Initially described in 1976, X-linked dystonia parkinsonism (XDP) is a neurodegenerative disease that can be characterized by the presentation of dystonia and parkinsonism symptoms. Although this disease bears some resemblance to other neurodegenerative diseases in terms of symptomatology, the pathological signature of XDP is still unclear, in part because of the limited research that has been conducted. This study aims to delineate in detail the neurochemical changes occurring in the post mortem human XDP striatum and to explore their relevance to clinical symptomatology. The profiles of immunohistochemical expression of multiple spiny projection neurons and projection fiber markers was assessed in the post mortem tissue from the basal ganglia of 18 XDP and 10 neurologically normal cases. We present evidence that degeneration of the XDP striatum follows a dorsoventral gradient, with greater vulnerability in the matrix compartment of the striatum. Considering the available clinical data of the cases investigated, we propose that this pattern of neurodegeneration is more closely associated with the duration of the disease than SINE-VNTR-Alu repeat length; however, repeat length is inversely correlated with XDP symptom onset and, therefore, influences the clinical timeline. Our findings provide a novel perspective on the pattern and degree of degeneration of the XDP striatum. We propose that the matrix compartment is more vulnerable to disease impact relative to striosomes than initially thought, and the pattern of striatal degeneration may be indicative of the breakdown of a wider cortico-basal ganglia neural circuit over the duration of the disease. ANN NEUROL 2026.
Spinal muscular atrophy (SMA) is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene and subsequent reduction in the expression of survival motor neuron (SMN) protein. The disease is characterized by degeneration of α motor neurons and subsequent muscle atrophy. Postnatal disease modifying therapies improve outcomes yet fall short of a cure. We have investigated a prenatal therapeutic strategy using the SMNΔ7 mouse model of SMA. A risdiplam-like compound was administrated by oral gavage to pregnant mice with treatment initiated mid-gestation and halted on day of birth. Reproductive metrics, liver toxicology, and immune function were assessed in the pregnant dams during gestation and post-birth. Progeny were monitored phenotypically, and pathological hallmarks of SMA were investigated including, but not limited to motor neuron, neuromuscular junction, and muscle health. Maternal-fetal drug transfer was safe for the pregnant dam and substantially increased weight, motor function, and survival of severe SMA mice. It also rescued and maintained myofiber area. Presynaptic components of the neuromuscular junction were marginally improved in SMNΔ7 pups, whereas postsynaptic endplate size was increased following prenatal risdiplam treatment. Motor neuron pathology was not fully rescued by prenatal exposure to SMN protein, likely because of the lack of continued postnatal intervention. By restricting risdiplam treatment to the prenatal period, we have isolated and assessed therapeutic effects attributable solely to embryo exposure of the therapeutic. Our efforts demonstrate a combination of prenatal and postnatal therapy must be used for optimum therapeutic outcomes in the treatment of patients with SMA. ANN NEUROL 2026.
To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.
The objective of this study was to investigate the ability of patient-reported/administered outcomes to capture disability worsening and progression independent of relapse activity (PIRA) in multiple sclerosis (MS). We included patients from the longitudinal multicenter MS PATHS cohort with ≥3 assessments and >6 months follow-up. PIRA was defined on the patient-determined disease steps (PDDS) and self-administered tests assessing walking speed, manual dexterity, and processing speed, in the absence of self-reported relapses. We assessed (i) prevalence of PDDS/self-administered test-based disability worsening and PIRA definitions; (ii) their concurrent validity, through the association with worsening and PIRA definitions based on the expanded disability status scale (EDSS; Barcelona subcohort); and (iii) their clinical meaningfulness, through the correlation with brain magnetic resonance imaging (MRI) and quality-of-life (QoL) data trajectories. We included 9,088 patients (73% female patients; age = 46.8 years; disease duration = 14.2 years). Over a 3-year follow-up, 4,066 (45%) patients worsened on ≥1 patient-reported/administered outcome, of which 2,357 (58%) developed PIRA. In the Barcelona subcohort (N = 279), 68 (24%) patients developed EDSS-based worsening, of which 30 (44%) developed EDSS-based PIRA; 99 of 279 (35%) worsened on ≥1 patient-reported/administered test, of which 78 of 99 (79%) had PIRA. Worsening (but not PIRA) on PDDS was associated with EDSS-based worsening (odds ratio = 3.03 [1.42; 6.43], p = 0.004). PDDS/self-administered-test-based worsening or PIRA strongly correlated with accelerated brain atrophy and T2 lesion volume increase compared to non-worseners (p < 0.05), and showed worse QoL (p < 0.05). Despite only partial agreement with EDSS-based definitions, PDDS/self-administered test-based worsening and PIRA definitions were clinically meaningful, by identifying patients with greater brain damage and poorer QoL, supporting their use in clinical practice. ANN NEUROL 2026.
