Annals of Neurology

Blood-based (BB) biomarker investigations in Parkinson disease (PD) and in mild traumatic brain injury (mTBI) have substantially grown over the past decade. High risks for PD in young post-mTBI veterans have been inferred from medical record data using actuarial modeling. However, potential utility of BB biomarkers to quantify risks vs. no risk for PD in young post-mTBI veterans has not been established. Previously we reported post-mTBI veterans performed significantly below the standardized normative scores for their age and education level on specific domains of executive functioning, on par with senior aged individuals with early-stage PD. Here, we examined serum brain-derived neurotropic factor (BDNF), ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein {beta} (S100B) in association with executive functioning outcomes in search of a bio-cognitive model suitable to differentiate risk from no risk for prodromal PD. A reference range of bio-cognitive cut-points were derived from Area Under the Curve (AUC) sensitivity and specificity methods. Our data revealed two bio-cognitive signatures with reference range cut-points when GFAP was paired with cognitive flexibility / attention scores, and when S100B was paired with categorical / semantic verbal memory scores. Both bio-cognitive signatures revealed prodromal PD risk vs.no-risk parameters that remained relevant for differentiating young veterans who had encountered a past mTBI and those who had not experienced a mTBI. Subjects with early-stage PD who had withstood a mTBI up to 10- to 40-years earlier were also differentiated from those who had no mTBI history. These results indicate the predictive utility of expanding the biomarker field to include reference ranges, cut-points, and specific cognitive domains to estimate risks for PD in a clinic setting. These preliminary data also add value in establishing a quantifiable bio-cognitive risk signature to identify prodromal PD risks in young adults prior to obvious cognitive and motor decline. While encouraging, these data require further follow-up with a larger sample size in a longitudinal design to validate these findings.

Isolated rapid eye movement sleep behavior disorder (iRBD) is characterized by nigro-striatal deficits, comprising dopaminergic denervation of the striatum and loss of dopaminergic cells in the substantia nigra (SN), that may herald phenoconversion to clinically manifest synucleinopathy. While phenoconversion has repeatedly been shown to relate to pre-synaptic dopaminergic deficits in the striatum, potential involvement of loss of dopaminergic cells in the SN remain unclear. In addition, phenoconversion may independently relate to noradrenergic deficits, stemming from cell loss in the locus coeruleus/subcoeruleus (LC/LsC) complex. Fifty-six iRBD patients were included and clinically followed over an 11-years as part of the ICEBERG study. Putamen dopamine denervation was quantified using 123I-FP-CIT single-photon emission computed tomography. Cell loss in the SN and LC/LsC was quantified using neuromelanin-sensitive magnetic resonance imaging (MRI). SN cell loss was additionally characterized as free water, derived from diffusion-weighted MRI. The primary outcome was time to phenoconversion. Cox proportional hazards regression was used to investigate relationships between phenoconversion risk and imaging predictors, estimated as hazard ratios (HRs). Out of 56 patients, 24 (41%) converted to a clinically manifest synucleinopathy [PD=14 (58%), DLB=8 (33%), MSA=2 (8%)] over a maximum period of 11 years. We replicated the well-established finding that reduced putamen DaT confers an increased phenoconversion risk [HR (95%CI)=3.1 (1.7-5.5), P<0.001]. We extend on this by showing a similar relationship for SN neuromelanin [HR (95%CI)=2.5 [1.3-4.6], P=0.004], SN free water [HR (95%CI)=1.54 (1.06-2.24), P=0.025], and LC/LsC neuromelanin [HR (95%CI)=2.1 (1.2-3.7), P=0.011], demonstrating involvement of the broader nigro-striatal dopaminergic system along with potential involvement of noradrenergic neurotransmission. When adjusting for putamen DaT, the relationship between phenoconversion risk and SN neuromelanin was attenuated [P=0.16], suggesting partial overlap between the metrics. In contrast, when modelled together, SN neuromelanin [HR (95%CI)=2.8 (1.4-5.6), P=0.003] and LC/LsC neuromelanin [HR (95%CI)=2.3 (1.1-4.8), P=0.037] contributed to phenoconversion risk independently of each other, indicating a differential contribution of dopaminergic and noradrenergic neurotransmitter deficits to iRBD phenoconversion. We demonstrate that phenoconversion in iRBD relates similarly to dopaminergic denervation of the putamen and cell loss in the SN. This opens possibilities for using NM-MRI, which can simultaneously capture dopaminergic and noradrenergic deficits, as an alternative to nuclear imaging techniques when estimating phenoconversion risk in iRBD.

