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At least 19 recordsLinked to original sources

PubMed2025

Vanishing White Matter Disease With EIF2B2 c.254 >A Variant: Mild Clinical and MRI Findings.

OBJECTIVES: Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges. METHODS: We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.1 Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant. RESULTS: A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance. DISCUSSION: This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings.

Journal Article↗

PubMed2024

Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. METHODS: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. RESULTS: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HIGHLIGHTS: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.

Humans↗

PubMed2025

Causal relationship between white matter structural connectivity and epilepsy.

White matter structural connectivity has recently been linked to epilepsy pathogenesis, yet its causal role remains unclear. This study used Mendelian randomization (MR) to investigate the causal relationship between white matter structural connectivity and epilepsy. GWAS summary statistics for white matter structural connectivity were sourced from the UK Biobank, while epilepsy data were obtained from FinnGen R10 and the International League Against Epilepsy (ILAE). Our MR analysis revealed significant causal links between white matter structural connectivity and epilepsy risk. Increased connectivity between the right hemisphere visual and salience/ventral attention networks (RH Vis to RH Sal/VentAttn WMSC) was associated with higher epilepsy risk in FinnGen_R10_FE_STRICT (OR = 2.25, 95 % CI = 1.43-3.56, p < 0.01, FDR P = 0.019). Conversely, increased connectivity between left and right hemisphere salience/ventral attention networks (LH Sal/VentAttn to RH Sal/VentAttn WMSC) was linked to reduced epilepsy risk in FinnGen_R10_GE_STRICT (OR = 0.17, 95 % CI = 0.07-0.46, p < 0.01, FDR P = 0.033). A total of 15 nominally significant associations were identified across datasets. These findings suggest a causal relationship between white matter structural connectivity and epilepsy, offering insights into disease mechanisms and potential therapeutic targets.

Humans↗

PubMed2025

Blood phenylalanine lowering partially reverses white matter changes in a mouse model of phenylketonuria.

Phenylketonuria (PKU) is a genetic defect caused by lack of the liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood phenylalanine (Phe) levels and neurotoxicity, which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering by analyzing the corpus callosum (CC) of adult Pahenu2 (PAH-deficient) mice. MRI and immunostaining demonstrated a significant reduction in CC volume in Pahenu2 mice. Treatment with an adeno-associated vector (AAV) encoding mouse PAH for 3.5 months improved but did not completely normalize CC volume. Total cholesterol, a major component of myelin, was unchanged in the CC of Pahenu2 mouse, while some sterol intermediates were significantly reduced by treatment. Single-nuclei transcriptomics showed an upregulation of oxidative stress-related pathways and increased expression of transthyretin, ApoE, Cst3, and Cd81 in CC in Pahenu2 mice. Normalization of blood Phe restored gene expression to levels comparable to those of heterozygous mice and was associated with the generation of differentiated myelin-producing oligodendrocyte subtypes and neuroprotective astrocytes. In summary, Pahenu2 mice showed white matter abnormalities and changes in transcriptome and sterol profiles, which were partially corrected by the normalization of blood Phe.

Animals↗

PubMed2025

Genetic background of neurological disorders with basal ganglia calcification.

BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC. METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history. RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease. CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.

Humans↗

PubMed2026

Neuroimaging in cerebral folate deficiencies.

Cerebral folate deficiency refers to neurological disorders associated with a reduced cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5-MTHF), arising from primary defects in folate transport or metabolism, or secondarily from acquired or other inherited conditions. Clinical presentation ranges from infancy to adulthood, with manifestations including developmental delay, seizures, cognitive impairment, and neuropsychiatric symptoms. Folate plays a central role in one-carbon metabolism, requiring interaction with other B-vitamins, most notably vitamin B12, to support nucleotide synthesis, methylation reactions, and myelin production. Disruption of folate-dependent pathways contributes to the imaging findings of cerebral folate deficiencies, which include abnormal white matter, calcifications, cerebral or cerebellar atrophy, and in some cases, stroke, or stroke-like lesions. This review outlines folate biochemistry, transport mechanisms into the central nervous system, and associated genetic defects, followed by a discussion of imaging features in primary and secondary cerebral folate deficiencies. Relevant differential diagnoses, particularly cobalamin-related disorders, are also examined. Importantly, many cerebral folate deficiencies are potentially reversible with timely recognition and therapy, underscoring the important role of neuroimaging in diagnosis and follow-up of these disorders.