To evaluate the effectiveness and safety of ocrelizumab in self-identified black and Hispanic people with relapsing multiple sclerosis. The Characterization of Ocrelizumab in Minorities with Multiple Sclerosis (CHIMES) trial, a prospective, open-label, single-arm, phase 4 study, intentionally recruited underrepresented populations in the US, Puerto Rico, and Kenya. Black and Hispanic people with relapsing multiple sclerosis aged 18-65 years with Expanded Disability Status Scale score 0-5.5 received ocrelizumab for 2 years. The primary endpoint was the proportion of participants with no evidence of disease activity in 3 components at week 48: protocol-defined relapse, 24-week confirmed disability progression, and disease activity on magnetic resonance imaging. Of 113 black and 69 Hispanic people with relapsing multiple sclerosis, most were women (72%), with a mean age of 35.5 (SD 10.5) years, body mass index of 31.0 (SD 7.4) kg/m2, and Expanded Disability Status Scale score of 2.4 (SD 1.4). Genetic ancestry aligned with self-identified race or ethnicity. At week 48, 50.5% of CHIMES participants had no evidence of disease activity, including 94.5% free from 24-week confirmed disability progression, 95.1% free from relapse, 95.6% free from T1-contrast-enhancing lesions, and 52.7% free from new/enlarging T2 lesions. Serious adverse events were experienced by 8.2%, and 2.2% discontinued treatment. Infusion-related reactions were more frequent in Hispanic versus black participants (42.0% vs 29.2%), whereas gastrointestinal adverse events were more frequent in black versus Hispanic participants (23.0% vs 1.4%). Ocrelizumab treatment controlled disease activity in black and Hispanic people with relapsing multiple sclerosis. Results were consistent with pivotal ocrelizumab trials, supporting ocrelizumab's effectiveness and tolerability in these populations. ANN NEUROL 2026.
Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance. Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment. Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology. Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.
Randomized trials from high-income countries have shown that endovascular treatment (EVT) yields similar benefits in elderly and non-elderly patients with large vessel occlusion stroke (LVOS). However, evidence from low/middle-income countries remains scarce. We aimed to assess the impact of age on outcomes and determine whether age modifies the effect of EVT under the resource-limited conditions of a public healthcare system in a developing country. Pre-specified subgroup analysis of the RESILIENT trial, a multicenter, randomized, controlled trial in Brazil comparing EVT versus medical treatment alone in anterior circulation LVOS. Patients were categorized as non-elderly (<70 years), elderly (≥70 years), and very elderly (≥80 years). The primary endpoint was functional independence (modified Rankin scale 0-2) at 90 days. Logistic regression was performed to identify independent predictors of outcome and to assess age as an effect modifier. Among 221 randomized patients (47.1% females; median [IQR] National Institutes of Health Stroke Scale, 18 [14-21]), 89 (40.2%) were elderly and 37 (16.7%) very elderly. Increasing age was independently associated with lower odds of functional independence in the entire study population (odds ratio [OR]: 0.97; 95% confidence interval [CI]: 0.95-0.99, p = 0.01). Age significantly modified the treatment effect of EVT. Non-elderly patients derived substantial benefit from EVT (OR: 4.08; 95% CI: 1.71-9.76), whereas the benefit was attenuated in elderly (OR: 0.90; 95% CI: 0.17-5.42; pinteraction = 0.03) and very elderly (OR: 0.36; 95% CI: 0.11-3.21; pinteraction = 0.03). The effect of EVT appears significantly diminished among elderly patients in a public healthcare system in a developing country. Further studies are needed to understand the mechanism underlying these findings and properly assess the efficacy of EVT in this vulnerable population. ANN NEUROL 2026.