Pathogenic missense variants in the X chromosome gene UBQLN2 cause amyotrophic lateral sclerosis (ALS), often accompanied by frontotemporal dementia (FTD). As an X-linked gene, UBQLN2 is subject to X chromosome inactivation (XCI), a process wherein one X chromosome in each cell is randomly inactivated to a Barr body throughout the body in females, creating a mosaic of allelic expression in the tissues of heterozygotes. Despite heterozygous females constituting a majority of reported cases of UBQLN2-linked ALS/FTD, and the known influence of XCI on neurological disorders at large, no current disease models account for XCI. Here we report the characterisation of 12 iPSC clones carrying the ALS/FTD-causing p.T487I (c.1460C>T) UBQLN2 variant. These clones, originally derived from 3 heterozygous carrier fibroblast lines, underwent validation of homeostatic Barr body retention. Erosion of XCI in a subset of the lines was correlated with biallelic expression (of both wildtype and mutant UBQLN2), as measured through a novel allele-selective qPCR (AS-qPCR) assay and verified by amplicon-based Illumina sequencing and Sanger chromatogram quantification, enabling selection of iPSC clones best retaining XCI. Together, this UBQLN2 AS-qPCR assay and selected iPSC clones will enable studies of the role of XCI and its skew in female resilience to UBQLN2 p.T487I-linked ALS/FTD and enable development of allele-selective therapies.

Cognitive impairment is a disabling feature of Long COVID with no established disease-modifying therapy, and little is known about the biological changes accompanying clinical improvement. Microtesla Magnetic Therapy (MMT) is a low amplitude radiofrequency electromagnetic field intervention delivered to the whole brain. In a randomized, sham-controlled feasibility trial, at home MMT was feasible, safe, and well tolerated, with evidence of clinical improvement among treated participants. We explored molecular changes associated with response using SomaScan 11K plasma proteomics on paired baseline and week 4 samples. Participants were classified post hoc within each treatment arm using a clinician-selected response phenotype integrating cognitive and symptom domains. These groups were used for proteomic, pathway, and OrganAge analyses. MMT response was associated with selective proteome remodeling and an exploratory 17 protein response pattern in which Hedgehog interacting protein (HHIP), a Hedgehog signaling antagonist, was most strongly associated with response. Directional pathway analysis identified patterns consistent with lower inflammatory and injury biology and higher repair and adaptive remodeling. OrganAge analysis showed trends toward lower Brain and Organismal OrganAge with MMT. These findings prioritize HHIP and the exploratory 17 protein response pattern for prospective validation and support evaluation of plasma proteomics for monitoring treatment response.

Isolated REM sleep behaviour disorder (RBD) is the strongest prodromal marker of Parkinson's disease (PD) and dementia with Lewy bodies, yet diagnosis requires video-polysomnography with assisted montage and expert scoring and does not scale to screening or trial enrichment. We developed a fully automated, self-applied system that detects RBD from a pair of electrodes placed behind the ears, with no manual scoring at any stage. A novel bipolar mastoid ExG derivation enables both sleep staging and quantification of REM sleep without atonia (RWA). A fine-tuned deep-learning 1-channel model staged sleep at a Cohen's kappa of 0.65 in PD, iRBD and controls ({kappa} = 0.73 for the 2-channel model). Automated mastoid RWA correlated strongly with expert chin SINBAR scoring (r = 0.82). In self-applied home recordings from 76 participants, the 1-channel system detected RBD with an AUC of 0.95 (sensitivity 94%, specificity 86%), reproduced on in-lab polysomnographies (AUC 0.93, n = 378). In RBD, between-night RWA variability warrants repeated nights for prognostic monitoring. The system provides a scalable tool for RBD detection and a continuous RWA measure for longitudinal studies of neurodegeneration.

