Journal of Lipid Research

Background & Aims: Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the leading cause of chronic liver disease in children. However, accurate, noninvasive diagnostic tools remain limited. Current screening methods are invasive or lack sensitivity. Breath-based volatile organic compound (VOC) analysis offers a simple approach with potential for point of care screening. This study aimed to identify and validate breath VOC signatures of pediatric MASLD. Approach & Results: We conducted a prospective IRB approved cohort study at the Childrens Hospital of Philadelphia (CHOP). Children aged between 7 and 20 years with MASLD (n=22), as defined by hepatic steatosis either by liver biopsy or imaging and 1 cardiometabolic risk factor, and a control group without MASLD (n=20) were enrolled. Breath samples were collected using a standardized protocol and analyzed by untargeted comprehensive two-dimensional gas chromatography-mass spectrometry (GCGCMS). Machine learning and unsupervised clustering were applied to identify discriminatory VOCs and assess heterogeneity. Untargeted GCGCMS analysis identified a distinct breath VOC signature in children with MASLD compared with non MASLD controls. A Random Forest model achieved a sensitivity of 73% and specificity of 65%, with AUC of 0.84. The VOC 2,4-dimethyl-1-heptene demonstrated strong diagnostic performance in the discovery cohort with a sensitivity of 85%, specificity of 77% and an AUC of 0.81. Unsupervised clustering revealed four MASLD subgroups with distinct volatile phenotypes associated with differences in liver enzymes and metabolic parameters. External validation in a second pediatric cohort confirmed reproducible reductions in o/p-xylene in subjects with MASLD. Conclusions: Pediatric MASLD is associated with a reproducible breath VOC signature identified by untargeted GCGCMS. These findings support breath analysis as a scalable, noninvasive screening and stratification tool for pediatric MASLD and warrant validation in larger, longitudinal studies.

INTRODUCTION: Alzheimers disease (AD) is a multifactorial disorder, yet current research largely focuses on downstream biomarkers with limited attention to environmental contributors. Experimental studies suggest that per and polyfluoroalkyl substances (PFAS) may contribute to neuroimmune and neurodegenerative pathways relevant to AD. OBJECTIVE: To examine associations between PFAS exposure and neuroimmune and AD related plasma biomarkers in cognitively unimpaired rural adults. METHODS: In a cross sectional pilot study (n=48), serum concentrations of 33 PFAS were measured, including four legacy compounds (PFOS, PFHxS, PFOA, PFNA). Plasma neuroimmune related (ITGB2, SMOC1, TREM2, GFAP) and AD related biomarkers (Ab42/40, ptau217) were detected using proteomic analysis. RESULTS: PFOS showed moderate associations with ITGB2, SMOC1, and Ab42/40 in unadjusted analyses, which attenuated after adjustment for age. PFOA and PFNA demonstrated consistent inverse associations with TREM2 before and after adjustment. DISCUSSION: Findings suggest possible compound specific PFAS associations with immune and amyloid related biomarkers, supporting further investigation in longitudinal and PFAS mixture based studies.

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD

Objective: Cognitive impairment is common among older adults with epilepsy, although efficient screening tools suitable for routine use are lacking. Here we examine, for the first time, the utility of the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a screening tool to identify cognitive impairment in older adults with epilepsy. Methods: Participants included 83 adults (ages over 55) with epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimers Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog and a comprehensive neuropsychological battery to identify cognitive phenotypes (intact vs impaired). Performance on individual ADAS-Cog items and the total score was assessed, and diagnostic efficiency statistics were determined. Results: Epilepsy participants (mean age=66.4 years) performed significantly worse across the ADAS-Cog total score and 8 of the 13 individual test items compared to controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d=0.87) and delayed word recall (d=1.06). An ADAS-Cog total score of at or exceeding 15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment. Significance: The ADAS-Cog is sensitive to detecting cognitive impairment in older adults with epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages. Plain language summary: Cognitive decline is common among older adults with epilepsy, although sufficient evidence supporting the use of screening tools to identify cognitive impairment in this population is lacking. The ADAS-Cog may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across cultures and healthcare settings.

