Journal of the Neurological Sciences

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is frequently complicated by delayed cerebral ischaemia (DCI), for which current therapies incompletely target the underlying multifactorial pathophysiology. Transauricular vagus nerve stimulation (taVNS) modulates inflammatory, vasoactive and autonomic pathways and may attenuate secondary brain injury after aSAH. Methods: We conducted a prospective, single-centre, single-blind, randomised, sham-controlled pilot trial in adults within 5 days of aneurysm securing for non-traumatic aSAH. Participants were allocated 1:1 to active taVNS (left tragus) or sham (left earlobe) using a portable device delivered for 45 minutes twice daily over 5 days. Primary outcomes were safety (taVNS-related serious adverse events), acceptability, and compliance; secondary outcomes included inflammatory biomarkers, DCI, in-hospital complications, and functional outcomes to 1 month. Results: Thirty patients were randomised (16 taVNS, 14 sham), with numerically more severe aSAH at baseline in the taVNS arm. No taVNS-related serious adverse events occurred; side effects were generally mild and transient, and over 80% of planned sessions were completed. TaVNS produced greater reductions in serum tumour necrosis factor- and trends towards reductions in interleukin-1{beta} and interleukin-10, with numerically fewer DCI events (6.6% vs 35.7%) and neurological impairments (16.7% vs 53.8%), although functional outcomes were not statistically different at 1 month. Conclusions: Early taVNS after aSAH is safe, acceptable, and feasible in the neurocritical care setting and shows biologically plausible signals warranting evaluation in larger multi-centre trials.

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.

Background: On-call clinicians frequently report the anecdotal impression of 'theme shifts' during which specific acute neurological diagnoses appear to cluster. Whether such clustering reflects a statistically true and reproducible phenomenon has not been systematically investigated; the present paper examines seasonality and temporal clustering within six different acute neurological conditions. Methods: In this retrospective, single-center cohort study, we identified all patients admitted to a tertiary neurological department between July 2016 and June 2026 with acute unilateral vestibulopathy, cerebral artery dissection, generalized epileptic seizures, primary intracerebral hemorrhage, peripheral facial nerve palsy, or transient global amnesia (TGA) (n = 2,140). Monthly and seasonal distributions were assessed using chi-squared goodness-of-fit and cosinor analysis. Short-term temporal clustering was tested by Monte Carlo permutation across time windows from 24 hours to 90 days, and endogenous cluster dynamics were characterized using Hawkes self-exciting point process modeling. Results: Admissions for generalized epileptic seizures showed a statistically significant deviation from a uniform monthly distribution with a winter distribution (p<0.001 and q = 0.002), and a significant temporal clustering across time windows from 72 hours to 90 days (all q < 0.05). Peripheral facial nerve palsy presented significant clustering at the 90-day window (q = 0.029) and TGA at 60-day time window (q = 0.041) without seasonality; the diagnostic groups of acute unilateral vestibulopathy, cerebral artery dissection and primary intracerebral hemorrhage showed neither seasonality nor clustering after correction for multiple comparison. No diagnostic group showed clustering within a 24-hour window, statistically significant self-excitation in Hawkes process modelling, or a significant linear trend in monthly case counts over the study period. Conclusion: The anecdotal impression of diagnostic 'theme shifts' among on-call neurologists appears to have a measurable basis, although clustering is confined to specific conditions and rather on a time scale of weeks to months. Generalized epileptic seizures were the only diagnostic group that uniquely combined seasonality with temporal clustering, suggesting a shared trigger, while facial palsy and TGA showed episodic, yet non-seasonal clustering.

