Polymicrogyria (PMG) is one of the most common human malformations of cortical development and is often classified by its radiographic pattern of distribution. Unilateral polymicrogyria (uPMG) is a subtype of PMG affecting a portion or all of one cerebral hemisphere. As most PMGs occur bilaterally, there has been no specific investigation as to whether the genetic underpinnings of uPMG comprise a subset of or a distinct entity from bilateral PMG. In this study, our goal was to assess both the genetic etiology of uPMG and the value of diagnostic genetic testing in this setting. We conducted a retrospective analysis of clinical data from individuals with uPMG seen in the Brain Development and Genetics Clinic and/or research participants of the Walsh Laboratory at Boston Children's Hospital. The final study cohort included 35 individuals from 30 families who were diagnosed with uPMG on brain magnetic resonance imaging (MRI) and also underwent genetic testing. A likely genetic cause was identified in 26.7% (8/30) of unrelated individuals with uPMG in this cohort and segregated within one family (10/35 total subjects). Recessive genetic causes included ASPM, WDR62, and TMEM216. Dominant causes included 22q deletion syndrome, DYNC1H1, SCN3A, and hereditary hemorrhagic telangiectasia (HHT) genes, ACVRL1 and ENG. This is the first report of variants in DYNC1H1, TMEM216, and ACVRL1 in association with uPMG. The genetic causes of bilateral PMG and uPMG can overlap, but some are unique to certain distributions of the malformation. Genetic explanations for uPMG are found at comparable rates to bilateral PMG, suggesting that germline testing for this unique presentation is warranted. ANN NEUROL 2026;99:1277-1286.
The concept of "normal pressure hydrocephalus" dates back to the description by Hakim and Adams in 1965 of 2 series of patients with enlarged lateral ventricles, high normal cerebral spinal fluid (CSF) pressure and a triad of cognitive impairment, urinary incontinence, and gait apraxia. The validity of this concept is based upon the reversal of its symptoms by a shunting procedure. However, all of these patients had secondary communicating hydrocephalus after previous episodes of meningitis, brain trauma, or subarachnoid hemorrhage. Nevertheless, shunting procedures for "idiopathic normal pressure hydrocephalus" with similar symptoms but no antecedent cause for communicating hydrocephalus became widely performed, although they were not tested by randomized, placebo-controlled trials for their value until a series of recent publications. These trials do not find improvement in either cognitive function or continence after shunting, and show that there is a small (approximately 25%) improvement in gait speed. They also confirm earlier studies that these patients suffer an approximately 10 to 15% incidence of severe adverse events in the first year after shunting, which may further accumulate with time. In the absence of value for shunting in reversing cognitive impairment and incontinence, the entire concept of "idiopathic normal pressure hydrocephalus" is called into question. ANN NEUROL 2026;99:838-843.
SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS. We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance. We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels. Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.
Biallelic variants in PRKN cause autosomal recessive Parkinson's disease (PD) with a median age at onset of 31 years. When evaluating the 16 previously published carriers of a homozygous deletion of Exon 2 from the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) database, the median age at onset is later (39.5 years) than in carriers of other PRKN pathogenic variants. We investigated whether these carriers show delayed disease onset compared with carriers of other pathogenic PRKN variants and explored the underlying molecular mechanism. We compared 26 homozygous PRKN Exon 2 deletion carriers with carriers of other pathogenic variants. Using human-induced pluripotent stem cell (hiPSC)-derived neuronal cell models from an unaffected 86-year-old carrier, genome-edited control lines, neuroblastoma cell lines, and in silico prediction, we investigated the underlying mechanism. Patients with PRKN Exon 2 deletions showed a later age at onset compared with carriers of other pathogenic variants. We discovered elevated levels of an N-terminally truncated Parkin proteoform lacking amino acids 1-79 due to internal translation initiation. This truncated protein partially retained ubiquitin ligase activity at endogenous levels. Treatment with Parkin modulator BIO-2007817 enhanced this residual function but reduced endogenous full-length Parkin activity. Residual truncated Parkin function provides a molecular explanation for a delayed disease onset in PRKN Exon 2 deletion carriers. Whereas this retained activity can be pharmacologically enhanced, the modulator's inhibitory effect on endogenous full-length Parkin may mandate strict patient stratification based on genotype. This finding offers mutation-specific counseling opportunities and highlights a potential therapeutic approach for appropriately selected patients with PARK-PRKN. ANN NEUROL 2026.
