Neurology

Background: In atrial fibrillation (AF), cerebral microbleed (CMB) burden guides anticoagulation decisions, yet AF is itself inconsistently associated with CMBs, a paradox unexplained by frameworks that treat CMBs as a unitary marker of small vessel disease. We hypothesized that the white matter hyperintensity (WMH) context in which CMBs arise modifies their vascular meaning, and that this context-dependence underlies the inconsistent AF-CMB association. Methods: From a multicenter Korean stroke registry, we analyzed 5,735 first-ever ischemic stroke patients imaged at nine centers using susceptibility-weighted MRI. WMH volume and CMB count were extracted by validated deep learning pipelines. Patients were cross-classified by age-adjusted WMH residual (median split) and CMB count (2) into four groups. The AF-CMB association was estimated by multivariable logistic regression within each WMH stratum with formal interaction testing. Spatial CMB distribution was analyzed against the Automated Anatomical Labeling atlas. Results: In the full cohort (mean age 69.5 years; 57.7% male), AF was not associated with CMBs (OR 1.04; 95% CI 0.87-1.25). Stratification yielded divergent estimates: the adjusted AF OR was 1.46 (1.11-1.93; P = 0.007) in the WMH-low stratum and 0.95 (0.73-1.22; P = 0.665) in the WMH-high stratum, with significant interaction (OR 0.56; P < 0.001). The discordant phenotype (low WMH, high CMB; 8.9%) was enriched for AF (28.0%) and showed fronto-temporal cortical predominance with deep structure sparing. AF independently reduced the proportion of deep CMBs (IRR 0.80; P = 0.040). The interaction was preserved across prespecified sensitivity analyses. Conclusions: The AF-CMB association is confined to patients with low WMH burden relative to age and is accompanied by a topographically distinct CMB distribution. Clinical assessment of small vessel disease based on WMH alone may overlook a CMB phenotype linked to AF.

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+/-}SD, 25.9{+/-}3.2 years), sex (53% female), or number of visits (2.1{+/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Background and Objectives: Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy. Methods: Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE. Results: Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, p<0.001), reflecting reduced thickness/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, p=0.050), memory performance ({beta}= 0.30, p=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age. Discussion: AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.

Introduction: Aphasia is an acquired language disorder with a significant negative functional impact. Much of the research on aphasia has focused on word-level language comprehension and production. Further evaluation of discourse-level tasks, both at behavioral and neural levels, will allow for an ecologically valid understanding of the functional implications of language impairment in this population. Method: This study evaluated bilateral frontal, temporal, and parietal cortical activity during computer-based narrative production in 14 young neurotypical individuals, 17 individuals with post-stroke aphasia, and 15 age-matched neurotypical participants using functional near-infrared spectroscopy (fNIRS). Oxygenated hemoglobin (HbO) was measured during narrative production following short video clips and compared to HbO during counting aloud. In addition, behavioral measures quantifying in-task performance were correlated with averaged HbO values. Results: Young neurotypical individuals showed greater cortical activity in bilateral language regions for narrative production compared to counting aloud. In contrast, people with aphasia showed positive condition-related effects in the right frontal ROI and the age-matched group showed positive condition-related effects in the left frontal and right precentral ROIs. Each group showed different patterns in relationships between cortical activity and discourse performance measures. Conclusion: Overall, young participants showing more consistent condition-related effects for narrative discourse production than individuals with aphasia and age-matched controls. This study shows the potential for fNIRS to evaluate cortical activity for ecologically valid language tasks in individuals with post-stroke aphasia.

Background: Post-stroke apathy (PSA) is a common, disabling syndrome with few evidence-based treatment options. We evaluated the safety, feasibility, acceptability, and evidence of effects of a three-day accelerated intermittent theta burst stimulation-repetitive transcranial magnetic stimulation (iTBS-rTMS) protocol targeting the left dorsomedial prefrontal cortex (dmPFC) in chronic stroke survivors with apathy. Methods: Stroke survivors with symptomatic apathy received open-label iTBS-rTMS at the left dmPFC (21,600 pulses across 36 sessions; 3 treatment days; 12 sessions/day within one week). Safety endpoints included adverse events, neuroradiological findings, and objective cognitive performance. Secondary outcomes included measures of apathy and other neuropsychiatric symptoms as well as psychosocial functioning, including quality of life and caregiver burden. Participants were followed up for one month. Results: Fourteen participants (mean age = 61.8 {+/-} 14.0 years; mean time since stroke = 55.6 {+/-} 31.6 months) completed the iTBS-rTMS treatment course. No serious adverse events occurred. Participants rated the treatment as highly acceptable, and cognitive performance was stable from pre- to post-rTMS with no treatment-related changes on structural MRI. Regarding apathy, participants had significant improvements with moderate to large effect sizes on the Lille Apathy Rating Scale (LARS), on both self (d = 0.78) and caregiver-rated versions (d = 1.28), p<0.05 pretreatment-to-one-month follow-up. In addition, secondary measures of psychosocial function also showed improvement with moderate to large effect sizes (Stroke Specific Quality of Life Scale: d = 0.62; Zarit Burden Interview: d = 0.72), and the Brief Inventory of Psychosocial Function: d = 0.89). Conclusions: In chronic stroke survivors with PSA, accelerated iTBS-rTMS targeting the left dmPFC appears to be safe, feasible, tolerable, and highly acceptable, with preliminary evidence suggesting a potential role in reducing apathy and secondarily promoting improvements in quality of life, caregiver burden, and broader psychosocial function.

