Journals
2026 EN
Oubre Brandon · Yang Faye · Luddy Anna C.
+8 more
Objective Sensitive behavioral measures are needed for clinical trials in ataxias and other neurodegenerative diseases. We hypothesized that quantitative analysis of eye movements during a natural multi‐component task (passage reading) could produce a measure capable of capturing subclinical signs and disease progression. Methods Binocular gaze sampled at 1000 hertz (Hz) was collected from 102 individuals with ataxia (including 36 spinocerebellar ataxias, 12 Friedreich's ataxia, and 5 multiple system atrophy) and 70 healthy controls. Longitudinal data were available for 26 participants with ataxia in the ongoing Neurobooth natural history study. The Reading Eye Abnormality Digital (READ) score was developed by training a regression model to aggregate saccade and fixation kinematics. Results Mean displacement of fixations, the number and frequency of saccades, and the proportion of regressive saccades were related to oculomotor dysfunction, speech dysfunction, and overall ataxia severity. The READ score was reliable (intraclass correlation coefficient [ICC] = 0.96, p < 0.001) and correlated with Brief Ataxia Rating Scale (BARS) total score ( r = 0.82, p < 0.001), oculomotor ( r = 0.52, p < 0.001), and speech ( r = 0.73, p < 0.001) subscores, and patient reports of function including patient‐reported outcome measures (PROM)‐Ataxia ( r = 0.51, p < 0.001) and the Dysarthria Impact Scale (DIS; r = 0.53, p < 0.001). The READ score detected subclinical oculomotor (area under the curve [AUC] = 0.69, p = 0.02) and speech signs (AUC = 0.72, p < 0.001) and disease progression ( d = 0.36, p = 0.03). The BARS total did not reach statistical significance in capturing progression between study visits in this cohort ( d = 0.27, p = 0.08). Interpretation Digital measures of eye movements are a promising approach for sensitively measuring ataxia in clinical trials (including early‐stage disease) and may have utility in other neurodegenerative diseases affecting speech or ocular control. ANN NEUROL 2026;99:84–95
Journals
2026 EN
Lyden Patrick
In multiple disease areas, neurology has failed to translate promising treatments from positive preclinical studies to successful clinical trial results. Despite this history, we persist in testing new, putative neuroprotectants using the same concepts, approaches, and methods without much modification. Recent novel data and new concepts offer an opportunity to break with past doctrine decisively, and open a new era of different approaches, methods, and strategies for studying future protections for brain injury. Cerebroprotection is a fresh framework for designing neurological therapy that targets glia and vascular cells, in addition to neurons. ANN NEUROL 2026;99:19–34
Journals
2026 EN
SimpsonYap Steve · Morwitch Ellen · Tanner Samuel A.
+22 more
Objectives Multiple sclerosis (MS) onset risk factors include Epstein–Barr virus (EBV) indices (including host response), lower serum 25‐vitamin D (25(OH)D) levels, low sun exposure, and HLA‐DRB1*1501 . The underlying molecular mechanisms are unclear. Here, we examined mediation through differential DNA methylation (DNAm) to better understand possible epigenetic programming. Methods Two case‐control studies (Ausimmune Study, Australia = 206 cases + 348 controls; and Epidemiologic Investigations of MS [EIMS], Sweden = 140 cases + 139 controls). DNAm was measured using Illumina arrays. Dimension‐reduction methods generated MS‐associated DNAm modules. Pathway enrichment analyses were used to describe DNAm modules’ system‐level biological characteristics. Individual and joint associations with MS risk were assessed using logistic regression. DNAm module mediation of risk factor‐outcome associations were assessed using mediation analysis. A range of temporality analyses were used. Results EBV indices (infectious mononucleosis history and anti‐EBNA IgG titer), lower 25(OH)D, low sun exposure, and HLA‐DRB1*1501 risk variant were individually and jointly associated with MS risk. In each study, 2 DNAm modules were found which mediated multiple exposure‐MS associations. Proportions mediated ranged from 21 to 47% in Ausimmune and 25 to 53% in EIMS. Results were robust to sensitivity analyses. Top‐ranked genomewide association study (GWAS) MS risk‐associated genes were over‐represented in both Ausimmune DNAm modules, A1 3.5‐fold ( p = 0.004) and A2 3‐fold ( p = 0.015). Reactome pathways enriched for DNAm had cross‐study overlap – 45% of pathways enriched in Ausimmune DNAm modules were also enriched in EIMS (4.82‐fold, p < 0.001). Interpretation EBV, lower vitamin D, low sun exposure, and HLA‐DRB1*1501 risk variant act in concert and through common epigenetic pathways to impact MS onset risk. ANN NEUROL 2026;99:341–355