INTRODUCTION: Knowledge about how Alzheimer's disease (AD) and AD-related dementia (AD/ADRD) plasma biomarkers relate to global and domain-specific cognitive functioning across diagnostic groups remains limited, particularly in heterogeneous, community-dwelling populations with multiple comorbidities. METHODS: We evaluated associations between baseline plasma biomarker levels (A{beta}42/40, p-tau181, p-tau217, NfL, GFAP) and cognitive performance at baseline and longitudinally (up to 7 years). Participants (n=590) enrolled in the Wake Forest Alzheimer's Disease Research Center Clinical Core (314 cognitively unimpaired [CU]; 206 mild cognitive impairment [MCI]; and 70 dementia) completed annual cognitive assessments including the Uniform Data Set (UDSv3; NACC). Domain-specific cognitive composites including memory, executive function, attention, language, visuospatial ability, and phonemic fluency, as well as a modified Preclinical Alzheimer's Cognitive Composite (PACC5), were evaluated. General linear and mixed-effects models were adjusted for demographics (age, sex, race, education), APOE-{epsilon}4 status, comorbidities (estimated glomerular filtration rate; BMI), and cardiometabolic health factors (hypertension, diabetes). Effect modification by cognitive diagnosis was evaluated. RESULTS: Baseline plasma biomarkers, particularly p-tau217, were associated with poorer baseline cognitive performance and greater longitudinal decline on the PACC5 and all cognitive domains assessed, except phonemic fluency (strongest for memory). Post-hoc analyses indicated associations between plasma biomarker levels and cognition were generally more pronounced in MCI compared with CU participants. Effect modification by baseline cognitive status was limited and attenuated when all biomarkers were modeled simultaneously. Comorbidities and cardiometabolic factors modified select associations. DISCUSSION: Plasma AD/ADRD biomarkers, particularly p-tau217, were associated with cognitive impairment and decline in a heterogenous community cohort.

The course of multiple sclerosis (MS) is highly heterogeneous, yet the biological mechanisms underlying this variability remain incompletely understood. Although metabolic alterations have increasingly been associated with disease progression, existing observational evidence is limited by confounding, reverse causation, and an inability to establish causal mechanisms. To bridge this gap, we used a metabolome-wide Mendelian Randomization (MR) framework, including thorough sensitivity analyses, to identify metabolites genetically linked to MS severity that can causally affect it. Bidirectional MR analyses revealed a subset of amino acid and lipid pathways with strong, consistent effects across different MR approaches, confirmed by tests for heterogeneity, horizontal pleiotropy, and LD confounding. For metabolites prioritized by metabolome-wide MR with evidence of causal effects, we conducted genetic colocalization at loci encompassing proximal enzyme-encoding genes, leveraging the corresponding instrumental variants to assess shared underlying genetic signals. This process revealed shared genetic signals between metabolite levels and MS severity, mapped to the FADS1/2 and CYP4F2 loci. A subsequent pathway-resolved set of cis-MR analyses across FADS1/2-derived polyunsaturated fatty acid (PUFA) metabolites, using a functional variant that proxies reduced {triangleup}5-desaturase activity, showed consistent effects indicating that FADS1 perturbation is associated with MS severity. Collectively, these results highlight FADS1 as a key driver of PUFA-related causal effects on MS severity in both systemic (circulating metabolites) and brain cell-specific contexts. Additional supportive cis-MR evidence implicates the disruption of CYP4F2 as another PUFA-metabolizing enzyme.