Both high and declining blood pressure (BP) are associated with risk of cognitive decline in older adults, and women have higher rates of hypertension and faster cognitive decline in late-life. In old age, the relationship between changes in BP and changes in cognition is complex, and although sex differences in cognitive function and decline are recognized, little is known about the relationship of longitudinally collected BP and cognition, simultaneous changes in BP and cognition, or whether they differ by sex. We investigated the association of simultaneous change in BP and cognition in older adults followed annually for an average of 9 years. A total of 4,719 older adults without baseline dementia (mean age = 76.7 [standard deviation = 7.7] years; 74% women) from 5 prospective community-based cohort studies completed annual assessments of BP and cognition, yielding composite global and 5 domain-specific scores. BP and cognition were modeled simultaneously using joint bivariate linear mixed-effects models. Among 3,502 women and 1,217 men, faster decline in systolic BP was associated with faster decline in global cognition (r = 0.20, p < 0.01). Stratified models revealed a stronger relationship in women (r = 0.26, 95% confidence interval [CI]: 0.17-0.37) than men (men: r = 0.01, 95% CI: -0.13 to 0.11). In secondary analyses, decline in systolic BP was related to decline in 5 cognitive domains in women but none in men. This large longitudinal study reports evidence of a relationship between simultaneous decline in systolic BP and cognition in women, but not men. As women experience a disproportionate burden of both hypertension and cognitive decline in late-life, declining systolic BP, a routine clinical measure, may serve as an important indicator of concurrent cognitive decline in older women. Understanding these sex-specific associations may help advance the understanding of drivers behind sex differences in cognitive decline. ANN NEUROL 2026.
Cerebral ischemia remains a major cause of disability, and the contribution of the hyperacute immune response is increasingly recognized. The aim of this study was to investigate the local inflammatory response in the affected brain of stroke patients with large vessel occlusion during the hyperacute phase of stroke. To decipher the role of myeloid immune cells in stroke-induced inflammation, we performed an unsupervised multiomics analysis of innate immune pathways in ischemic blood obtained directly from the occluded middle cerebral artery in 54 patients undergoing mechanical recanalization. Paired nonischemic arterial blood served as an internal control. Stroke triggered a local hyperacute activation of classical monocytes and neutrophils in the ischemic cerebral vasculature, with interleukin (IL)-1β emerging as a key mediator of inflammation. Elevated plasma adenosine triphosphate levels and inflammasome priming in intravascular monocytes were associated with IL-1β production within the occluded middle cerebral artery within 4.5 hours of stroke onset. IL-1β release coincided with increased neutrophil-attracting chemokines (C-X-C motif chemokine ligand 1 [CXCL1], IL-8). Locally activated neutrophils formed neutrophil extracellular traps (NETs) within the ischemic vasculature, a hallmark of thromboinflammation. Postmortem analyses revealed NET deposition within ischemic brain parenchyma. These findings indicate increased IL-1β expression and enhanced NET formation within the cerebral circulation in stroke caused by large vessel occlusion, suggesting that these mechanisms might contribute to early stroke pathophysiology and represent potential targets for immunomodulatory strategies. ANN NEUROL 2026.