The extent of neuronal loss in Parkinson's disease (PD) and the pathogenic processes underlying neuronal dysfunction and loss remain poorly understood. Here, we analyzed the expression of key molecules representing different cell death signaling pathways and their association with Lewy pathology, dopaminergic (DA) neuron loss and stage of PD progression in human postmortem brain tissue. We performed neuropathological and molecular analyses on 47 postmortem substantia nigra (SN) tissue samples from PD cases and healthy controls to investigate neuronal cell death pathways. An average loss of 54% of dopaminergic neurons was found in the SN of PD cases, which correlated strongly with PD Braak staging. The apoptosis markers, cleaved subunits of caspases 3 and 8, were absent. Levels of the active necroptosis kinase, phosphorylated RIPK3 (pRIPK3), were significantly increased in advanced-stage PD. Although phosphorylated MLKL (pMLKL) levels were not significantly different, both active markers were detected in small numbers of PD neurons by immunofluorescence, suggesting focal necroptotic pathway activation. In contrast, evidence for ferroptosis was more pronounced, particularly in advanced-stage PD. This was supported by significantly increased transferrin receptor 1 (TFR1) protein levels and significantly decreased glutathione peroxidase 4 (GPX4) RNA and protein levels. Our findings implicate ferroptosis, and to a lesser extent necroptosis, in PD neuronal death, with ferroptosis potentially playing a larger role in advanced disease. We propose a "2-hit" model where early synucleinopathy-driven insults are amplified in advanced disease by a neuromelanin-iron-driven feedback loop, establishing ferroptosis as the predominant cell death mechanism. This stage-dependent shift provides critical insights into PD pathogenesis and suggests distinct therapeutic windows for neuroprotection. ANN NEUROL 2026.
The objective of this study was to examine whether machine learning has the capacity to prospectively identify and predict the emergence of Fragile X-associated tremor/ataxia syndrome (FXTAS) among male fragile X premutation carriers (PCs). We explored neuropsychological and motor evaluation metrics, brain magnetic resonance imaging (MRI), and health metrics in 103 male participants (72 PCs, mean = 60.4 years at enrollment) and 31 healthy controls (HCs; mean = 57.8 years at enrollment) across a total of 299 visits to identify optimal FXTAS risk markers. We compared different machine learning model and feature selection method combinations to identify the best features and models for (a) identifying patients with FXTAS and (b) for predicting which individuals were likely to later develop FXTAS in the study to date. Using an optimal set of features (including age, psychological symptoms, executive function and motor measures, IQ, body mass index (BMI), and structural brain measurements), we developed random forest binary classifiers for the 2 tasks. We split the dataset randomly into multiple different train and test splits and observed the average classification performance metrics across all the splits. The models showed promising ability to identify and pre-emptively predict the emergence of FXTAS and achieved a reasonable balance between precision and recall. Accumulation of body fat (BMI), executive function weaknesses, slower reaction time and dexterity, and mental health changes, are clinical factors that may significantly increase a carrier's risk. Structural brain MRI measurements significantly added to the predictive power of the models. These results suggest that machine learning has the potential to inform prediction of risk for FXTAS early, enabling better planning, timely interventions, and provision of necessary care. ANN NEUROL 2026.