Background: Evidence regarding delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains sparse. We aimed to identify its predictors and occurrence and evaluate its role in ischemic stroke and functional outcome under treatment with interventional rescue therapy (IRT). Methods: This retrospective single-center study included 628 adults with aSAH from 2014?2023. The primary endpoint was occurrence of refractory DCI (= refractory despite induced hypertension) treated with at least one IRT. Multivariable models evaluated refractory DCI, new ischemic stroke, and poor functional outcome (mRS 3?6) at 6?12 months. Results: Among 628 included patients, 61 who died within 3 days were excluded from DCI analysis; 166/567 (29%) developed refractory DCI. Younger age (OR = 0.98; P<0.001), female sex (OR = 0.57; P=0.007), and higher WFNS grade (OR = 1.18; P=0.011) were independently associated with refractory DCI. Earlier first IRT was associated with longer DCI duration (IRR = 0.88; P<0.001) and more required IRTs (IRR = 0.91; P<0.001). IRT was performed later than day 14 in 29/166 patients (17.5%); none was older than 70 years. Refractory DCI was associated with new ischemic stroke (OR = 4.68; P<0.001) and poor functional outcome (OR = 2.37; P<0.001); earlier first IRT was associated with poor outcome within the refractory DCI subgroup (OR = 0.86; P=0.03). Outcomes after 1?2 IRTs did not differ from those without refractory DCI (P=0.4), whereas ?3 IRTs were associated with poor outcome (P=0.04). Conclusions: Refractory DCI affected 29% of aSAH patients, predominantly younger women and patients with poorer initial neurological status, and extended beyond day 14 in nearly 20% of affected patients, none of whom was older than 70 years. Refractory DCI and earlier onset were associated with poorer radiological and functional outcomes. The absence of a detected outcome difference after 1?2 IRTs suggests that favorable outcomes may remain achievable despite refractory DCI.

Background: Storage symptoms after stroke-isolated urgency, urgency with frequency, and isolated frequency are common but traditionally attributed to a single overactive bladder mechanism via suprapontine disinhibition. However, clinical heterogeneity in symptom presentation suggests distinct underlying mechanisms. We aimed to characterize the neural substrates of three storage symptom subtypes after stroke using comprehensive lesion-symptom mapping. Methods: We prospectively evaluated 1,498 consecutive subacute stroke patients admitted for inpatient rehabilitation (1,105 men, 73.8%; median age 61 years). Storage symptoms were classified into three subtypes: isolated urgency (n=109), urgency with frequency (n=32), and isolated frequency (n=19). Multivariable logistic regression models with Bonferroni correction identified independent predictors across demographic, clinical, white matter hyperintensity (WMH), brain atrophy, and lesion location variables. Results: The three subtypes demonstrated largely distinct sets of independent predictors. The left genu of the corpus callosum (aOR=20.06, 95% CI 7.78-51.74, P<0.001) and the inferior frontal gyrus (aOR=3.48, 95% CI 1.81-6.67, P<0.001) were independently associated with isolated urgency and survived Bonferroni correction, together with a right IFG-insula synergistic effect (OR=21.46, 95% CI 10.49-43.88, P<0.001). Urgency with frequency was associated with a broad fronto-cingulate network-the IFG (aOR=11.45, 95% CI 3.10-42.33, P<0.001, surviving Bonferroni correction) and the ACC (aOR=11.53, 95% CI 2.40-55.49, P=0.002) with diffuse right-hemisphere dominance, older age and brain atrophy. Isolated frequency was associated with anterior corona radiata involvement (aOR=5.46, 95% CI 1.92-15.54, P=0.002) and male sex (aOR=10.62, 95% CI 1.36-82.98, P=0.024), though none reached the strict Bonferroni threshold. Conclusions: These findings identify three mechanistically distinct post-stroke storage symptom subtypes with separable neural substrates, lateralization profiles, and clinical determinants. The triple dissociation across subtypes supports a discrete pathway model over the traditional unitary OAB framework, providing a neuroanatomically grounded basis for subtype-stratified treatment Keywords: storage symptoms; subacute stroke; hemispheric lateralization; structural synergy; lesion-syndrome mapping