Drug-resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short-chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti-inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease-modifying effects in a preclinical model of DRE. Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE. SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3-fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut-brain axis dysfunction to disease progression. These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance. ANN NEUROL 2026.
ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk. Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest. Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding. Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.
The objective of this study was to provide clinical and pathological characterization, and evaluation of the diagnostic and prognostic implications of levodopa response in Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Long-duration levodopa response in patients with pathology-confirmed PD, MSA, and PSP was collated from medical records. Associations between definite levodopa response (>50% motor improvement sustained >2 years) with clinical and pathological features were reported. Risk of disease milestones using multivariate Cox regression and diagnostic accuracy parameters were estimated for several measures of levodopa response. Fourteen percent of 132 patients with PD (57.1% men, age at onset 60.0 ± 11.8 years) did not have a definite levodopa response associated with older age and postural-instability and gait-difficulty subtype without global or nigral pathological differences. Definite levodopa responders had 55% lower falls, 69% lower dementia risk, and 69% increased survival. Eight percent of 115 patients with MSA (55.7% men, age at onset 57.9 ± 10.4 years) showed a definite levodopa response without distinctive clinical or pathological features, and no impact on disease milestones. Two percent of 191 patients with PSP (64.4% men, age of onset 67.6 ± 7.6 years) showed a definite levodopa response associated with a PSP-parkinsonism subtype, and more frequent and severe Lewy copathology. Definite levodopa response showed excellent diagnostic accuracy (sensitivity 86.4% and specificity 95.8%) to distinguish PD from MSA and PSP. Short-duration (acute dopaminergic drug challenge) response had suboptimal diagnostic value and modest correlation with long-duration response. Levodopa response in PD, MSA, and PSP has important clinical, pathological, diagnostic, and prognostic implications. ANN NEUROL 2026;100:305-318.
The objective of this study was to investigate the autoantibody profile in immune checkpoint inhibitor (ICI)-induced optic neuritis (CBON) and identify key autoantibodies for diagnostic and therapeutic purposes. In this multicenter retrospective study (January 2020-June 2025), we screened 327 neuro-ophthalmic patients from a bio-repository of 2,321 ICI-treated individuals, identifying 88 patients with CBON across 3 independent cohorts (n = 25, 29, and 34). Longitudinal serum samples (pre-ICI, prodromal, onset, and follow-up) were available for 12 patients. A matched control group of 49 ICI-treated patients without neuro-ophthalmic symptoms was included. Serum samples were analyzed using cell-based assays for 25 neural-specific IgG autoantibodies. Longitudinal samples were assessed for antibody dynamics. Correlations between serostatus and clinical features were evaluated. Autoantibody profiling revealed a highly focused immune response concentrated against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG). Seropositivity rates for these antibodies ranged from 17.3% to 32.4% across cohorts, whereas other neural antibodies were detected at markedly lower frequencies (<12%). Longitudinal analysis demonstrated a clear seroconversion pattern, with antibodies undetectable at pre-ICI baseline but emerging at symptom onset, which remained detectable during follow-up in a subset of patients. These AQP4/MOG antibodies were virtually absent in control patients (0-2%). This study establishes AQP4 and MOG as the dominant autoantibodies in CBON, providing a serological framework for diagnosis and classification. The persistent antibody response following ICI-induced seroconversion offers direction for future mechanistic investigations. ANN NEUROL 2026.