Background: Patients in socioeconomically disadvantaged neighborhoods face barriers to care. Missing BP documentation may signal gaps in risk-factor management, a crucial component of primary and secondary prevention of intracerebral hemorrhage (ICH). We tested whether neighborhood deprivation was associated with absent electronic health record (EHR) blood pressure (BP) documentation surrounding ICH and whether absent documentation predicted subsequent uncontrolled BP. Methods: We conducted a case-only study within the NIH All of Us Research Program. We included ICH survivors (ICD-10 I61.x, surviving >=1 year) with available ZIP3-based Deprivation Index. Deprivation was categorized as Privileged, Intermediate, or Deprived using cohort-based tertiles. We excluded BP measurements collected by All of Us. Outcomes were (1) absent EHR-derived BP documentation and (2) uncontrolled BP (mean systolic BP >=140 mmHg) during three windows: 1-365 days before ICH; 30-365 days and 1-5 years after ICH. Multivariable logistic regression tested associations adjusting for age, sex, and race/ethnicity. Results: 1,474 ICH survivors were included (mean age 60.1, 50.4% female). Compared to privileged neighborhoods, those living in deprived neighborhoods had higher odds of absent EHR BP documentation in the year prior to ICH (OR 2.10, 95% CI 1.60-2.76; p<0.001), 30-365 days post-ICH (OR 2.82, 95% CI 2.14-3.73; p<0.001) and 1-5 years post-ICH (OR 2.81, 95% CI 2.13-3.71; p<0.001). Absence of EHR BP documentation in the year before ICH predicted uncontrolled BP 30-365 days (OR 1.97, 95% CI 1.36-2.85; p<0.001; N=888) and 1-5 years (OR 1.83, 95% CI 1.24-2.69; p=0.002; N=814) after ICH. Absence of BP documentation 30-365 days post-ICH also predicted uncontrolled BP 1-5 years post-ICH (OR 1.66, 95% CI 1.10-2.50; p=0.017; N=814). Conclusions: Neighborhood deprivation is associated with persistent gaps in EHR BP documentation surrounding ICH, and absent documentation before or soon after ICH predicts subsequent uncontrolled BP. These findings highlight the need for community-level strategies that ensure equitable BP monitoring for socioeconomically disadvantaged populations.

Blood biomarker models are increasingly used in Alzheimer's disease and related dementia translational research, but predictive performance can be inflated when the same dataset is used for both model development and evaluation. We assess the effect of data double dipping using simulations and NULISA proteomic data from the MYHAT-NI community-based cohort to predict brain amyloid-beta neuroimaging status. In both settings, training AUC increased as more biomarkers were added, while testing AUC peaked earlier and then declined. These findings show that data double dipping can inflate model performance and highlight the need for external validation or internal validation with data partitioning.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

Objectives: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder with predominant striatal pathology in affected males, who frequently show hyperechogenicity of the lentiform nucleus on transcranial sonography. We aim to investigate female mutation carriers and female healthy controls using transcranial sonography to identify potential abnormalities in the striatum, substantia nigra, and ventricular system. Methods: We examined 81 participants (35 female mutation carriers and 46 female controls) using transcranial sonography to assess the presence of hyperechogenicity of the lentiform nucleus, the area of substantia nigra hyperechogenicity, and the widths of the lateral and third ventricles. Clinical evaluation focused on dystonic and parkinsonian symptoms, and we determined genotypes relevant for four X-linked dystonia-parkinsonism genetic modifiers. Results: Female mutation carriers showed more subtle parkinsonian signs compared with controls. The prevalence of hyperechogenicity of the lentiform nucleus was higher in female mutation carriers and was associated with a more unfavorable genetic modifier profile. No relevant abnormalities were observed in the substantia nigra or the ventricular system. Imbalanced X-chromosome inactivation in favor of the wildtype allele expression was not significantly associated with clinical severity or hyperechogenicity of the lentiform nucleus frequency, although female mutation carriers with such an imbalance showed no parkinsonian signs and only rarely hyperechogenicity of the lentiform nucleus (1/8, 13%). Conclusions: Women carrying the X-linked dystonia-parkinsonism-causing variant display subtle parkinsonian signs and frequently exhibit hyperechogenicity of the lentiform nucleus, supporting hyperechogenicity of the lentiform nucleus as a sensitive imaging marker of early neurodegenerative change, especially in those with higher genetic risk.

INTRODUCTION: Synaptic markers are altered in the CSF of Alzheimer's disease (AD) patients, but their quantification in plasma remains challenging. We evaluated plasma synaptic markers in MCI and mild AD using the nucleic acid linked immunosandwich assay (NULISA) and their correlation with APOE genotype. METHODS: 272 participants (154 CSF confirmed AD, 118 controls) underwent plasma assessment with the NULISA CNS panel. A subset (n=48) also had CSF measurements. Analyses were adjusted for age, sex, comorbidity, and renal function. RESULTS: NULISA revealed plasma alterations in NPTX2, NPTXR, SNAP25, and VSNL1 in AD, with SNAP25 and NPTXR already altered at MCI stage. APOE e4/e4 carriers showed higher plasma SNAP25. Plasma SNAP25 and NPTXR correlated positively with pTau217. No plasma/CSF concordance was observed. DISCUSSION: NULISA identifies plasma synaptic biomarker alterations in early AD, with APOE e4 influencing SNAP25 levels. Associations with pTau217 suggest a link between synaptic damage and tau phosphorylation. Longitudinal studies are warranted.