Acute traumatic spinal cord injury comprises a primary mechanical injury followed by a delayed secondary cellular injury cascade. No current monitoring modality directly detects ongoing cellular damage or its response to treatment. Essentially all spinal serotonin derives from descending raphe-spinal projections that travel alongside spinal motor and sensory pathways. Experimental spinal cord injury results in a robust release of serotonin into the surrounding interstitial tissue. We therefore asked whether cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), the stable metabolite of serotonin, tracks primary and secondary spinal cord injury in humans. In this prospective observational cohort study at a single level-one trauma center, cerebrospinal fluid was collected at 8-hour intervals for up to 5 days through indwelling lumbar drains from 11 participants with acute cervical or thoracic traumatic spinal cord injuries (American Spinal Injury Association Impairment Scale [AIS] grade A-C) and from 7 non-injured control participants. Cerebrospinal fluid 5-HIAA was quantified by high-performance liquid chromatography. Participants with acute traumatic spinal cord injury demonstrated a reproducible rise in cerebrospinal fluid 5-HIAA within 12 hours of injury that regressed toward control values. Two participants neurologically declined during the 5-day observation period, and in both a delayed secondary 5-HIAA elevation accompanied the decline; in one participant this elevation coincided with a documented episode of critical spinal cord hypoperfusion and resolved within 8 hours of its correction. Across the cohort, the 5 participants with a secondary 5-HIAA elevations above 400 nM more than 36 hours after index trauma were AIS A at 12 months regardless of initial injury severity, whereas all 6 participants without a secondary elevation in cerebrospinal fluid 5-HIAA levels were AIS C or better. In this small exploratory cohort, cerebrospinal fluid 5-HIAA was associated with the presence of acute traumatic spinal cord injury, with acute secondary neurological decline, and with long-term motor outcome. Unlike glial fibrillary acidic protein and neurofilament light chain, whose concentrations evolve over days to weeks, 5-HIAA rose and regresses within hours, a kinetic profile compatible with real-time detection of secondary injury and confirmation of treatment response. These findings are hypothesis-generating and require validation in larger, multicenter cohorts before clinical application.

Recent studies show that pallidal and subthalamic local field potentials (LFPs) encode locomotor state and can guide adaptive deep brain stimulation (DBS) for gait impairment in Parkinson's disease. Here, in one participant implanted with the Picostim DyNeuMo-2c, we demonstrate a simpler and more direct approach for inferring locomotor state using the device's onboard accelerometer. Triaxial acceleration was classified independently on each axis to select among preconfigured stimulation programs. Using a cranially mounted digital twin, we characterized inertial signatures across medication and activity states, developed a classifier that distinguished walking from rest while rejecting tremor, and verified the intended stimulation switches during walking. In an exploratory comparison, a gait-adaptive program improved objective gait measures relative to open-loop stimulation optimised for resting tremor. These findings provide a first-in-human demonstration of the feasibility of device-embedded inertial sensing for gait-responsive DBS. They establish a practical framework for further evaluation in larger cohorts.