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

BACKGROUND: Subarachnoid hemorrhage (SAH) induces inflammatory responses and subsequent immune cell activation, which may contribute in cerebral vasospasm, microcirculatory impairment and poor neurological outcomes. Although cerebral vasospasm has traditionally been considered a major cause of delayed cerebral ischemia after SAH, therapies targeting angiographic vasospasm have not consistently improved functional outcomes. Early inflammatory responses may contribute to microcirculatory impairment, cerebral vasospasm, and subsequent neurological injury. Herein, we investigated whether interleukin-10 (IL-10), an anti-inflammatory cytokine, improves these outcomes in an experimental SAH model. METHODS: Mice received intramuscular injections of either an adeno-associated virus encoding IL-10 (AAV/IL-10) vector or an AAV expressing green fluorescent protein (AAV/GFP) vector (control). India ink angiography was performed to assess the diameter of the sphenoidal segment of the middle cerebral artery (MCA), the total length of the visible cortical arteries, and cortical staining intensity, as indices of cerebral vasospasm, microcirculatory impairment, and cerebral perfusion, respectively. Perivascular inflammatory cell infiltration and cytokine levels were assessed using immunohistochemistry and ELISA. We also evaluated the therapeutic efficacy of the AAV/IL-10 vector when administered immediately after SAH induction. RESULTS: IL-10 overexpression significantly improved neurological outcomes after SAH and was associated with attenuated cerebral vasospasm and microcirculatory impairment, as well as preservation of cerebral perfusion. It also significantly reduced neutrophil and macrophage infiltration around the internal carotid artery and attenuated SAH-induced elevations in IL-6 and matrix metalloproteinase-3 levels. Mice treated with the AAV/IL-10 vector immediately after SAH induction showed significant improvements in neurological scores and cerebral perfusion. CONCLUSIONS: AAV-mediated IL-10 overexpression improves neurological outcomes after SAH, likely by attenuating inflammatory responses, cerebral vasospasm, and microcirculatory impairment. These findings suggest that IL-10-based anti-inflammatory therapy is a promising therapeutic strategy for SAH.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.

Background The time trend in long-term survival after a stroke is to some extent unknow due to (relatively) short follow up periods in available data. The objective of this study is to identify and quantify differences in long-term stroke survival in Sweden between men and women and patients with different attained educational levels, comparing two time-periods, 2000-2009 and 2010-2022. Methods This study employs total population Swedish register data pertaining to hospital-based care and mortality due to stroke for the period 2000-2022 in order to estimate survival (all-cause mortality) after ischaemic and haemorrhagic stroke, respectively, and pertaining to attained educational level. Kaplan-Meier survival functions are estimated stratifying for time-period, sex and educational level. Cox regressions are employed to quantify mortality hazard ratios between the strata. Age is taken into account in complementary analyses (supplement). Results Taking only time-period (2000-2009 vs 2010-2022) into account resulted in significantly higher survival in the second period for ischaemic stroke patients (HR: 0.84; 95% CI: 0.83-0.84), while no significant difference could be detected for haemorrhagic stroke. Stratifying for sex showed that men gained more than women in terms of reduced mortality hazard rate between the periods. Further stratifying by educational level and estimating survival separately for men and women showed that, for both men and women, patients with the lowest education were relatively worse off (compared to patients with higher education) in the second period. Further analyses, taking age into account, reversed the relative hazard ratio between men and women, but corroborated the result that low education is associated with poorer outcome than high education. Conclusions The results suggest that there are considerable differences in expected long-term survival after stroke between the sexes, but that this may be due to differences in age between the sexes at the time of stroke. Moreover, lower educational level is significantly associated with lower long-time survival.

Purpose. Prognostic assessments after acute brain injury are largely narrative, and how prognostic language relates to subsequent care has not been measured at scale. We quantified where it is written and its association with a subsequent code-status limitation. Materials and Methods. Multidatabase observational study of adults with acute brain injury or a related neurologic emergency, using MIMIC-IV (2008-2019; discharge summaries and radiology reports) and a timestamped MIMIC-III cohort (notes and code-status orders). The exposure was documented prognostic language; outcomes were its association with a subsequent full-code-to-limitation transition, note-stream location, and completeness of documented command-following relative to structured Glasgow Coma Scale (GCS) motor scores. Results. Among 31,993 admissions (27,054 patients; median age, 69 years; 54.9% male), prognostic language in the timestamped cohort (MIMIC-III) was associated with a subsequent code-status limitation after multivariable adjustment (adjusted hazard ratio, 4.3; 95% CI, 2.9-6.5; unadjusted 14-day cumulative incidence, 40% vs 8.5%), including the comfort-measures component (3.9), a higher-risk subgroup (4.4), and after acute-physiology adjustment (4.1); the association was concentrated in the first 3 days. Non-prognostic severity language showed no comparable association (hazard ratios, 1.1-1.3). Prognostic language localized almost entirely to the narrative (4.9% of discharge summaries vs 0.015% of radiology reports); command-following was undocumented in 55.7% of summaries, and no final-24-hour GCS motor score was charted in 72.8%. Conclusions. Documented prognostic language after acute brain injury was written in the narrative, not structured fields, and was associated with a subsequent code-status limitation after multivariable adjustment. This observational association cannot establish causation but warrants prospective study.