The objective of this study was to assess the heterogeneity in treatment effect of intensive blood pressure (BP)-lowering across hematoma volume after acute intracerebral hemorrhage (ICH). We undertook a pooled analysis of individual patient data from the pivotal trials of early intensive BP-lowering in ICH (the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 4 [INTERACT4] and Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 [ATACH-2] studies). The primary outcome was functional recovery, defined by the distribution of scores on modified Rankin scale (mRS). Secondary outcomes were hematoma expansion (HE) over 24 hours, defined by absolute (<0, 0-6, 6-12.5, and >12.5 ml) and relative HE (<0, 0-33, 33-66, and >66%). Generalized linear mixed models with trial as a random effect were conducted. We further assessed effect modification by hematoma volume and plotted the treatment effect curve. Among 6,125 individuals with available hematoma volume, intensive BP-lowering improved functional recovery (odds ratio [OR] for unfavorable shift in mRS score = 0.90, 95% confidence interval [CI] = 0.82 to 0.99, p = 0.027). In 3,897 participants with available HE, intensive BP-lowering reduced the risk of absolute (OR = 0.88, 95% CI = 0.78 to 0.99, p = 0.043) and relative (OR = 0.88, 95% CI = 0.78 to 0.99, p = 0.034) HE. We found effect modification of treatment on functional outcome and absolute HE by hematoma volume (p for interaction = 0.043 and 0.025, respectively). U-shaped curves were observed, with benefits seen in cases with hematoma volume of 7.5 to 27.5 and 7.0 to 32.5 ml, respectively, both peaking at 20 ml. Early intensive BP-lowering improves functional outcome and reduces HE in ICH. Heterogeneity by hematoma volume indicates the importance of patient selection in future trials and clinical practice. ANN NEUROL 2026.
Sleep-predominant network hyperexcitability is increasingly recognized as a potential disease-accelerating comorbidity in Alzheimer's disease (AD). However, its prevalence and risk-factors remain debated, largely due to cohort-specific and methodological differences across studies. In this prospective case-control study, we investigated potential ways of improving detection, from translational approaches focusing on rapid eye movement (REM)-sleep to refined electroencephalogram (EEG) setups and added clinical questionnaires. We recruited 30 patients with early-stage AD without a history of epilepsy and 30 age-matched controls. Participants underwent overnight polysomnography with video-EEG. Interictal epileptic discharges (IEDs) were identified through a structured 3-step review by multiple independent experts using recommended criteria. Neuroanatomic patterns and sleep-related abnormalities were investigated as potential risk factors. Clinical symptoms in favor of epileptic seizures were evaluated through a tailored questionnaire at follow-up. IEDs were detected in 3 patients (10%) and 1 control (3.33%), a difference not reaching statistical significance (p = 0.612). Most events occurred during non-REM (NREM) sleep. Eight patients (26.67%) reported symptoms compatible with epileptic seizures-one of whom also presented with IEDs. Patients with IEDs or reported symptoms suggestive of potential seizures exhibited more severe sleep-disordered breathing and reduced precuneus volume compared with those without. Despite efforts to optimize detection accuracy, our findings reveal a lower-than-expected percentage of patients with AD with IEDs, yet support previous findings suggesting that sleep-disordered breathing and specific atrophy patterns could flag at-risk patients, guiding screening in clinical settings. Our findings also favor validation efforts of questionnaires to support the diagnostic process. Finally, we highlight methodological issues in IED detection and call for the re-evaluation and standardization of diagnostic methods and criteria in this population to improve patient care. ANN NEUROL 2026;99:1046-1058.
Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood. We investigated sex-specific genetic architecture in an Italian ALS cohort with whole-genome sequencing (1,333 ALS cases, 755 controls). We performed a sex-stratified burden analysis of rare variants in ALS-associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort (n = 723). Gene-specific sex ratios and familial history for C9ORF72, SOD1, and TARDBP were examined in an expanded dataset of 2,301 Italian ALS patients. Sex-stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60-34.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05-1.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10-2.26). Gene-level analyses of TARDBP carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03-4.39). Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex-related differences in genetic liability. Gene-level analyses indicate that the influence of sex varies across ALS genes, particularly TARDBP. These findings help explain epidemiological patterns and have implications for the identification of sex-linked protective mechanisms. ANN NEUROL 2026.