Importance: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants. Objective: Does return of research results (RoRR) negatively impact longitudinal symptoms of depression and cognition. Design: Randomized, noninferiority, delayed-start clinical trial, 2021-2025 Setting: AD biomarker research results offered to CU participants in a longitudinal study of aging Participants: CU participants age 65+ were offered research AD biomarker results (APOE genotype and either plasma AB42/40 or amyloid PET and MRI hippocampal volume) with an estimated 5-year risk of symptomatic AD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): 147 participants were randomized to receive results either soon after consent (RoRR arm, N=73) or one year later (delayed-start arm, N=74). Main Outcome(s) and Measure(s): Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging. Results: 187 participants received results: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (AB+) and in those without elevated amyloid (AB-) for GDS (AB+ difference 0.7, 95% CI 0.0-1.3; AB- difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (AB+ difference 0.0, 95% CI -0.1-0.1; AB difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (AB+ difference -0.10, 95% CI -0.25-0.06; AB- difference -0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing. Conclusions and Relevance: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study. Trial Registration: NCT04699786

Background: Progressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time. Methods: We repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS/MS in 244 participants from the 96-week SPRINT-MS randomized trial of oral ibudilast, up to 100 mg daily, versus placebo. Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolite groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes, defined as p < 0.05, were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data. Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis. Findings: Higher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0/18:0) levels were associated with slower BPF decline in SPRINT-MS (beta = 0.016 [95% CI: 0.008, 0.024]; p = 4.35 x 10^-5) and replicated in HEAL-MS (beta = 0.108 [95% CI: 0.006, 0.211]; p = 3.90 x 10^-2). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species, such as palmitoyl sphingomyelin (d18:1/16:0; beta = 0.185 [95% CI: 0.085, 0.286]; FDR = 1.79 x 10^-2), and decreased levels of amino acid-related metabolites, such as anthranilate (beta = -0.270 [95% CI: -0.403, -0.137]; FDR = 3.87 x 10^-2). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS. Interpretation: Distinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.

Purpose: To evaluate the safety and exploratory outcomes of a single intravitreal injection of OGX110, a peptide agonist of CXCR3, in eyes with persistent fluid secondary to neovascular age-related macular degeneration (nAMD) despite ongoing anti-vascular endothelial growth factor (anti-VEGF) therapy. Methods: This prospective, open-label, sequential dose-escalation phase I study (NCT05904691) enrolled subjects receiving standard-of-care intravitreal anti-VEGF therapy. Subjects received a single intravitreal injection of OGX110 at 0.5 mg, 1.0 mg, or 2.0 mg (n=3 per cohort), 7 to 14 days after the anti-VEGF injection. Results: All nine enrolled subjects completed follow-up through day 56. Two subjects (22%) experienced at least 1 adverse event (AE); all were mild and unrelated to study treatment. Exploratory analyses showed a BCVA change of +1.4 letters following anti-VEGF injection and +4.4 letters from OGX110 baseline to 4 weeks (P < 0.05). Six of 9 subjects gained at least 3 ETDRS letters after OGX110. Anatomic responses were heterogeneous. Four eyes showed a reduction in CRT after anti-VEGF injection that was maintained after OGX110 administration. One additional eye demonstrated a substantial reduction in CRT after OGX110 despite minimal response to anti-VEGF treatment. Conclusions: A single intravitreal injection of OGX110 was well tolerated. Exploratory functional and anatomic findings suggest biologic activity; interpretation is limited by small sample size, open-label design, absence of a concurrent control group, and inter-subject heterogeneity. These results support further study in a controlled trial. Translational Relevance: OGX110 represents a mechanistically distinct investigational approach for nAMD that may warrant further evaluation in eyes with persistent.