BACKGROUND: Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics. METHODS: In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro. Pericyte-deficient mice (Pdgfr{beta}+/-) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice (Vgll3{Delta}PC) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging. RESULTS: After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfr{beta}+/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction. CONCLUSIONS: Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH.

Background and Objectives: Recurrence following burr-hole drainage of chronic subdural haematoma (cSDH) occurs in 10-25% of cases, sustained by neovascularisation of the subdural neomembrane supplied by the middle meningeal artery (MMA). MMA embolisation reduces recurrence; whether incidental burr-hole intersection of MMA branches during drainage confers similar benefit is unknown. Methods: We performed a multicentre retrospective cohort study of consecutive adults undergoing burr-hole drainage for cSDH at two UK tertiary neurosurgical centres. Postoperative thin-slice CT was used to classify burr-hole intersection of the underlying MMA groove (no hit, distal-branch hit or main-branch hit) and measure perpendicular burr-hole-to-MMA-groove distance. Co-primary outcomes were radiological recurrence and recurrence requiring intervention. Patient-clustered multivariable logistic regression adjusted for prespecified clinical covariates and treating site. Results: 227 patients (284 operated hemispheres) were included. Radiological recurrence decreased from 34.4% with no branch hit to 22.9% with main-branch intersection, with the gradient confined predominantly to unilateral cSDH. Main-branch intersection was associated with lower adjusted odds of radiological recurrence in unilateral cSDH (adjusted OR 0.30, 95% CI 0.11- 0.81; P = .018), with a similar but non-significant association in the overall cohort (adjusted OR 0.53, 95% CI 0.26-1.07; P = .075). Burr-hole-to-MMA-groove distance demonstrated a more consistent association: in the overall cohort, each 5-mm increase independently increased the odds of radiological recurrence (adjusted OR 1.38, 95% CI 1.04-1.82; P = .025). In unilateral cSDH, each 5-mm increase was independently associated with both radiological recurrence (adjusted OR 1.45, 95% CI 1.03-2.04; P = .034) and recurrence requiring intervention (adjusted OR 1.52, 95% CI 1.05-2.20; P = .027). Conclusion: Main-branch intersection of the middle meningeal artery during routine burr-hole surgery is associated with lower recurrence of unilateral cSDH, while the accompanying burr-hole-to-MMA-groove distance gradient provides biologically plausible support for a dose-response relationship. Together, these findings provide mechanistic rationale for prospective evaluation of intentional neuronavigation-guided MMA targeting (BURR-MMA; NCT07549893).

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

Background: Brain age is a biomarker of brain tissue integrity associated with disability in multiple sclerosis. While new lesion formation is central to MS diagnosis and treatment monitoring, its direct relationship to brain aging has not been established. Methods: We analyzed 163 people with MS with clinical and MRI assessments at baseline and years 3, 6, and 8. Brain age was estimated using BrainAgeNeXt. Annualized brain age acceleration was modeled as a function of radiological activity using generalized estimating equations, adjusting for age, sex, disease duration, baseline T2 lesion volume, normalized brain volume (NBV), brain age difference (BAD), and disease-modifying therapy. Secondary analyses examined dose-response effects, post-activity recovery, paramagnetic rim lesion (PRL) associations, and disability associations. Results: 105 participants had at least one new T2 lesion over 8 years. Radiologically active intervals (138 of 333) were associated with +0.19 yr/yr greater brain age acceleration than stable intervals (95% CI: 0.03-0.37; p=0.022), scaling with lesion count (beta=+0.18; p=0.001) and volume. Older age, greater baseline BAD, and NBV were independently associated with reduced brain age acceleration. Brain age acceleration in individuals with new lesions normalized during subsequent stable intervals (0.41 vs -0.06 yr/yr; p=0.001). Both PRLs and non-PRL lesions were associated with greater brain age acceleration than stable intervals. Baseline BAD, but not annualized acceleration, predicted Expanded Disability Status Scale (EDSS) and Nine-Hole Peg Test (9HPT) worsening. Conclusions: New focal lesion formation is associated with a quantifiable, dose-response acceleration of brain aging in MS that normalizes once lesion activity is suppressed.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