Pathogenic variants in GNAO1 cause a spectrum of epilepsy, movement disorders, and developmental impairment. Clinical heterogeneity complicates prognosis and therapeutic development. We present the first longitudinal natural history study of GNAO1-related disorders (GNAO1-RD) to delineate phenotypic trajectories. Sixty-six individuals with GNAO1-RD were included in a cross-sectional analysis. Of these, 21 were enrolled in a prospective natural history arm (March 2021-December 2024), undergoing annual standardized evaluations with validated clinical scales to monitor phenotypic progression. Our cohort exhibited broad phenotypic and severity variability. GNAO1-RD severity scores ranged from 0.5 to 13. Neurodevelopmental impairment varied: 45.5% lacked head control, whereas 22.7% achieved independent walking; and 65% had no expressive language. Movement disorders were nearly universal (95.5%), with dyskinetic crises in 54.5%. Epilepsy affected 51.5%, with different seizure types. Individuals carrying recurrent variants showed consistent phenotypes and severity, supporting a genotype-phenotype correlation reinforced by molecular functional data. Molecular functional analysis for 20 of 31 missense variants correlated with severity scores. Longitudinal data from 21 patients in the natural history cohort showed overall stability or mild improvement across most functional domains. No significant deterioration was observed in global severity, motor function, cognition, or quality of life. However, severe patients experienced progressive worsening of movement disorder. This largest GNAO1-RD cohort and first longitudinal natural history study provide insights into disease progression. GNAO1-RD generally follows a non-degenerative course, showing stability or mild improvements over time in cognition, language, adaptive skills, and motor function. Importantly, although global severity scores remained stable overall, severe cases showed cumulative functional burden driven by progressive movement disorder, rather than global neurodegeneration. Mortality occurred in a subset of patients because of complications from dyskinetic crises, infections, and epilepsy-related events. Genotype-phenotype data and the GNAO1-RD severity score support early risk stratification and personalized treatment development. ANN NEUROL 2026.
Restless legs syndrome (RLS) is a sensorimotor disorder marked by an uncontrollable urge to move the legs. A pathophysiological hallmark of RLS is brain iron deficiency. The endothelial cells (ECs) of the blood-brain barrier (BBB) are responsible for regulating brain iron uptake. Our objective is to determine if brain iron uptake is altered in ECs in RLS. Human ECs were generated from induced pluripotent stem cells (iPSCs). ECs were exposed to RLS (n = 14) or control cerebrospinal fluid (CSF) (n = 15), and 57Fe-Transferrin transport was determined. Immunoblotting and quantitative polymerase chain reaction were used to analyze protein, microRNA (miRNA), and messenger RNA (mRNA) expressions. We performed miRNA and transferrin receptor 1 (TfR1) 3' iron-responsive elements (IRE) interaction in HEK-293 cells by using a pMIR-REPORTER luciferase vector. Free and protein-bound iron in CSF from RLS subjects were decreased compared to controls. Exposure of ECs to RLS CSF significantly decreased the uptake and transport of 57Fe compared to the control. TfR1 expression decreased while iron regulatory proteins (IRP) increased in RLS-CSF exposed ECs. TfR1 expression was also regulated by miRNAs. The miR-124-3p levels were higher in RLS CSF-derived extracellular vesicles than in the control. It binds the TfR1 3' IRE sequence in the pMIR-REPORTER vector, reducing luciferase expression. When ECs are treated with CSF from RLS patients, they show a profile of iron deficiency, except that the TfR1 expression does not increase as would be predicted. The decrease in TfR1 protein expression is because of a reduction in TfR1 mRNA stability by the binding of increased miR-124-3p. ANN NEUROL 2026.