Persistent neurological symptoms are among the most disabling manifestations of post-COVID-19 syndrome (PCS), yet the contribution of ongoing CNS immune activation remains uncertain. CSF studies including clinically relevant COVID-19 recovered control cohorts are scarce. In this prospective single-center study, we enrolled 50 patients fulfilling the WHO criteria for PCS (COVIDpost, mean age +/- standard deviation [SD] 43.41 +/- 11.99 years, 30 % male, 70 % female) and 50 individuals who had fully recovered from COVID-19 (COVIDreco, mean age +/- SD 39.38 +/- 13.45, 42 % male, 58 % female). Both cohorts were comparable regarding age (p = 0.07), sex (p = 0.30), and education (p = 0.84). All participants underwent paired CSF and serum analyses together with comprehensive neuropsychological assessment. Routine CSF parameters, blood-CSF barrier integrity, oligoclonal bands (OCB), SARS-CoV-2 RNA in CSF and blood, pathogen-specific antibody indices, and neuronal autoantibodies were investigated. Despite marked differences in cognitive performance (p < 0.001) and fatigue severity (p < 0.001), patients with PCS showed no evidence of disease-specific CSF abnormalities compared to recovered controls. Routine CSF parameters, blood-CSF barrier dysfunction, CSF-restricted OCB, SARS-CoV-2 RNA in CSF and blood, intrathecal SARS-CoV-2 antibody synthesis, polyspecific antiviral immune responses, and neuronal autoantibodies were comparable between groups. SARS-CoV-2-specific IgG concentrations in CSF correlated positively with serum concentrations (COVIDpost: r [95%CI] = 0.78 [0.62 - 0.87]; COVIDreco: r [95%CI] = 0.86 [0.75 - 0.92]; both p < 0.001) and albumin quotient (COVIDpost: r [95%CI] = 0.52 [0.26 - 0.71], p < 0.001; COVIDreco: r [95%CI] = 0.37 [0.10 - 0.60]; p = 0.01), consistent with passive transfer across the blood-CSF barrier rather than compartmentalized intrathecal immune activation. Furthermore, SARS-CoV-2-specific antibody measures were not associated with cognitive performance (p > 0.72) or fatigue severity (p > 0.88). This study provides no evidence that persistent neurological symptoms after COVID-19 are accompanied by ongoing adaptive CNS immune activation, disease-specific neuronal autoimmunity, or intrathecal SARS-CoV-2-specific humoral immune responses. The inclusion of a carefully phenotyped COVID-19 recovered comparison cohort strengthens the conclusion that routine CSF abnormalities largely do not seem to reflect mechanisms specific to PCS. These findings argue against routine CSF diagnostics as a source of disease-specific biomarkers in unselected PCS patients and support future studies focusing on alternative mechanisms underlying persistent neurological symptoms.

Background: Timely carbidopa-levodopa administration is a recognized inpatient safety priority in Parkinson disease, and mistiming is common, but where in the medication-use process it arises is uncharacterized. Objectives: To localize where inpatient mistiming arises and where to target intervention. Methods: In a single-center retrospective analysis of hospitalized adults with Parkinson disease on home carbidopa-levodopa, each dose's administration time was compared with the individualized home schedule. Mistiming was defined a priori as more than 15 minutes from the home time (Parkinson's Foundation Hospital Care Standard 2). We characterized the deviation distribution, tested whether administrations tracked the schedule or the standard grid, and examined length-of-stay and readmission. Results: Across 947 doses in 101 patients, ordering was accurate, yet 62.9% (596 of 947) missed the home time by more than 15 minutes and 99% of patients had at least one mistimed dose. Administrations tracked the individualized schedule almost exactly (Pearson r 0.98), not the standard grid: only 10% fell within 15 minutes of the default times, and the median dose sat 24 minutes from its home time but 76 from the nearest default. Deviation was symmetric drift (median absolute deviation 24 minutes; 16.5% beyond 60 minutes). Conclusions: Mistiming in this study reflected imprecise bedside execution, not ordering or a mismatch between fixed rounds and individualized regimens. These findings may point medication-safety efforts toward protecting bedside administration as complementary redesigning orders.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's Disease (PD), but identifying optimal stimulation contacts is time-intensive. Beta-band activity (13-35 Hz) from local field potentials (LFP) correlates with motor symptoms and attenuation by dopaminergic therapy and DBS supports its role as a programming biomarker. The recently introduced Electrode Identifier (EI) feature of Medtronic PerceptTM neurostimulators may facilitate beta-guided contact selection. Objective: To evaluate whether pseudo-monopolar STN beta power obtained using EI predicts optimal stimulation contacts and compare its performance with reconstructed bipolar recordings and MPR. Methods: LFPs were recorded in 69 patients using EI and Electrode Survey (ES). Prediction accuracy was assessed using predefined ranking rules and compared with clinically selected contacts. Agreement between EI, ES, and MPR was evaluated. Motor outcome was assessed using MDS-UPDRS-III. Results: EI predicted clinically selected contacts above chance (TOP1: 45%, p = 0.010; TOP2-80: 57%, p = <0.001), whereas ES exceeded chance only under more inclusive selection criteria (TOP1: 38%, p = 0.073; TOP2-80: 55%, p = 0.0021). Accuracy did not differ between methods (TOP1: p = 0.720; TOP2-80: p = 1.000). EI showed highest agreement with MPR and tended to select ventral contacts. Neither method predicted motor outcome, although EI-matched contacts showed a trend toward greater improvement. Due to technical constraints, one-third of EI recordings were excluded. Conclusions: Pseudo-monopolar STN beta power provides clinically relevant information for DBS contact selection with performance comparable to bipolar approaches. Further improvements are needed before clinical implementation.