Background: Mocravimod is an oral sphingosine-1-phosphate (S1P) receptor modulator. This Phase 1 multiple-ascending-dose study evaluated its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers. Methods: In this double-blind, randomized, placebo-controlled, parallel-group trial, 60 healthy male volunteers were enrolled in five cohorts. Mocravimod was administered once daily at 0.3, 0.6, 1.2, or 3.0 mg for 14 days, or at 2.0 mg for 28 days. Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiography, and Holter monitoring. PK of mocravimod and its active metabolite, mocravimod-phosphate, and PD effects on absolute lymphocyte count (ALC) and leukocyte subsets were assessed. Results: Fifty-nine of 60 participants completed the study. One participant in the 3.0 mg cohort discontinued treatment because of asymptomatic transaminase elevation. No deaths or serious AEs occurred. AEs were mostly mild or moderate, transient, and showed no clear dose relationship. Mocravimod produced dose-dependent reductions in ALC from 0.6 mg onward, with maximum geometric mean reductions of 65%, 74%, 83%, and 77% at 0.6, 1.2, 2.0, and 3.0 mg, respectively. ALC values recovered to above the lower limit of normal during follow-up in all cohorts. Holter monitoring showed an initial placebo-corrected reduction in heart rate of approximately 10-15 beats/min at doses of 1.2-3.0 mg, which attenuated with continued dosing. One participant in the 3.0 mg cohort had a recurrent daytime second-degree atrioventricular block (Mobitz I/Wenckebach), reported as a mild non-dose-limiting AE. No QT prolongation was observed. Exposure to mocravimod and mocravimod-phosphate increased approximately dose-proportionally. Steady state was reached by Day 14 (Day 28 in the 2.0 mg cohort), accumulation was approximately five- to sevenfold, terminal half-lives were approximately 100-40 hours for both analytes, and parent-to-metabolite exposure ratios were close to 1. Conclusions: Once-daily mocravimod up to 3.0 mg for 14 days and 2.0 mg for 28 days was generally well tolerated and showed predictable S1P-modulator class effects on lymphocyte counts and heart rate, with PK properties supporting once-daily dosing and further clinical development.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting more than 450,000 individuals worldwide and is frequently diagnosed more than 12 months after symptom onset, delaying intervention during a critical early window. Because up to 80% of patients develop dysarthria within two years, subtle changes in speech provide a signal of early bulbar motor neuron degeneration. However, existing speech-based systems rely on supervised classification trained on limited datasets, achieving moderate sensitivity and depending heavily on labeled disease examples, which restrict scalability and early detection. This study introduces SPEAK-NORM, the first-ever normative speech modeling framework for early ALS diagnosis, which learns age- and sex-conditioned motor-speech distributions exclusively from healthy individuals. A conditional variational autoencoder models coordination of hypoglossal, laryngeal, and respiratory motor pathways, and deviation from this healthy manifold is quantified through latent representations and reconstruction error to form a 354-dimensional profile. A calibrated linear Support Vector Machine performs subject-level classification under subject-disjoint validation. On the VOC-ALS database (n = 153), SPEAK-NORM achieves 98% accuracy with balanced sensitivity and specificity, significantly outperforming established clinical acoustic indices and prior systems. The framework maintains strong performance under cross-task generalization and when retrained on healthy controls in independent dementia and Parkinson disease cohorts, demonstrating disease-specific deviation patterns rather than generic neurodegenerative change. Spectral, temporal, and latent separations further support interpretability. By modeling healthy speech instead of memorizing disease examples, SPEAK-NORM enables scalable early neuromotor screening using recording devices, with potential to support earlier diagnosis, differential classification, and monitoring of ALS progression.

Objective Astrocyte activation is increasingly recognized as an important component of multiple sclerosis (MS) pathology. Natalizumab (NTZ), a highly effective therapy for relapsing-remitting MS (RRMS), primarily blocks leukocyte trafficking into the central nervous system. However, its effects on astrocytic metabolism remain unclear. We investigated astrocyte-associated metabolic changes after NTZ treatment using quantitative 1-11C-acetate positron emission tomography (PET). Methods Seven patients with RRMS underwent quantitative 1-11C-acetate PET before and after NTZ treatment. PET-derived k2, an index of oxidative acetate metabolism, was analyzed voxel-wise and within GM and white-matter volumes of interest. Clinical status and brain magnetic resonance imaging (MRI) findings were assessed, and cognitive performance was evaluated using Rao's Brief Repeatable Battery of Neuropsychological Tests. Results After NTZ treatment, k2 decreased in all patients compared with pretreatment levels. Both gray and white matter showed significant reductions, and voxel-based analysis demonstrated widespread decreases across cortical and subcortical regions of the cerebrum and cerebellum, with no regions showing significant posttreatment increases. MRI showed no worsening; Expanded Disability Status Scale scores were stable or improved, and cognitive performance was generally stable, with improvements in selected subtests. Interpretation Quantitative 1-11C-acetate PET demonstrated a whole-brain reduction in astrocyte-associated metabolism after NTZ treatment in RRMS, most prominently in gray matter. NTZ may modulate astrocyte activity, in addition to its established effects on peripheral immune cell trafficking.