This study aimed to evaluate the safety and effectiveness of adjunctive intra-arterial tenecteplase (TNK) in patients with acute ischemic stroke (AIS) due to cardioembolism (CE) and non-CE who achieved near-complete to complete reperfusion (defined as an expanded thrombolysis in cerebral infarction score of 2c-3) following endovascular treatment (EVT). This prespecified secondary analysis of the POST-TNK randomized, open-label, blinded outcome assessment trial categorized 540 patients by stroke etiology into CE (n = 272) and non-CE (n = 268) subgroups. The primary outcome was freedom from disability at 90 days, defined as a modified Rankin Scale score of 0 to 1. Safety outcomes included 90-day mortality, symptomatic intracranial hemorrhage (sICH) within 48 hours, and any intracranial hemorrhage (ICH) within 48 hours. Among 272 patients with CE (median age, 73 years [interquartile range, 66-78]; 47.1% male), 137 were assigned to the control group and 135 to the intra-arterial TNK group. Compared with the control group, intra-arterial TNK was associated with significantly higher odds of freedom from disability at 90 days (adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.02-3.16; p = 0.04; inverse probability of treatment weighting adjusted odds ratio, 1.58; 95% CI, 1.12-2.22; p = 0.01). No significant differences were observed in 90-day mortality, sICH, or any ICH within 48 hours between groups. Conversely, intra-arterial TNK was not associated with improved functional outcomes in patients with AIS due to non-CE. In patients with AIS due to CE who achieved near-complete to complete reperfusion after EVT, adjunctive intra-arterial TNK was associated with a higher likelihood of freedom from disability at 90 days, without increasing the risk of mortality or ICH. However, this benefit was not observed in AIS patients due to non-CE. ANN NEUROL 2026.
Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally. We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [11C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation. Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA. Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.
Dysarthria is one of the most common and disabling side effects of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Stimulation often exacerbates speech dysfunction beyond the effects of PD progression, likely because of current spread to structures surrounding the STN. This study aimed to develop speech biomarkers sensitive to DBS-induced dysarthria by isolating stimulation side effects and mapping their emergence across incrementally increased amplitudes. Twenty-four PD patients with bilateral STN-DBS completed a standardized speech assessment in each hemisphere separately, including sustained phonations, rapid syllable repetitions, and reading passages across 7 increasing stimulation amplitudes defined relative to a clinically determined stimulation-induced dysarthria threshold. A composite dysarthria index based on 7 key acoustic features, patient perceptual self-ratings, and intelligibility scores were extracted. More than 2,500 speech task recordings were analyzed. Both the composite dysarthria index and subjective self-ratings worsened rapidly with increasing stimulation amplitude above a threshold (p < 0.001), whereas intelligibility scores varied markedly and did not reach significance. Among individual acoustic features, phonation duration, voice quality, and monopitch exhibited significant sensitivity to increasing stimulation amplitudes. Left-sided stimulation induced greater speech deterioration than right-sided stimulation. We systematically identified speech biomarkers that capture DBS-induced dysarthria, characterized the progressive deterioration of speech with increasing amplitude, and highlighted the pivotal role of left basal ganglia circuitry in speech production. Our objective metric holds promise as safety outcome measure for surgical therapies, guidepost for initial and troubleshooting DBS programming, and input for adaptive, closed-loop stimulation control. ANN NEUROL 2026.
The pathophysiology of idiopathic intracranial hypertension (IIH) is poorly understood and disease-specific biomarkers are lacking. We aimed to shed light on IIH pathophysiology and identify disease-specific biomarkers. This prospective cross-sectional cohort study included patients with new-onset IIH and age-, body mass index-, and sex-matched healthy controls from 2 tertiary Danish Headache Centers (discovery cohort). Liquid chromatography coupled to tandem mass spectrometry analysis was used to measure reproducible proteomic profiles for paired serum and cerebrospinal fluid (CSF) samples. Results were validated using 3 validation cohorts comprising patients with IIH (pwIIH), cerebral sinus venous thrombosis (pwCSVT), and normal pressure hydrocephalus (pwNPH). We included 53 pwIIH and 35 controls. PwIIH presented with papilledema and increased median lumbar puncture opening pressure (interquartile range [IQR]) (38.0 [33-46] vs 19.0 [17.0-23.0] cmH2O; p < 0.001) compared to controls. Machine learning analysis identified 20 IIH-predicting proteins for serum and CSF segregating pwIIH, but neither pwCSVT nor pwNPH, from controls with areas under the curve (AUC) of 0.84 and 0.92 (pwIIH, discovery cohort), 0.99 and 0.90 (pwIIH, validation cohort 1), 0.63 (plasma; pwCSVT), and 0.67 (CSF; pwNPH), respectively. Serum carbonic anhydrases (CA) 1 and 2 were upregulated and among the most IIH-predicting proteins as were amyloid precursor protein (APP), S100P, and S100A12. We identified a panel of independently validated IIH-specific candidate biomarkers. The serum candidate biomarkers pointed toward CA2 driven CSF hypersecretion in IIH providing a possible explanation for the therapeutic efficacy of CA inhibitors. The regulation of markers associated with neuronal impairment (APP, S100P/S100A12) confirmed the non-benign character of IIH. ANN NEUROL 2026;100:255-267.