Humans↗

PubMed2026

A spatially resolved genomic-molecular atlas of human white-matter microstructure.

Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.

Journal Article↗

PubMed2025

Axonal injury is a targetable driver of glioblastoma progression.

Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.

Glioblastoma↗

PubMed2026

A comparative evaluation of multiple enlarged perivascular space segmentation tools.

BACKGROUND: Enlarged perivascular spaces (ePVS) are a marker of cerebral small vessel disease, potentially reflecting reduced waste clearance. Because manual quantification is unfeasible in large datasets, we developed and evaluated an automated tool. METHODS: Detection Of Regions of Enlarged perivascular Spaces (DORES), a 3D nnU-Net-based deep learning algorithm was developed for ePVS segmentation using T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging (MRI). DORES was developed in two stages: an initial model trained on 35 manually segmented scans and a final model on 1460 pseudo-labeled sessions from the Vanderbilt Memory and Aging Project (VMAP). A subset of VMAP participants with 3 T brain MRI underwent whole-brain manual ePVS tracing (n = 35, 73 ± 9 years, 51% male) and visual rating (n = 388, 71 ± 8 years, 54% male) by a neuroradiologist. DORES was evaluated and compared against three other segmentation tools using Dice and F1 scores, absolute volume and element differences, correlation, and agreement. External validation used an Alzheimer's Disease Neuroimaging Initiative 3 subset with manual tracings (ADNI3, n = 18, 73 ± 9 years, 67% female). RESULTS: DORES achieved Dice scores of 0.61 ± 0.16 (white matter) and 0.72 ± 0.08 (basal ganglia) in VMAP, with strong correlations and agreement for ePVS count and volume. Performances modestly declined in ADNI3 across algorithms. Scanner-stratified analyses showed stronger correlations for Philips versus Siemens images in the basal ganglia, indicating scanner-dependent differences in measurement consistency. CONCLUSIONS: DORES provides a multimodal nnU-Net-based pipeline for ePVS segmentation in older adults. The model demonstrates robust within-cohort performance and reasonable external validity, though scanner-related effects limit application across sites.

Humans↗

PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗

PubMed2026

Epilepsy Is Part of the CNS Phenotype in Classic Infantile Pompe Disease.

BACKGROUND AND OBJECTIVES: Enzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unrecognized central nervous system (CNS) involvement. In this international study, involving patients from the Netherlands, Italy, Argentina, Germany, the United Kingdom, and Taiwan, we investigated whether epilepsy should be considered part of the CNS phenotype. METHODS: We included patients with classic infantile Pompe disease, defined by the presence of hypertrophic cardiomyopathy, symptom onset < 6 months of age, complete acid α-glucosidase (GAA) deficiency, and/or 2 severe variants in the GAA gene, who developed epilepsy. Data on epilepsy characteristics, electroencephalogram (EEG), cognitive testing, serum neurofilament light chain (NfL), and brain magnetic resonance imaging (MRI) were retrospectively collected. RESULTS: Seventeen patients from 10 centers were identified. The median follow-up duration was 13.7 years (range 3.3-19). Seven patients had deceased at the time of analysis. The median age at first seizure was 11.5 years (range 2.5-17.5). Seizure semiology was variable: six patients experienced generalized tonic-clonic seizures and 3 focal seizures with impaired consciousness only; 6 had multiple seizure types, and 7 experienced seizures during fever or infection. Seizure frequency varied considerably (in 9 occasionally, 5 monthly, 2 weekly, 1 daily). The most common EEG findings were a slowed background activity and focal epileptiform discharges, not substantially activated by sleep. Levetiracetam was most frequently used as antiseizure medication. Overall, 70% of patients became seizure-free. Serum NfL was elevated in all 6 patients in whom it was measured, and 8 of 10 patients had an intelligence quotient ≤66 at onset of epilepsy. Although brain MRI was not always performed at the age of first seizure, 14 of 15 patients showed white matter abnormalities, which were extensive in 11 of 14 (score ≥7/12). Brain atrophy was present in 9 cases and calcifications in 4. DISCUSSION: Our findings suggest a potential increased frequency of seizures in classic infantile Pompe disease in comparison with unaffected children, occurring predominantly after the age of 7, and that epilepsy is part of the CNS phenotype. The risk of seizures should be evaluated during follow-up in long-term survivors with classic infantile Pompe disease.

Journal Article↗

PubMed2026

Association Between cnm-Positive Streptococci and Cerebral Small Vessel Disease: Insights From Oral Health and Microbiome Status.