To characterize Fc-glycosylation profiles in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) and assess their association with antibody compartmentalization (cerebrospinal fluid [CSF] vs serum), disease triggers (viral, tumor-related or idiopathic), and 1-year outcomes. We analyzed immunoglobulin (Ig) G1 and IgG2/3 Fc-glycosylation by liquid chromatography-mass spectrometry in paired serum/CSF samples from 50 age- and sex-matched patients with NMDARe identified in IDIBAPS/Hospital Clinic of Barcelona database and the Spanish study on herpes encephalitis. Patients were classified by disease trigger as post-herpetic, tumor-related, or idiopathic. One-year outcomes were defined as good (modified Rankin Scale [mRS] ≤2) or poor (≥3). Fc glycoprofiles were quantified for fucosylation, sialylation, galactosylation, and bisecting N-acetylglucosamination. Across IgG subclasses (IgG1-3), CSF antibodies showed significantly reduced sialylation and galactosylation compared to serum (p < 0.0001), indicating a pro-inflammatory compartmentalized response within the central nervous system. These inflammatory Fc-glycoforms were predominant in post-herpetic cases of NMDARe (p < 0.01) compared to tumor-related and idiopathic forms, suggesting that viral-induced NMDAR may alter antibody Fc-glycosylation via B-cell glycosylation pathway modulation. Furthermore, reduced sialylation, galactosylation and fucosylation in CSF and serum were associated with poor 1-year outcomes (p < 0.05), suggesting that compartmentalized inflammation and enhanced innate immune activation, including natural killer (NK) cell-mediated cytotoxicity driven by afucosylated antibodies, might contribute to neurological dysfunction. In NMDARe, CSF Fc-glycosylation profiles are both compartment- and trigger-specific. Because glycan signatures shape innate immune interactions (e.g., with NK cells), these findings highlight distinct pathogenic mechanisms and support Fc-glycosylation profiling as a potential prognostic biomarker. ANN NEUROL 2026.
To characterize the magnetic resonance imaging (MRI) lesion dynamics, comorbidities, predictors of relapse, and outcomes in anti-γ-aminobutyric acid type A receptor (GABAAR) encephalitis, and assess the utility of LIM-domain-only-protein 5 (LMO5) antibodies as tumor markers. GABAAR antibodies were confirmed by 2 techniques in serum or cerebrospinal fluid. Long-term outcomes were defined as good (modified Rankin scale, mRS = 0-1) or poor (mRS 2-5) at ≥12 months. LMO5 antibodies were assessed by cell-based assays and Western blot. Thirty-three patients were identified (4 children, 29 adults; median age, 5.5 and 60 years; 61% male). Ten patients (10/32, 31%) had concurrent systemic autoimmunity. Adults presented with seizures and cognitive/behavioral symptoms, often with thymoma, gastrointestinal, or other tumors (18/33, 55%), whereas children frequently had seizures and ataxia with cerebellar MRI lesions. Multifocal T2/fluid-attenuated inversion recovery hyperintensities were present at onset in 23 of 31 (74%) or developed later in those with absent or single lesions. Lesions showed dynamic changes, suggesting ongoing inflammation even without clinical correlate. Relapses occurred in 17 of 31 (55%, all adults) and were associated with older age (p = 0.02) and lack of second-line immunotherapy (p = 0.02). Four patients (4/33, 12%) died. After a 32.5-month median follow-up, 9 of 20 (45%) had persistent cognitive deficits, and 6 of 20 (30%) had a poor outcome, which was associated with relapses (p = 0.04). LMO5 antibodies were absent in patients and controls. Anti-GABAAR encephalitis shows age-dependent presentations, most commonly seizures. MRI reveals dynamic changes consistent with an ongoing "clinically silent" inflammation. Relapses and cognitive sequelae are common and associate with not receiving second-line immunotherapy. LMO5 antibodies lack tumor-predictive value. ANN NEUROL 2026.