In some countries, melatonin is sold without a physician prescription and dosage is unregulated. Transdermal products have become popular including those marketed for children. We measured consumer assumptions about these products among adult residents of the United States, analyzed lot-to-lot variability, and compared the pharmacokinetics of melatonin administered in oral, lotion, and bath product forms. Survey respondents (n=199) believed oral melatonin was more effective than transdermal products and that all melatonin products were relatively safe. Melatonin lotion products analyzed by HPLC displayed lot-to-lot variability as well as changes in formulation and product claims. To determine pharmacokinetics, three different treatments (oral tablets, lotion, and bath immersion) were administered to twelve undergraduate participants in a randomized, crossover design. Five additional participants completed bath product treatment only. Participants collected saliva samples up to 48 hours after administration, which were analyzed for melatonin by enzyme-linked immunosorbent assay. Oral (n=11) and lotion formulations (n=12) caused maximum salivary melatonin levels within 30 minutes after administration, but bath immersion did not cause increases in saliva melatonin (n=17). The half-life of oral melatonin was 1.17 [0.69 -- 1.65] hours versus 5.72 [3.75 -- 7.68] hours for lotion treatment (p = 0.011, effect size r = 0.770). Melatonin lotion may pose a risk to consumers who assume it is safe and less effective than oral tablets, when in fact it may be very potent and remain at high physiological levels into the following day. This study is registered on clinicaltrials.gov (NCT06382610) and was funded by the Sleep Research Society.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

Background: Immune-mediated mechanisms are increasingly implicated in childhood arterial ischemic stroke (AIS), but the associated inflammatory pathways and how they differ by stroke subtype and outcome remain poorly understood. Understanding immune responses to AIS may identify subtype-specific mechanisms and inform targeted strategies to reduce ischemic injury. Methods: We conducted a prospective cohort study with cross-sectional transcriptomic analysis through the Vascular Effects of Infection in Pediatric Stroke Study Part II (VIPS II) at 22 academic centers in the United States, Canada, and Australia between December 2016 and January 2022. Children aged 28 days to 18 years with centrally confirmed AIS were enrolled within 72 hours of stroke onset, in addition to enrollment of stroke-free well children. Peripheral blood RNA sequencing was performed on samples collected within 72 hours of stroke or at enrollment for controls. Differential gene expression (DGE) and pathway analyses were performed comparing all AIS cases to stroke-free well children. Additional cross-sectional analyses stratified by stroke subtype and neurological outcomes were performed. Results: Transcriptomes were available in 190/205 AIS cases (median age 11.7 years) and 91/100 stroke-free children (11.8 years). Stroke subtypes included 67 definite arteriopathic, 74 probable arteriopathic, 23 cardioembolic, and 26 idiopathic, with similar demographics but smaller infarct size for idiopathic cases. 47 genes (false discovery rate (FDR) <0.05 and log2 fold-change (log2FC)>1) were differentially expressed in AIS versus stroke-free well children, with upregulated pathways reflecting innate immune responses. Stratification by subtype revealed these inflammatory responses occurred after arteriopathic and cardioembolic AIS, but not idiopathic AIS; in sensitivity analyses, these findings were not explained by infarct size. Four immune-related genes were differentially expressed in children with good versus poor neurological outcomes at hospital discharge or 12 months; upregulation of one (Joining Chain; JCHAIN) correlated with poor outcomes at both timepoints. Conclusions: Compared with stroke-free children, children with AIS, particularly arteriopathic and cardioembolic subtypes, have upregulated innate immune pathways, including neutrophil activation and interleukin-1 signaling. Differential expression of immune-related genes also correlated with neurological outcomes. These findings support immune dysregulation as a key feature of early pediatric AIS while highlighting differences across subtypes and clinical outcomes, with implications for targeted immunomodulatory therapies and future biomarker development.