Background: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with no known cure. Disease progression in people living with ALS is heterogeneous, hindering personalized treatment development. The current gold standard for measuring disease progression in ALS, the ALS Functional Rating Scale - Revised (ALSFRS-R), is widely used but based on subjective measurements. Blood-based neurofilament light (NfL) has been studied as a diagnostic and prognostic biomarker but less information exists on its utility as a disease progression biomarker. Methods: We present results from blood draws of 300 participants in the FDA-funded Clinic-Based Multi-Site ALS Natural History and Biofluid study of the ALS Natural History Consortium (NHC). Plasma NfL levels were measured and analyzed against different disease progression metrics based on the ALSFRS-R. Results: NfL levels were found to be correlated with the ALSFRS-R average rate of change (r=-0.53, 95% CI -0.62 to -0.42). This association differed at a cutoff value of 61 pg/mL, with stronger correlations below this cutoff (r=-0.51 vs r=-0.18). Survival differed stratifying by this cutoff value, with participants under the cutoff having higher survival probabilities. The predictive value of NfL when predicting time to death was higher compared with the first ALSFRS-R across different event horizons. A model including both was better when predicting events up to 2 years after diagnosis. Conclusions: These results highlight the utility of NfL as a disease progression biomarker in ALS alongside ALSFRS-R based disease progression metrics. The cutoff value can aid in clinical trial stratification, pragmatic trial planning, and clinical care.

Deep brain stimulation is an established treatment for Parkinson's disease but does not adapt to dynamic changes in brain state. Here, in four patients with sensing-enabled DBS systems, we evaluated a movement-responsive DBS (mDBS) paradigm that modulated subthalamic stimulation based on volitional motion decoded from cortical activity. During structured motor tasks, mDBS improved average forearm speed and mitigated the progressive bradykinetic slowing observed under constant-amplitude DBS (cDBS), accompanied by a cumulative increase in sensorimotor cortical beta activity and connectivity. In unconstrained, daily activities, mDBS lowered average bradykinesia severity and demonstrated progressive symptom reduction over hours of therapy, which gradually reversed upon switching to cDBS. These findings highlight the enhanced therapeutic benefit of mDBS and its potential to reinforce functional motor circuits in disorders of movement.