The relative risks of bleeding with apixaban and aspirin remain unclear. We compared bleeding end points on apixaban versus aspirin in the ARCADIA trial. ARCADIA was a multicenter, double-blind, randomized trial of apixaban versus aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. International Society on Thrombosis and Hemostasis (ISTH) criteria were used to classify bleeding as intracranial, symptomatic intracranial, major non-intracranial hemorrhages, and any major and minor hemorrhages. We calculated annualized incidence rate differences (IRDs) between apixaban and aspirin. Our primary analysis included the safety sample which censored patients who permanently stopped taking the study drug. Sensitivity analyses included the intention-to-treat sample. Among 1,015 patients assigned to apixaban or aspirin and followed for a mean 1.8 (±1.2) years, 115 (11.3%) patients experienced 146 hemorrhages: 27 (18.5%) major and 119 (81.5%) minor hemorrhages. Apixaban resulted in significantly fewer intracranial hemorrhages than aspirin in both the safety sample (IRD = -1.4%, 95% confidence interval [CI] = -2.3% to -0.5%) and intention-to-treat sample (IRD = -1.0%, 95% CI = -1.8% to -0.2%). Findings were similar for the risk of symptomatic intracranial hemorrhage in the safety sample (IRD = -1.1%, 95% CI = -1.8% to -0.3%), although this was not statistically significant in the sensitivity analysis of the intention-to-treat sample (IRD = -0.7%, 95% CI = -1.4% to 0.0%, p = 0.11). Risks of major non-intracranial hemorrhage, any major hemorrhage, and minor hemorrhage did not differ significantly between apixaban and aspirin. We found no increase in any hemorrhage type and a decrease in intracranial hemorrhage with apixaban relative to aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. ANN NEUROL 2026.
Changes in the gut microbiome may be involved in the pathogenesis and progression of Parkinson's disease (PD). This randomized, placebo-controlled, double-blinded study aimed to assess the effects of fecal microbiota transplantation (FMT) on the manifestation of the motor symptoms of PD (The Movement Disorders Society - Unified Parkinson's Disease Rating Scale Part III [MDS-UPDRS III]) over a 12 month long observation and non-motor symptoms as secondary objectives: the Movement Disorders Society-Non-Motor Rating Scale; EuroQol-5 Dimension; PD Quality-of-Life Questionnaire; Montreal Cognitive Assessment (MoCA); UPDRS I, II, and IV; Gastrointestinal Dysfunction Scale for PD; modified Constipation Assessment Scale; and levodopa equivalent dose. The patients were randomly assigned to receive either fecal microbiota (Mbiotix, Human Biome Institute) or placebo (auto-fecal microbiota, prepared from the patient's stool) in a 1:1 ratio. The fecal microbiota transplantation was performed via colonoscopy. Assessments were performed before and after 12 months for the MoCA and at 1, 3, 6, and 12 months for the other scales. Intention-to-treat analysis was performed using a multivariable mixed regression model. Of the 59 patients included, 28 were randomly assigned to the Mbiotix group (median age = 65 years; 15 male patients) and 31 to the placebo group (median age = 63 years; 14 male patients). No significant differences were observed in the MDS-UPDRS III "OFF" state score at 12 months between groups (1.50 points, 95% confidence interval [CI] = -4.28 to 7.28, p = 1.00), however, some non-motor symptoms improved in different study timepoints. A single FMT does not influence motor symptoms manifestation in patients with PD but could improve non-motor functioning via gut-brain axis. Trial registration information: Clinical Trial ID NCT05204641 was submitted on November 29, 2021. The first patient was enrolled on January 4, 2022. ANN NEUROL 2026.
In temporal lobe epilepsy (TLE), the amygdala in the epileptogenic network is underestimated compared to other regions such as the hippocampus. Recent advances in anatomical neuroimaging and stereoelectroencephalography (SEEG) signal analyses could help better understand the involvement of the different amygdala nuclei in the genesis of temporal lobe seizures. We retrospectively included 51 patients suffering from TLE who underwent SEEG over the past 5 years. The Virtual Epileptic Patient atlas with an integrated amygdala atlas was used to automatically localize SEEG contacts within the brain regions, including 9 amygdala nuclei. The Epileptogenicity Index (EI) and Connectivity Epileptogenicity Index (cEI) were computed on ictal SEEG recordings. We used a beta mixed model to evaluate the relative effects of amygdala nuclei, TLE subtypes, and lateralization of the epileptogenic zone on the epileptogenicity. We used the Wilcoxon rank sum test to study the associations between epileptogenicity level of distinct amygdala nuclei and ictal semiology (sensory, affective, cognitive, motor, and autonomic). We observed higher epileptogenicity within the basolateral (BL) nucleus compared to other nuclei of the basolateral complex (lateral (LA), accessory basal (BM), and paralaminar (PL) nuclei) across all TLE subtypes. Regarding semiology, BL was more epileptogenic in patients with sensory phenomena and LA in patients with autonomic phenomena, while PL was less epileptogenic in patients with cognitive phenomena. Our findings disentangle the different epileptogenicity of amygdala nuclei in temporal lobe seizures. The observed epileptogenicity variance across amygdala nuclei can be explained by underlying neuronal and cytoarchitectural substrates. ANN NEUROL 2026.