Journals
2026 EN
Dergai Oleksandr · Wuu Joanne · KoziczakHolbro Magdalena
+14 more
Objective Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large‐scale proteomic study in well‐phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression. Methods Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off‐rate modified aptamer (SOMAmer)‐based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest. Results We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p ‐value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log‐fold elevation, whereas ANTXR2 and ART3 had the greatest log‐fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log‐fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue‐specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB. Interpretation We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2026;99:393–407
Journals
2026 EN
Lee Ikjae · Jang Grace · Cheung Ying Kuen (Ken)
+36 more
Objective The primary lateral sclerosis ( PLS ) consensus diagnostic criteria and functional rating scale ( PLSFRS ) were recently established to facilitate and optimize future PLS clinical trials. We examined the trajectory of the PLSFRS and other functional outcome measures and biomarkers in the PLS Natural History Study ( PLS NHS ) to understand their performance in this prospective cohort. Methods The PLS NHS is a prospective, longitudinal, multicenter study of people living with PLS in different diagnostic categories: early (disease duration <2 years); probable (2–4 years); and definite PLS (4–15 years). PLSFRS scores and other functional outcome measures were collected at baseline, 3‐, 6‐, 9‐, and 12‐month follow‐up visits. Baseline characteristics were compared between the groups. The slopes of the PLSFRS and other functional outcome measures over 12 months were examined in the overall cohort and subgroups using linear mixed‐effect models. The associations between baseline characteristics and the rate of PLSFRS decline were analyzed with linear regression models. Results A total of 76 participants were included: early (n = 6); probable (n = 26); and definite (n = 44) PLS . Baseline PLSFRS total scores were highest in the early PLS group, followed by the probable and definite PLS groups. In the overall cohort, the PLSFRS total score declined by 0.33 points/month (95% confidence interval [0.27–0.39], adjusted p < 0.05). The rate of decline was steepest in the early PLS group, followed by the probable and definite PLS groups. Baseline neurofilament light chain level was associated with the rate of PLSFRS decline over 1 year ( p = 0.001). Interpretation In PLS, the rate of functional decline, as measured by the PLSFRS total score, is faster during the early phase of the disease. Neurofilament light might serve as a prognostic biomarker in PLS. ANN NEUROL 2026;99:418–428
Journals
2026 EN
Leigh Richard · Kern Kyle C. · Wang NaeYuh
+2 more
Objective The objective of this study was to test if blood–brain barrier (BBB) disruption, detected using dynamic susceptibility contrast (DSC) imaging, would predict progression of white matter hyperintensities (WMHs) over the subsequent year in patients with chronic cerebrovascular disease. Methods The study included patients with a history of stroke and at least early confluence of WMH. Magnetic resonance imaging (MRI) scans performed at baseline (> 3 months from stroke) and again 1 year later were segmented to calculate the WMH volume expressed as a fraction of the total brain volume. Change in WMH volume between the 2 timepoints and progression of WMH were the outcome measures. BBB disruption was measured using DSC imaging on the baseline MRI. WMH masks were dilated by 3 mm to create a mask of the adjacent normal appearing white matter (penumbra). BBB disruption was averaged within the WMH and the penumbra. Results Fifty patients were included; median age was 69 years, and 46% were women. The mean WMH fraction was 1.25% at baseline and 1.36% at 1 year. The mean baseline BBB disruption was 0.20% in the WMH and 0.22% in the penumbra. More severe BBB disruption was associated with greater WMH progression when measured in the WMH ( ß = 0.95, confidence interval [CI] = 0.39–1.51, r 2 = 0.19, p = 0.001) and in the penumbra ( ß = 0.81, CI = 0.10–1.53, r 2 = 0.10, p = 0.027). The best predictor of progression was BBB disruption in the penumbra with an odds ratio (OR) of 2 (OR = 2, CI = 1.01–3.96, p = 0.046) for each 0.1% increase in BBB disruption. Interpretation More severe BBB disruption was predictive of greater WMH progression in patients with chronic cerebrovascular disease. ANN NEUROL 2026;99:437–448
Journals
2026 EN
Glass Hannah C. · Numis Adam L. · Soul Janet S.