Multiple sclerosis (MS) is a chronic autoimmune disease where B cells play a central pathogenic role. Cladribine, an oral therapy, provides durable benefits by reshaping lymphocyte populations, yet its specific long-term impact on distinct B-cell subsets is not fully understood. This study aimed to define cladribine's longitudinal effects on B-cell subsets and characterize their inflammatory properties. We conducted a 48-month longitudinal study of 36 persons with relapsing-remitting MS treated with cladribine who had completed 2 annual treatment cycles, using high-parameter flow cytometry to track B-cell subset dynamics. In a parallel cross-sectional analysis, B cells from 16 untreated patients and 16 healthy donors were profiled for polyfunctional cytokine production granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and key surface markers. Cladribine induced profound, sustained depletion of memory B cells, with marginal zone-like (MZ-like) cells showing the deepest and most persistent loss, alongside reconstitution of transitional and naïve populations. Functionally, MZ-like B cells were the most potent polyfunctional producers of proinflammatory cytokines and immunoglobulin M (IgM), a capacity significantly enhanced in persons with MS compared to healthy donors, and expressed the highest levels of CD1c and CD1d, consistent with specialization in lipid antigen presentation. MZ-like B cells are a dominant, polyfunctional inflammatory subset in MS, equipped for non-canonical lipid antigen presentation and IgM secretion. They represent a preferential pharmacological target of cladribine. Sustained reduction of this pathogenic memory pool, followed by repopulation with less inflammatory B cells, offers a mechanistic basis for cladribine's durable clinical benefit and nominates MZ-like cells as biomarkers of response and therapeutic targets. ANN NEUROL 2026.
The Parkinson's Progression Markers Initiative (PPMI) has addressed a key gap in the availability of long-term longitudinal data in sporadic Parkinson's disease (sPD) with extensive biological characterization. With biological characterization in the neuronal synuclein disease (NSD) framework, longitudinal outcomes are observed in cohorts defined by biological characteristics rather than based on conventional clinical diagnostic criteria. We recently reported our observations on 5 years of follow up in this cohort, and here, we provide our earliest findings on a comprehensive long-term description of disease progression in 344 sPD participants followed for up to 11 years. Although data collection is ongoing, these early findings highlight the heterogeneity in the early PD population as defined by clinical diagnostic criteria and affirm the importance of shifting to biologically and functionally based criteria in clinical research studies. ANN NEUROL 2026.
To better understand the earliest stages of alpha-synucleinopathy, the Parkinson's Progression Markers Initiative (PPMI) has enrolled participants prior to the diagnosis of Parkinson's disease (PD) or dementia with Lewy Bodies (DLB). In this review, we describe lessons learned from prior enrollment and current strategies for PPMI eligibility. Severe hyposmia remains the strongest clinical predictor of aggregated synuclein as measured by a positive cerebrospinal fluid alpha-synuclein seed amplification assay (CSF aSyn SAA). CSF aSyn SAA is positive before dopamine transporter binding decreases, as measured by dopamine imaging. PPMI's adaptive eligibility criteria have enabled efficient identification of people in the early stage of neuronal synuclein disease defined by biomarkers alone and can inform future therapeutic studies. ANN NEUROL 2026.