Heightened sensitivity to noxious stimulation is a hallmark of chronic pain. Emerging evidence suggests heightened unpleasantness to non-noxious (eg, auditory) aversive stimulation also characterizes chronic pain, but its magnitude, neural mechanisms, and treatment modifiability remain unknown. We compared behavioral and neural responses to auditory and pressure stimulation in 142 adults with chronic back pain (CBP) relative to 51 pain-free controls. CBP patients then entered a randomized trial of pain reprocessing therapy (PRT) versus placebo and usual care. During functional magnetic resonance imaging, participants experienced low- and high-intensity aversive sounds and mechanical pressure and provided unpleasantness ratings. Univariate analyses examined responses in primary sensory, sensory-integrative, and midline default mode network regions. Multivariate analyses tested 4 a priori whole-brain patterns, including patterns predictive of fibromyalgia. CBP patients versus healthy controls reported heightened unpleasantness to auditory stimuli (Hedges' g = 0.95-1.03; p < 0.001) and mechanical pressure (g = 0.49-0.66; p < 0.001). For patients versus controls, auditory stimulation revealed hyperresponsivity in primary auditory cortex and insula, hyporesponsivity in the precuneus and medial prefrontal cortex (g = 0.33-0.59, p < 0.05), and increased expression of generalized and auditory-specific aversive processing patterns (g = 0.33-0.39, p < 0.05) and of fibromyalgia-derived multisensory sensitivity patterns (g = 0.43-0.50, p < 0.01). Longitudinal analysis found that PRT versus placebo led to reduced unpleasantness of low-intensity auditory stimulation, along with increased medial prefrontal cortex responses for PRT versus usual care. CBP is associated with pronounced auditory hyperresponsivity via modality-specific and modality-general neural pathways, and brain mechanisms overlap with fibromyalgia. PRT versus control produced small reductions in this hyperresponsivity, suggesting potential for PRT to yield broader "central desensitization". ANN NEUROL 2026.
The objective of this study was to elucidate differences in the cumulative incidence of Leucine-rich repeat kinase 2 (LRRK2) p.Gly2019Ser-related Parkinson's disease (PD; LRRK2-PD) between ancestries and countries. We included 922 unrelated p.Gly2019Ser variant carriers (affected = 762 and unaffected = 160) from the Global Parkinson's Genetics Program (GP2) in addition to cohorts recruited from the Israeli Ashkenazi Jewish and Tunisian Arab-Berber population. Cox proportional hazard models were applied to examine differences in cumulative incidence across ancestry groups and countries. All analyses were adjusted for biological sex and were exploratory. The median age at onset (AAO) of LRRK2-PD was 5 years younger in the North African (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.18-1.86, p = 7.0 × 10-4) compared with the European ancestry group. In contrast, the median AAO was 5 years older in the Ashkenazi Jewish (HR = 0.61, 95% CI = 0.50-0.75, p = 4.0 × 10-6) compared with the European ancestry group. Additionally, patients from Israel (HR = 1.59, 95% CI = 1.30-1.39, p = 4.0 × 10-6) and Tunisia (HR = 2.57, 95% CI: 2.16-3.06, P < 2.0 × 10-16) had a median 5-year and 10-year younger AAO compared with patients from the United States, respectively. Last, when focusing only on individuals with an Ashkenazi Jewish background, patients from Israel still had a younger AAO than those from the United States (HR = 1.82, 95% CI = 1.48-2.24, p = 1.5 × 10-8). Analogously, assessing only patients from the United States, the Ashkenazi Jewish ancestry group still had an older AAO than the European ancestry group (HR = 0.51, 95% CI = 0.39-0.67, p = 1.3 × 10-6). Our results provide evidence that a person's genetic ancestry and country of origin are associated with the AAO of LRRK2-PD. This highlights the potential impact of both genetic and environmental factors on LRRK2-PD AAO. ANN NEUROL 2026.