Background Blood biomarkers are increasingly used to support the diagnosis and monitoring of neurodegenerative diseases. However, their interpretation is complicated by physiological determinants, including age, sex, body-mass index, and renal function, and by differences in absolute concentrations between analytical methods. We aimed to develop population-based reference equations allowing individualized interpretation of the main blood biomarkers used in neurology. Methods In this cross-sectional study, we analysed plasma samples from cognitively unimpaired participants selected from the French CONSTANCES and Three-City population-based cohorts. Generalized additive models for location, scale, and shape were used to model neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), amyloid-{beta}40, amyloid-{beta}42, and their ratios according to age, sex, body-mass index, and renal function. The resulting equations provided individualized expected concentrations, percentiles, and Z-scores. Previously established disease-specific concentrations were converted into Z-score. Cross-calibration equations were developed for NfL measurements across analytical methods and sample matrices. Findings The final reference populations comprised 5123 participants for amyloid biomarkers and p-tau181 and 5122 for NfL and GFAP; median age was 52.3 years and half were women. Between ages 40 and 80 years, expected NfL and GFAP concentrations increased by an average of 2.6% and 2.2% per year, respectively. Renal function, body-mass index, and sex had additional biomarker-specific effects. Application of the equations to clinical cohorts preserved distinct disease-associated profiles: NfL Z-scores were increased across disorders characterised by neuroaxonal injury, whereas p-tau181 and GFAP showed its greatest increase in Alzheimer disease. NfL cross-calibration equations showed excellent agreement between methods and matrices, with intraclass correlation coefficients greater than 0.90. Interpretation This population-based multibiomarker framework enables blood biomarker concentrations to be interpreted relative to individuals with similar physiological characteristics. Publicly available equations, reference curves, and standardized Z-scores could improve individualized interpretation and comparability across biomarkers, laboratories, and clinical populations.

BackgroundThe relationship between essential tremor (ET) and Parkinsons disease (PD) remains controversial. Beyond viewing ET as a discrete risk factor for PD, recent frameworks propose that an ET phenotype may represent a clinical presentation of prodromal PD (pPD), consistent with the current reconceptualization of ET as a syndrome. Whether co-occurring subtle motor signs alter pPD probability in ET remains unknown. MethodsUsing the MDS research criteria, we calculated pPD probability in a large cohort of ET patients with and without subtle motor signs (rest tremor, hypomimia, isolated rigidity, reduced arm swing, altered repetitive movements, global slowing). Multivariable regression was used to identify independent predictors of pPD probability. ResultsAmong 599 ET patients (median disease duration: 12 years), only 6 (1.0%) met criteria for probable pPD. Although ET patients with subtle motor signs exhibited higher continuous pPD probability scores than those without, the frequency of possible or probable pPD did not differ significantly between groups. In multivariable regression, neither ET nor individual subtle motor signs, but hypomimia, were independent predictors of pPD probability, which was primarily driven by older age and male sex. ConclusionsLong-standing ET, whether isolated or accompanied by subtle motor signs, is not associated with pPD, with the possible exception of co-occurring hypomimia.

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

Spinocerebellar ataxia type 3 (SCA3) is an inherited, fatal neurodegenerative disease caused by a pathological CAG repeat expansion in the ATXN3 gene, resulting in the selective degeneration of vulnerable neuronal populations. Recent work has identified impairments in oligodendrocyte maturation as a novel and robust feature of SCA3 pathogenesis. Oligodendrocytes synthesize myelin structural components through the endoplasmic reticulum (ER), rendering this organelle essential for white matter integrity. Despite this, the role of ER function in SCA3 remains unclear. In this study, we show that loss of FICD-mediated AMPylation, a post-translational modification regulating the ER-resident HSP70 chaperone, BiP, rescues motor impairments in a transgenic SCA3 mouse model. Ficd-/- SCA3 mice exhibit significantly reduced levels of nuclear ATXN3 in vulnerable brain regions, while Ficd+/+ littermates show an increased burden of AMPylated BiP in the spinal cord, identifying aberrant AMPylation as a novel contributor of SCA3 pathology. Using unbiased proteomics, we demonstrate that Ficd deletion mitigates the pathological decrease in myelin structural proteins and oligodendrocyte maturation factors, restoring levels of mature, myelinating oligodendrocytes. In parallel, we show that Ficd activates SREBP2-dependent cholesterol biosynthesis to support myelination. Taken as a whole, these findings posit ER homeostasis as a critical driver of oligodendrocyte pathology and identify FICD as a novel target for alleviating non-neuronal toxicity in SCA3.

