate neuroimaging studies of each disorder suggest overlapping brain-structure alterations, however, relatively few studies have examined their comorbidity directly, and the neuroanatomical profile of co-occurring chronic pain and depression remains unclear. Methods Using UK Biobank data (n = 71,214), we conducted cross-sectional pairwise association analyses of brain structure (cortical measures, subcortical volumes, and white matter microstructure) comparing participants with current comorbid chronic pain and depression, current chronic pain only, current depression only, and controls. Results Compared with controls, the comorbidity group showed regional differences in cortical surface area and thickness ({beta} range = -0.096 to 0.098, pFDR < 0.05), widespread lower cortical volume ({beta} range = -0.096 to -0.050, pFDR < 0.05), lower thalamic (left: {beta} = -0.048, pFDR = 0.038; right: {beta} = -0.060, pFDR = 0.007), hippocampal (left: {beta} = -0.062, pFDR = 0.035; right: {beta} = -0.088, pFDR = 0.002) and left accumbens volume ({beta} = -0.073, pFDR = 0.011), and evidence of widespread white matter microstructure alterations (fractional anisotropy: {beta} range = -0.116 to -0.080, pFDR < 0.05; mean diffusivity: {beta} range = 0.063 to 0.137, pFDR < 0.05). Pairwise comparisons with the disorder-specific groups also identified several alterations unique to the comorbidity group. Compared to controls, those with chronic pain only had widespread lower cortical surface area and volume ({beta} range = -0.043 to -0.015, pFDR < 0.05), whereas non-comorbid depression showed more regionally specific lower cortical thickness and volume ({beta} range = -0.140 to -0.062, pFDR < 0.05) and lower thalamic volume (left: {beta} = -0.067, pFDR = 0.016; right: {beta} = -0.066, pFDR = 0.015), alongside widespread white matter microstructure deficits (fractional anisotropy: {beta} range = -0.104 to -0.083, pFDR < 0.05; mean diffusivity: {beta} range = 0.079 to 0.149, pFDR < 0.05). Conclusion These results provide a robust characterisation of brain structure alterations in comorbid chronic pain and depression, highlighting a distinct neuroanatomical profile and advancing understanding of its underlying neurobiology.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.