The benefit of intravenous thrombolysis (IVT) before endovascular treatment (EVT) in patients with acute ischemic stroke due to large vessel occlusion (LVO) who present directly to EVT-capable centers remains uncertain, and the effect may differ according to underlying stroke etiology. We assessed whether the benefit of IVT plus EVT versus EVT alone varied by stroke etiologies (large-artery atherosclerosis, cardioembolism, or other/undetermined). We performed an individual participant data meta-analysis of 6 randomized controlled trials (RCTs) that compared IVT plus EVT to EVT alone in patients with LVO within 4.5 hours of stroke onset or time last known well. The heterogeneity of treatment effect was assessed using ordinal logistic regression models with interaction terms for stroke etiology and treatment in the intention-to-treat population, followed by subsequent mixed-effects meta-analysis. An additional analysis was performed to assess whether the treatment effect of IVT plus EVT differed by atrial fibrillation status. Among 2,313 eligible patients from 6 RCTs, 1,160 were randomized to the IVT plus EVT group and 1,153 to the EVT alone group. Median age was 71 years (interquartile range [IQR] = 62-78 years), and 44.3% of patients were women. Stroke etiology was classified as cardioembolism in 977 of 2,313 patients (42%), large artery atherosclerosis in 430 (19%), and other or unknown/undetermined in 906 (39%). No evidence of treatment effect modification by stroke etiologies on the association between IVT and 90-day functional outcome was observed (P for interaction = 0.60). For patients with other/undetermined stroke etiology, IVT plus EVT was associated with better 90-day functional prognosis (adjusted common odds ratio for a lower level of disability = 1.34, 95% confidence interval [CI] = 1.05-1.69). No treatment effect modification by stroke etiology was found for safety outcomes. No treatment effect heterogeneity by atrial fibrillation was found for all outcomes. Among patients with LVO presenting directly to EVT-capable centers, stroke etiologies do not modify the overall efficacy or safety of IVT before EVT. The isolated benefit observed in the other/undetermined subgroup requires confirmation. ANN NEUROL 2026 ANN NEUROL 2026.
Focal cortical dysplasia (FCD) is the most common cause of surgically treatable, drug-resistant epilepsy in children. Anxiety and depression are frequent comorbidities in epilepsy. This study examined whether FCD overlap with large-scale functional networks, the default mode network (DMN) and the limbic network, is associated with parent-reported anxiety or depressive symptoms. Sixty-nine patients with FCD-related epilepsy completed the Child Behavior Checklist (CBCL), among whom 56 finished the 6 to 18 years version of CBCL (CBCL6-18). FCD overlap (%) with Yeo 7-networks was calculated. General linear models tested FCDDMN or FCDlimbic overlap with CBCL Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM)-Anxiety Problems or DSM-Depressive Problems Scores controlling for age and gender. Fifty-six patients had preoperative CBCL6-18 (median age = 12.8 years, 55% male patients). FCDDMN overlap (B = 0.08, 95% confidence interval [CI] = 0.002-0.16, partial η2 = 0.086, p = 0.045) and female gender were associated with higher DSM-Depressive Problems T-scores. This lesion-network depressive-symptoms effect was stronger in an adolescent-only model (52% male patients): FCDDMN overlap (B = 0.19, 95% CI = 0.068-0.32, partial η2 = 0.37, p = 0.004). Network overlap was not associated with DSM-Anxiety Problems in any age group. FCDDMN overlap is associated with increased depressive symptoms, particularly for adolescents, whereas FCDlimbic overlap is not. These findings underscore the importance of lesion-network colocalization contributing to depression vulnerability in developmental epilepsy and highlight DMN colocalization involvement as a potential neurobiological marker of depressive risk. ANN NEUROL 2026.