Impaired gait performance and stability is a key symptom often defining disease outcome in people with Multiple Sclerosis. Step-by-step foot placement control in response to variations in the center-of-mass kinematic state is a crucial gait stability mechanism, especially in the mediolateral direction. Even though it is known that people with Multiple Sclerosis are at an increased risk of falling, step-by-step foot placement control remains to be characterized in this population. Here, we explored characteristic foot placement control in ten people with early stage Multiple Sclerosis, compared to 21 controls walking at a similar average gait speed, during 1-minute steady-state treadmill walking. Kinematic data were analyzed using a linear feedback model that correlated foot placement with the center-of-mass kinematic state during the preceding swing phase. People with Multiple Sclerosis demonstrated step-by-step foot placement control in both the mediolateral and anteroposterior directions. No differences were found in foot placement precision between groups. However, foot placement responses to variations in center-of-mass velocity proved stronger in people with Multiple Sclerosis. Moreover, the contribution of mediolateral center-of-mass velocity feedback to the control mechanism was higher in people with Multiple Sclerosis as compared to neurologically healthy controls. Our results suggest that foot placement control is still retained in early clinically evident stages of Multiple Sclerosis, but is realized through differently weighted sensory feedback control.

Background and Objectives: Deep sequencing of brain tissue in the research setting has established that mosaic variants are a major cause of malformations of cortical development (MCDs) and epilepsy. However, genetic testing in the clinical setting primarily detects germline variants using clinically accessible samples. We aimed to determine the diagnostic yield and clinical utility of deep sequencing in the clinical setting to identify pathogenic mosaic variants for this population. Methods: We performed a retrospective cohort analysis of individuals at Boston Children's Hospital with MCDs with or without epilepsy who received clinical deep sequencing between September 2017 and February 2026. Demographic, clinical, and genetic testing data were abstracted from the medical record. For individuals without systemic features, we classified brain tissue as an affected tissue sample. For individuals with systemic features, we classified brain or relevant non-brain tissue as affected. The primary outcome was the diagnostic yield of clinical deep sequencing performed using affected vs unaffected tissue samples. The secondary outcome was the clinical utility of genetic diagnoses. Results: Our cohort included 37 individuals (19/37 (51%) female, 18/37 (49%) male) with MCDs, of whom 35/37 (95%) had epilepsy (25 with brain tissue samples available from epilepsy surgery) and 8/37 (22%) had systemic features. Most (35/37 (95%)) had dysplasia phenotypes on MRI and 12/27 (44%) with pathology available had Focal Cortical Dysplasia Type I or II. The diagnostic yield was 53% (17/32; 16 mosaic and 1 germline variant) when clinical deep sequencing was performed using an affected tissue sample vs 0% (0/6) using an unaffected tissue sample (p=0.016). Of the diagnosed cases, 13/17 (76%) had testing performed on brain tissue (1 with systemic features) and 4/17 (24%) on non-brain tissue (3 buccal and 1 duodenal tissue, all with systemic features). All but one diagnosis involved the mTOR pathway. All diagnoses had clinical utility. Discussion: Clinical deep sequencing, when performed using an affected tissue sample, has high diagnostic yield and clinical utility for individuals with MCDs, especially dysplasia phenotypes, and epilepsy. Our findings support implementation of clinical deep sequencing for this population, especially as the genetic diagnoses have implications for emerging precision therapies.

Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India Young Onset Parkinsons Disease project (GOPI YOPD). The cohort included 668 participants (463 males 69.3%) with a mean age at motor onset of 39.4+/-8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local network clusters. Terms meeting a Benjamini Hochberg false discovery rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene to pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations. At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy related processes (228/336, 67.9%) and regulation of synaptic vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway phenotype association remained significant after correction for multiple testing. Genetic findings in this Indian cohort converged across an interconnected mitochondrial autophagic lysosomal vesicular network, with different contributions from P/LP-associated and VUS associated gene sets. This study provides the first pathway resolved South Asian genetic profile and a framework for comparative studies across populations.