INTRODUCTION AND AIMS: Cerebral small vessel disease (CSVD) is associated with various severe neurological outcomes; while oral cnm-positive streptococci are suggested to be involved in cerebrovascular lesions, the specific associative features between these bacteria and CSVD have not yet been systematically investigated. This study aims to investigate the prevalence of cnm-positive streptococci in patients with CSVD and explore the correlation between infection and CSVD severity. By integrating oral health indices and microbiome sequencing, we evaluate the oral hygiene status and microbial dysbiosis characteristics of cnm-positive streptococci carriers. Furthermore, cnm-positive streptococci derived from CSVD patients will be isolated, identified, and subjected to whole-genome sequencing to provide a foundation for future research. METHODS: To explore cnm-positive streptococci prevalence and its association with CSVD, we conducted a case-control study comparing their oral detection rates between healthy controls and CSVD patients. We also performed 16S rRNA gene high-throughput sequencing of oral plaque microbiota and assessed oral health, including the simplified oral hygiene index (OHI-S), the decayed, missing, and filled teeth (DMFT) index, oral hygiene practices, gingival status, and saliva scores. RESULTS: cnm-positive streptococci were more prevalent in CSVD patients, correlating with higher OHI-S and microbial dysbiosis. Multivariable regression models (adjusted for demographic/vascular risk factors) linked cnm positivity to periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), Fazekas score, and total CSVD burden (not cerebral microbleeds (CMBs)/lacunes). CONCLUSION: Oral cnm-positive streptococci are independently associated with CSVD phenotypes, particularly those characterized by white matter injury. These findings presents a potential oral-cerebrovascular interaction and imply that managing specific virulent oral strains may be a noteworthy consideration in future clinical research.

Humans↗

PubMed2025

Diffusion tensor imaging in Chediak Higashi Disease.

AIM: To define the natural history of diffusion tensor imaging (DTI) in Chediak-Higashi Disease (CHD) participants in relation to normative development. METHODS: Twenty-five DTI scans from 15 CHD participants were compared with 100 DTI scans from 100 neurotypical controls (NC). Comparisons were evaluated for DTI metrics including fractional anisotropy (FA), and mean, axial, and radial diffusivity (MD, AD, RD, respectively). Correlational tractography was also performed to identify group differences between CHD and NC. RESULTS: Pediatric CHD participants had DTI metrics similar to NC, however, progressive pathogenic increases in MD, AD, and RD were observed in CHD participants compared to NC in white matter pathways of the whole brain, corpus callosum, and cerebellum. Correlational fiber tractography identified fiber tracts with decreased FA, and increased MD, AD, and RD in CHD compared to NC. INTERPRETATION: Progressive deviations in DTI metrics highlight the progressive neurodegeneration of CHD. Aberrations in cerebellar white matter is reflective of the clinical neurologic phenotype of CHD including cerebellar dysfunction and cognitive decline. The corollary of progressive aberrations in DTI metrics and progressive clinical neurodegeneration suggest DTI may be a suitable neuroimaging marker for CHD. Future studies should evaluate functional magnetic resonance imaging and volumetric studies in this cohort.

Chediak-Higashi Disease↗

PubMed2022

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from -0.08 to -0.11), tested cognitive deficits (β's from -0.36 to -0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Alzheimer’s disease↗

PubMed2026

Essence: A benchmarking-validated transformer framework for early diagnosis of Parkinson's disease using cerebrospinal fluid protein biomarkers.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The lack of objective molecular biomarkers limits early diagnosis and personalized treatment. Here, we propose Essence, a benchmarking-validated framework integrating cerebrospinal fluid (CSF) proteomics with traditional and deep learning models to identify robust protein signatures for PD. Using data from two independent cohorts, 1266 high-confidence proteins are quantified, among which 178 exhibit differential abundance between PD and healthy controls (HC). Through systematic benchmarking of ten machine learning algorithms and four neural architectures, the Transformer model consistently outperforms alternatives across multiple feature selection strategies, achieving an area under the receiver operating characteristic curve (AUC) of 1.0000 with only 35 features. Functional analyses of the top-ranked 35 proteins reveal enrichment in neuroinflammatory, synaptic, and oxidative stress-related pathways. Importantly, spatial transcriptomic profiling based on the Allen Brain Atlas shows region-specific expression of these biomarkers in PD-relevant brain structures, including the striatum, subthalamic nucleus, hippocampus, and white matter tracts. This anatomical alignment supports the functional relevance of the identified markers and highlights their potential utility in early-stage diagnosis and mechanistic understanding of PD.