Background: Cognitive impairment in Parkinson's disease (PD) is linked to degeneration of the cholinergic basal forebrain, particularly cholinergic nucleus 4 (Ch4) in the nucleus basalis of Meynert. Structural and diffusion MRI separately detect this degeneration, but few studies have combined these modalities across the PD cognitive spectrum. Methods: We analyzed 92 participants: 14 healthy controls (HC), 35 PD with normal cognition (PD-NC), 33 with mild cognitive impairment (PD-MCI), and 10 with dementia (PDD). For Ch4 and cholinergic nuclei 1, 2, and 3 (Ch1-3) in the medial septal/diagonal band complex, we determined TIV-normalized gray matter density (GMD) and free-water (FW) fraction. We evaluated group differences, cognitive correlations, adjusted multivariable regression, and exploratory ROC discrimination. Results: Ch4 GMD was significantly lower in PDD compared to PD-MCI (p=0.007), PD-NC (p<0.001), and HC (p<0.001). Ch4 GMD was also lower in PD-MCI versus HC (p=0.028); the PD-MCI versus PD-NC difference was not significant after correction (p=0.074). Ch1-3 GMD was lower in PDD versus PD-NC (p=0.008) and HC (p=0.009). Ch4 and Ch1-3 FW were elevated in PDD versus all other groups (all p<0.01). Among PD patients (n=78), MoCA was positively correlated with Ch4 GMD ({rho}=0.49) and Ch1-3 GMD ({rho}=0.42) and negatively correlated with Ch4 FW ({rho}=-0.51) and Ch1-3 FW ({rho}=-0.40; all p<0.001). In the full four-metric model, Ch4 GMD and Ch4 FW were the only independent basal forebrain predictors (Ch4 GMD {beta}=+2.04, p<0.001; Ch4 FW {beta}=-1.46, p=0.005) of MoCA score. The combined Ch4 GMD + Ch4 FW model showed high discrimination for PDD versus non-demented PD (AUC=0.934; optimism-corrected AUC=0.925). Conclusions: Structural and free-water diffusion MRI provide complementary information about Ch4 degeneration in PD. The combined Ch4 model showed promising exploratory discrimination of PDD; validation in larger independent samples is needed.

Introduction: Brain-predicted age, estimated from structural MRI data, is a machine-learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population. Methods: T1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic). Results: Higher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes. Conclusions: Elevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods: In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14; vg of an AAV9 vector encoding human NAGLU) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results: The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 {+/-} 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions: A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

Background: Neurological, neuropsychiatric, and neurodevelopmental disorders cluster in ALS families, sharing a common genetic architecture with ALS. Pathogenic variants in genes associated with other neurological, neurodevelopmental, or neuropsychiatric disorders may also co-occur in ALS and modify phenotype. We have sought to determine the prevalence and clinical pattern of likely-pathogenic/pathogenic (LP/P) non-ALS neurological, neurodevelopmental, and neuropsychiatric variants, alone and in combination with ALS-gene variants, in two large ALS cohorts. Methods: Whole-genome sequencing (WGS) of 469 Irish and 774 Answer ALS people with ALS (pwALS) was analysed for ClinVar LP/P variants associated with other neurological (n = 15541), neurodevelopmental (n = 9761), and neuropsychiatric (n = 321) phenotypes. Inheritance patterns for associated genes (autosomal recessive/autosomal dominant) along with the associated phenotype were validated using OMIM. Standardised clinical data included family history, site and age of onset, El Escorial category, survival, motor decline, and cognitive and behavioural assessments. Known ALS-gene variants and C9orf72 repeat expansion status were included for each cohort. Results: Non-ALS neurological variants were identified in 47/469 (10.0%) Irish and 69/774 (8.9%) Answer ALS participants, most frequently in hereditary spastic paraplegia-associated genes (3.2% Irish; 2.8% Answer ALS). Irish neurological variant carriers showed higher frequency of respiratory onset (10.6% vs 1.2%, Fisher's exact p = 0.002, {Phi} = 0.20) and fewer premorbid behavioural symptoms (0.92 +/- 0.56 vs 3.08 +/- 0.97, Cohen's d = -0.40). Neurodevelopmental variants occurred in 12/469 (2.6%) Irish and 20/774 (2.6%) Answer ALS participants. In the Irish cohort, neurodevelopmental variant carriers had significantly shorter survival in Cox proportional hazards model (log-rank p = 0.005), corresponding to a more than two-fold increased hazard of death (HR = 2.25, 95% CI 1.26-4.00), and had significantly increased familial burden of neuropsychiatric disorders among first- and second-degree relatives (negative binomial IRR for carriers = 2.41, 95% CI: 1.12-5.18, p = 0.025). Across combined cohorts, 18 individuals (Irish n = 8; Answer ALS n = 10) carried [&ge;]2 LP/P variants spanning ALS and non-ALS genes. Conclusion: Rare LP/P variants in genes associated with other neurological and neurodevelopmental disorders occur in up to 12% of pwALS across two independent cohorts. Carriers show distinct phenotypes, shorter survival, and characteristic family history patterns. These findings suggest that extended pleiotropic and oligogenic architectures may contribute to ALS heterogeneity.

Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently recognized cause of drug-resistant focal epilepsy. It is often MRI-negative or shows imaging features mimicking focal cortical dysplasias, which makes recognition difficult and limits presurgical counseling. We aimed to identify an intracranial EEG (iEEG) biomarker that distinguishes MOGHE from other developmental brain lesions encountered in epilepsy surgery. In a retrospective multicenter test cohort of 38 patients (18 MOGHE, 20 non-MOGHE), we analyzed long-term stereo-EEG and subdural recordings. Only MOGHE patients showed highly stereotyped clusters of very brief low-voltage fast activity (LVFA) events, organized into status-like 3 to 12-minute episodes that often lacked clear clinical symptoms. LVFA clusters were present in 16/18 MOGHE and 0/22 non-MOGHE patients. We then tested diagnostic performance in an independent, blinded single-center validation cohort of 22 patients (11 MOGHE, 11 non-MOGHE), in which visual identification of LVFA clusters correctly classified 10/11 MOGHE and 10/11 non-MOGHE cases (Cohens kappa=0.82). Penalized logistic regression further confirmed MOGHE histology as the strongest predictor of LVFA clusters, independent of age and lobe localization. Because LVFA clusters can be recognized visually on routine intracranial EEG recordings without specialized software, this biomarker is readily applicable in clinical practice and may improve presurgical identification of MOGHE. Future prospective studies should determine whether its recognition influences surgical planning, improves outcome prediction, or facilitates selection of patients for mechanism-based therapies.

Diabetic peripheral neuropathy (DPN) is a common and disabling condition for which no disease-modifying therapies are available. Glycemic and metabolic drivers do not fully explain why only a subset of individuals with diabetes develop DPN, and genetic contributors remain poorly defined. We aimed to perform a multi-population genome-wide association study (GWAS) of DPN to highlight potential new etiological pathways and therapeutic targets. Methods We performed a multi-population GWAS of neuropathy in people with and without diabetes using the VA Million Veteran Program and UK Biobank, followed by replication in the All of Us Research Program (AoU), and gene-based and gene-set analyses to identify implicated pathways. Causal relationships between circulating serine levels and DPN were further tested using two sample Mendelian randomization. To further evaluate pathogenic potential, we analyzed rare, high impact variants in GWAS implicated genes among individuals with unresolved inherited neuropathies using the GENESIS platform. Findings Among individuals with type 2 diabetes, we identified seven genome wide significant loci (p<5x10-): PHGDH and PSPH (key serine synthesis genes), TEAD1, CYP4F11, LARGE1, FTO, and COBLL1. No loci were significant in individuals without diabetes or with type 1 diabetes. Four loci (PHGDH, TEAD1, FTO and CYP4F11) replicated in AoU (p <0.05). Mendelian randomization demonstrated that higher genetically predicted serine levels were associated with lower DPN risk, consistent with a causal role of serine metabolism in disease pathogenesis. Rare-variant burden analyses revealed associations of predicted deleterious variants with inherited neuropathy case status in PHGDH (odds ratio [OR] 12.7 [95% CI 7.9, 20.4]), PSPH (OR 8.5 [7.2, 10.2]), PHKG1 (OR 4.8 [3.7, 6.3]), and LARGE1 (OR 0.007 [0.0004, 0.1]). Interpretation Convergent genetic evidence across common and rare variation implicates serine synthesis as a key pathway in DPN. These findings link diabetic and inherited neuropathies through a shared metabolic mechanism, identifying serine metabolism as a potential therapeutic target.

Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time x Condition interactions, indicating differential texture trajectories between Osc+ and Osc-. In the hippocampus, this pattern was further qualified by a Time x Condition x Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.

Rationale: Reliable electroencephalography (EEG) biomarkers of cortical excitability could improve diagnosis and longitudinal monitoring in epilepsy, yet it remains unclear which metrics best balance sensitivity across individuals with intra-individual stability over time. Methods: We analyzed scalp EEG recordings from the open-access Temple University Hospital EEG Epilepsy Corpus, comprising 1,404 recordings from 96 individuals with neurologist-confirmed epilepsy and 85 healthy controls across multiple sessions. Eight global measures were computed: aperiodic exponent and offset, sample entropy, detrended fluctuation analysis exponent and derived index, spatial gamma-band phase consistency, and absolute and relative alpha power. Group differences were assessed by permutation tests with false discovery rate correction at recording, session, and subject levels. Associations with antiseizure medication burden, temporal stability, and cross-metric correlation structure were evaluated as secondary analyses. Results: Aperiodic parameters showed the most robust case-control separation, remaining significant after subject-level averaging (exponent: median difference = 0.20, q = 0.010; offset: median difference = 0.25, q = 0.011). Entropy and alpha power distinguished groups at the recording and session levels, while gamma-band phase consistency was significant at the session level only; none of these survived subject-level averaging, suggesting greater state-dependency. Higher medication burden was associated with reductions in alpha power and detrended fluctuation analysis, and adjusting for it substantially attenuated group differences, though residual effects in the aperiodic exponent persisted. Cross-metric correlation structure was preserved between groups but modestly reorganized by medication burden. Conclusions: Aperiodic spectral parameters are the most robust EEG markers of epilepsy, reflecting stable trait-like network properties. Complexity and synchrony measures capture complementary, state-sensitive dimensions. Medication burden substantially influences multiple metrics, underscoring the need to account for pharmacological effects when interpreting EEG biomarkers in epilepsy.

Age-related hearing loss is a leading modifiable risk factor for dementia and is increasingly recognized as a non-motor feature of Parkinson's disease (PD). The apolipoprotein E (APOE) E4 allele is the strongest genetic risk factor for Alzheimer's disease and is associated with cognitive decline in PD, yet its relationship to hearing loss remains unclear. Therefore, we examined the independent and interactive effects of PD status and APOE E4 carrier status on age-related hearing loss using a validated web-based speech-in-noise (SIN) assessment in 239,620 23andMe Research Institute participants without PD and 4,361 PD cases. Generalized additive models for location, scale, and shape (GAMLSS) showed that both PD and APOE E4 independently exacerbated age-related hearing decline, with speech reception thresholds (SRTs) worsening non-linearly with advancing age, but without evidence of synergistic interaction. However, longitudinal analyses in a subcohort completing at least two assessments (1,434 PD cases; 36,242 controls) using GAMLSS mixed models showed a significant three-way interaction between PD status, APOE E4, and age2, such that SIN hearing loss accelerated more steeply with age in APOE E4 carriers with PD. Males and individuals with lower educational attainment also exhibited worse SIN hearing loss. These results identify APOE E4 carriers with PD as a priority population for hearing screening and intervention, and support the integration of SIN assessments into routine PD care to detect hearing decline that may compound cognitive and communicative burden in aging.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Background: Infants with critical congenital heart disease (CHD) are at high risk for abnormal brain development and later neurodevelopmental impairment. We hypothesized that the trajectory of perioperative whole-brain network development would predict neurodevelopmental outcomes in early childhood. Methods: This prospective longitudinal cohort of neonates with critical CHD (n = 97) underwent preoperative and/or postoperative brain MRI with diffusion imaging. Whole-brain network measures were derived from structural connectomes. Neurodevelopment was assessed between 1 and 4 years using the Bayley Scales of Infant and Toddler Development. Results: White matter injury was associated with slower perioperative growth in global efficiency (p = 0.013), a measure of network integration, whereas cardiac physiology was not associated with network development. Infants with greater perioperative increases in global efficiency had higher cognitive (p = 0.001), language (p < 0.001), and motor (p = 0.008) scores. For each 1-standard deviation increase in the trajectory of global efficiency, cognitive scores increased by 8.2 points (95% CI, 3.64-12.78), independent of brain injury and socioeconomic factors. Conclusion: In infants with critical CHD, longitudinal whole-brain network development was associated with neurodevelopment across multiple domains. Early network development may represent a candidate biomarker of neurodevelopmental risk and resilience in this population.