Background and Objectives: Genetic causes of epilepsy are well-established in children, but the genetics of adult-onset epilepsy is not well understood. There are few studies of epilepsy genetics in older adults, U.S. military Veterans, and people with acquired causes of epilepsy like traumatic brain injury (TBI) and stroke. To test if rare gene variants that cause pediatric epilepsy are associated with adult-onset epilepsy, we determined the prevalence of pathogenic germline variants (PGVs) in epilepsy-associated genes in an ancestrally diverse cohort of older Veterans and examined the penetrance of epilepsy among PGV carriers. We evaluated the effect of mode of inheritance (MOI), variant selection, single gene-level factors, and gene-disease relationship validity on prevalence and penetrance estimates. Methods: This retrospective cohort study used electronic health record (EHR) data from Veterans enrolled in the Million Veteran Program (MVP) biobank who had whole genome sequencing (WGS) data available. We identified Veterans with one or more rare (variant allele frequency [VAF] <0.01) pathogenic/likely pathogenic single nucleotide variants (SNVs) within one or more of 165 expert-curated epilepsy genes. Epilepsy phenotype was defined using a validated algorithm, and penetrance estimates were calculated using Bayes theorem and compared to civilian cohorts. Results: There were 102,624 MVP participants with WGS data. Mean age at censorship or death was 74.6 years, 6.1% were female and 6.3% had epilepsy. Among participants, 1.9% (n=1,955) carried at least 1 rare PGVs and 1.0% (n=1,041) carried ultrarare PGVs. Most carriers of autosomal dominant (AD) PGVs (89.7%) were not diagnosed with epilepsy, though carriers of both AD and autosomal recessive (AR) ultrarare PGVs had increased odds of epilepsy (odds ratios of 1.72 and 1.45, respectively) compared to non-carriers. Penetrance estimates were low for AD PGVs (8.2%), but similar to estimates from civilian biobanks. Discussion: Veterans carrying PGVs in AD-labeled epilepsy genes had increased risk for epilepsy, but only 10.3% were diagnosed. Unexpectedly, Veterans heterozygous for AR-labeled PGVs also had increased risk of epilepsy. Potential reasons for this include latent compound heterozygosity, misclassification of variant pathogenicity or gene MOI, or the possibility that PGVs in AR genes may be risk alleles for adult-onset epilepsy.

Amyloid plaques, one of the defining features of Alzheimer's disease, are associated with synapse loss and accumulation of pathological tau in dystrophic neurites and reactive glia in their immediate vicinity. Anti-amyloid-beta; immunotherapies have been shown to effectively remove a large proportion of plaques from the brain, but whether immunotherapies reduce pathological changes around remaining plaques or plaques that emerge after treatment remains unknown. We examined amyloid plaques, synapses, astrocytes, and phosphorylated tau in post-mortem brain tissue from people with Alzheimer's disease who received Amyloid-beta42 immunization in the AN1792 trial (Elan Pharmaceuticals), non-immunized or placebo-treated people with Alzheimer's disease, and neurologically healthy controls. In non-vaccinated individuals, we observe plaque-associated synapse loss, phospho-tau accumulation, and astrogliosis as previously reported. People who received Amyloid-beta42 vaccination had reduced pathology up to 14 years after receiving the vaccine including ameliorated plaque-associated synapse loss, less accumulation of phospho-tau around plaques (AT8 and pTau217), lower levels of astrogliosis, and lower levels of phospho-tau associated with synapses. These data indicate that anti-amyloid active vaccines may have lasting beneficial effects even around remaining plaques or plaques formed after immunization.

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

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.