Benchmarking↗

PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗

PubMed2026

Proteomic profiling identifies systemic drivers of blood-brain barrier injury in sickle cell disease.

Sickle cell disease (SCD) causes brain injury and cognitive disability. Systemic inflammation and endothelial injury are central to SCD pathophysiology, yet the relationship between systemic drivers of blood-brain barrier (BBB) disruption and brain injury remains understudied. This cross-sectional study assessed whole-brain and regional BBB permeability (Ktrans) using dynamic contrast-enhanced magnetic resonance imaging for 37 adults with SCD in steady state and 37 adults without SCD. Cerebral oxygen extraction fraction (OEF) and white matter mean diffusivity (MD) measured tissue hypoxia and microstructural injury, respectively. The SCD cohort showed elevated Ktrans compared with controls (3.6 × 10-4·min-1 vs 2.58 × 10-4·min-1; 95% confidence interval [CI] median difference, 0.36 × 10-4·min-1 to 1.30 × 10-4·min-1; P< .001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (β, 6.25 [95% CI, 1.72-10.77]; P = .008), independent of OEF (β, 0.22 [95% CI, 0.09-0.35]), and silent cerebral infarcts (β, 0.01 [95% CI, 0.00-0.02]). The interaction (P = .037) between Ktrans and OEF on MD suggested a combined, deleterious effect of BBB disruption and hypoxia on microstructural injury. High-throughput plasma proteomics followed by differential expression analysis, and weighted gene correlation network analysis in a subset of 61 participants revealed that 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipoprotein homeostasis, and arginine-proline metabolism pathways. All pathways were independently associated with microstructural injury. BBB permeability was a mediator of brain injury for all pathways except extracellular matrix degradation. Targeting specific systemic pathways to protect the BBB may represent a therapeutic approach to preserve brain health in SCD.

Humans↗

PubMed2025

Similarities and Differences in the Late-Onset GM2 Gangliosidoses: Tay-Sachs and Sandhoff Diseases.

The two predominating subtypes of late-onset GM2 gangliosidosis are late-onset Tay-Sachs (LOTS) and late-onset Sandhoff disease (LOSD). Due to shared deficiencies of ß-hexosamindase A and significant clinical overlap, the two diseases have been considered indistinguishable. However, a growing body of evidence supports the notion of several distinctions between the two diseases. In this study, we highlight these distinctions through the cross-sectional evaluation of 27 late-onset GM2 gangliosidosis participants. Twenty-one participants with LOTS and 6 with LOSD were included in this study. We performed physical examinations alongside assessments for gait, balance, muscle strength, ataxia, nerve conduction velocities, and analyzed brain magnetic resonance imaging. Lower limb weakness (95% in LOTS, 100% in LOSD) and later development of upper limb weakness (90% in LOTS, 83% in LOSD) was highly prevalent in both cohorts. Accompanying gait disturbances, balance issues, and dysmetria (as assessed by the brief ataxia rating scale [BARS]) were also prevalent in both cohorts. Strength testing for the quadriceps and hamstrings demonstrated weakness in both cohorts, primarily impacting extensor muscles. Supratentorial gray and white matter volumes in both cohorts were similar to normative data. In contrast, BARS scores for dysarthria and oculomotor dysfunction were present and heterogenous in LOTS participants and absent in LOSD participants. 24% of LOTS participants and none of the LOSD participants had a history of neuropsychiatric symptoms. Cerebellar volume including lobules V and VI were lower in LOTS compared to LOSD and normative data. However, length dependent sensory neuropathy was present in all LOSD participants but absent in LOTS participants. Dysfunction of the posterior cerebellum (lobules VI, VII, and IX) has been shown to cause cerebellar cognitive affective syndrome (CCAS), that includes cognitive and behavioral disturbances. Furthermore, cerebellar dysfunction of lobules V and VI has been linked to dysarthric speech, and dysfunction of the posterior cerebellum has been linked to oculomotor symptoms. The finding of low cerebellar lobule volumes in LOTS, suggests the distinctive features of the LOTS phenotype are related to cerebellar dysfunction. However, the sensory symptoms unique to LOSD remains a mystery. The molecular and biochemical basis for the dichotomy between the LOTS and LOSD phenotypes requires further investigation.

GM2 Gangliosidosis↗