+17 more
Objective The objective of this study was to characterize the neurodevelopment and risk factors for impairment at age 5 to 6 years after acute provoked neonatal seizures. Methods Multicenter study of neonates with acute provoked seizures. Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI‐IV), Vineland‐3 Adaptive Behavior Scales, Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, cerebral palsy (CP), and epilepsy were assessed at age 5 to 6 years. Latent class analysis defined outcome profiles. Least absolute shrinkage and selection operator (LASSO) was used to determine outcome predictors. Results We characterized 3 latent classes among 164 children: (1) Typical Development (63%); (2) Behavioral Dysregulation (13%; low likelihood of physical impairment or severely impaired cognition, high likelihood of attention deficit hyperactivity disorder [ADHD]); and (3) Multi‐Domain Impairment (24%; high likelihood of epilepsy and impairment across all domains). Among 144 children with standardized testing, mean WPPSI‐IV was 91 ± 25 and Vineland‐3 Adaptive Behavior Composite 90 ± 20. Twenty‐nine percent had ADHD or elevated attention/hyperactivity scores; 19% had autism or elevated Social Responsiveness scores; 20% had epilepsy, and 19% had CP. Risk factors for Multi‐Domain Impairment were abnormal neonatal neurologic examination (odds ratio [OR] = 3.94, 95% confidence interval [CI] = 1.74–8.95), impaired functional development at age 24 months (OR = 3.82, 95% CI = 1.25–11.66), and CP (OR = 3.71, 95% CI = 1.74–7.90). No neonatal or infant characteristics were significantly associated with Behavioral Dysregulation. Interpretation Nearly two‐thirds of 5 to 6‐year‐old children with provoked neonatal seizures had typical development. Yet, executive and behavioral dysregulation were prevalent, even with preserved cognitive and physical function. These findings can inform outcome discussions and interventions to promote neurodevelopment. ANN NEUROL 2026;99:777–791
Journals
2026 EN
Cousins Katheryn A.Q. · Boyle Rory · Morse Colleen
+9 more
Objective Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, which limits the generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers—phosphorylated tau 217 (p‐tau 217 ), β‐amyloid 1–42/1–40 (Aβ 42 /Aβ 40 ) and p‐tau 217 /Aβ 42 —in a real‐world, diverse clinical population with multimorbidities. Methods Participants (n = 617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse. International Classification of Diseases (ICD) Ninth and Tenth Revision codes determined AD dementia (ADD) (n = 43), mild‐cognitive impairment (MCI) (n = 140), unspecified/non‐AD cognitive impairment (CI) (n = 106), and cognitively normal cases (n = 328), and other medical histories. APOE ε4, body mass index (BMI), metrics of kidney function (eg, estimated glomerular filtration rate [eGFR]), and liver disease were derived from electronic health records. Multivariable models identified factors related to plasma levels. Previously established cutpoints classified AD status (“AD+,” “AD−,” or “Intermediate”). Results Plasma p‐tau 217 /Aβ 42 had the strongest association with known AD‐related factors—MCI, ADD, future progression to MCI/ADD, age, and APOE ε4—compared to p‐tau 217 and Aβ 42 /Aβ 40 . Plasma p‐tau 217 /Aβ 42 was also associated with eGFR, diabetes, and history of hearing loss. Importantly, AD‐related factors were most frequent/severe for AD+ classification by p‐tau 217 /Aβ 42 , whereas medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p‐tau 217 /Aβ 42 adjusted for eGFR to eliminate its influence on plasma levels. Interpretation In this real‐world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p‐tau 217 /Aβ 42 ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels. ANN NEUROL 2026;99:1030–1045
Journals
2026 EN
B. Szabo Anna · Curot Jonathan · Gérard Fleur
+12 more
Objective 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. Methods 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. Results 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. Interpretation 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
Journals
2026 EN
McCarthy Imelda
ABSTRACT This paper shows the journey of the author through her engagements with her own Indigenous traditions, literature and systemic practices within Ireland. Initially, this journey was undertaken to deconstruct the hold of an Anglo–American–European orientation within the family therapy field in the early 1980s. Given the country's long 800‐year history of colonisation by the English, the work of the author and her early colleagues was (a) to insert an Irish way of ‘seeing’ and ‘speaking’ in order to (b) deconstruct colonial traces in our culture and to (c) de‐pathologise the offerings of clients who sought therapeutic help or indeed were mandated to attend. Eventually, the metaphor of the fifth province will also be shown to open itself to the author's spiritual practices and to a way of Being in therapeutic conversations.