Brain [JOURNAL]
Sun
200 papers
Comparative transcriptomics reveal molecular convergence and divergence in parkinsonian disorders.
Geithus S, Flønes IH, Alves G … +5 more , Tysnes OB, van de Berg WDJ, Pihlstrøm L, Nido GS, Tzoulis C
Brain · 2026 Apr · PMID 42052893 · Publisher ↗
Neurodegenerative parkinsonisms are phenotypically diverse disorders including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. These...
Neurodegenerative parkinsonisms are phenotypically diverse disorders including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. These currently incurable diseases are characterized by overlapping but also distinct clinicopathological and molecular features, and largely unknown pathogenesis. Transcriptomic studies have offered insights, but are limited by small sample sizes, technical variability, and limited reproducibility. Here, we present a large comparative bulk transcriptomic analysis of parkinsonian syndromes, comprising n = 977 post-mortem prefrontal cortex samples from pathologically-confirmed Parkinson's disease (n = 448), dementia with Lewy bodies (n = 80), multiple system atrophy (n = 35), progressive supranuclear palsy (n = 42), corticobasal degeneration (n = 17), Alzheimer's disease (n= 72), and neurologically healthy controls (n = 283). Accounting for key covariates including age, sex, RNA integrity (RIN), brain bank origin, and cell type composition, we identify convergent and divergent gene expression and pathway profiles across parkinsonisms and Alzheimer's disease. All diseases showed neuronal transcript loss and enrichment of glial signatures, consistent with neurodegeneration. Across the parkinsonian spectrum, we identified consistent downregulation of pathways related to protein homeostasis, mitochondrial energy metabolism, RNA processing, and DNA repair, highlighting core processes associated with neurodegeneration. Lewy body diseases (Parkinson's disease, dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy and corticobasal degeneration) formed distinct similarity clusters, while multiple system atrophy occupied an intermediate position, possibly reflecting its glial pathology. To facilitate further research and discovery, we provide an open-access interactive web resource (https://parkdb.decode-pd.org) enabling researchers to query, visualize, and compare differential gene and pathway expression across disorders. This study establishes the most comprehensive comparative transcriptomic map of neurodegenerative parkinsonisms to date, identifies shared and distinct molecular mechanisms in α-synucleinopathies and tauopathies, and provides a resource for hypothesis generation and therapeutic target discovery.
Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease.
Wishart CL, Tan J, King NJC
Brain · 2026 Apr · PMID 42052880 · Publisher ↗
Monocyte-derived cells (MCs) are highly adaptable innate immune cells that play essential roles in central nervous system (CNS) inflammation. Their functional specialization is closely linked to their metabolic state, wh...
Monocyte-derived cells (MCs) are highly adaptable innate immune cells that play essential roles in central nervous system (CNS) inflammation. Their functional specialization is closely linked to their metabolic state, which is shaped by local cues such as nutrient availability, oxygen levels, and pro- and anti-inflammatory signals. In this review, we examine the major metabolic pathways that regulate MC behaviour, including glycolysis, oxidative phosphorylation, lipid metabolism, and amino acid metabolism. We assess how these pathways support specific effector functions such as cytokine production, phagocytosis, antigen presentation, and efferocytosis. Moving beyond the traditional M1/M2 framework, we discuss the context-dependent nature of MC metabolism and its role in driving diverse functional states. We then explore how these metabolic programs are engaged across key CNS disease settings, including sterile injury, demyelinating disease, and viral encephalitis. By integrating insights from immunometabolism and neuroinflammation, this review provides a framework for understanding the metabolic regulation of MCs in CNS pathology and highlights potential avenues for therapeutic intervention.
APOE shifts the tipping point: addressing pathological heterogeneity in Alzheimer's disease trials.
Tosun D
Brain · 2026 Jun · PMID 42052872 · Publisher ↗
Abstract loading — click title to view on PubMed.
Medial temporal lobe Tau-Neurodegeneration mismatch from structural imaging and plasma biomarkers.
Lyu X, Mundada NS, Brown CA … +16 more , Sadeghpour N, McGrew E, Xie L, Li Y, Wuestefeld A, Duong MT, Cook P, Gee J, Nasrallah IM, Chen-Plotkin AS, Shaw LM, Mechanic-Hamilton D, Wisse LEM, Yushkevich PA, Das SR, Wolk DA
Brain · 2026 Apr · PMID 42046390 · Publisher ↗
While tau pathology is closely associated with neurodegeneration in Alzheimer's disease (AD), our prior work using multi-modality imaging revealed that mismatch between tau (T) and neurodegeneration (N) may reflect contr...
While tau pathology is closely associated with neurodegeneration in Alzheimer's disease (AD), our prior work using multi-modality imaging revealed that mismatch between tau (T) and neurodegeneration (N) may reflect contributions from non-AD processes. The medial temporal lobe (MTL), an early site of AD pathology, is also a common target of co-pathologies such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), often following an anterior-posterior atrophy gradient. Given the susceptibility of MTL to co-pathologies, here we explored T-N mismatch specifically within MTL using plasma ptau217 and MTL morphometry for identifying vulnerabilities and resilience in cognitively impaired or unimpaired AD patients. We parcellated the MTL into 100 spatially contiguous segments and calculated their T-N mismatch using plasma ptau217 as a measure for T and thickness as a marker of N. Based on these mismatch profiles, we clustered 447 amyloid-positive individuals from ADNI cohort into data-driven T-N phenotypes. We characterized the T-N phenotypes by examining their cross-sectional and longitudinal atrophy both within the MTL and across the whole brain, as well as cognitive trajectories. This framework was replicated in an independent cohort and finally translated to a real-world clinical sample of 50 patients undergoing anti-amyloid therapy. Clustering identified three T-N phenotypes with different MTL T-N mismatch profiles, atrophy patterns, and cognitive outcomes, despite comparable AD severity. The "canonical" group, characterized by low T-N residuals (N ∼ T), showed AD-like neurodegeneration patterns. The "vulnerable" group, characterized by disproportionately greater neurodegeneration than tau (N > T), showed atrophy primarily in the anterior MTL that extended into temporal-limbic regions, both in cross-sectional and longitudinal analyses. This group also exhibited neurodegeneration that preceded estimated tau onset and experienced faster cognitive decline across multiple domains, aligning with the typical characteristics of mixed LATE-NC with AD. In contrast, the "resilient" group (N < T) showed minimal atrophy and preserved cognitive function. These phenotypes were reproducible in an independent research cohort. Importantly, in a feasibility study applying the model developed from ADNI to a clinical cohort of patients receiving lecanemab, we identified vulnerable individuals with LATE-like atrophy patterns. This highlights its potential utility for identifying individuals with co-pathology in clinical settings. Our findings demonstrate that T-N mismatch within MTL using MRI and plasma biomarkers can reveal AD groups with varying vulnerability/resilience, with the vulnerable group displaying structural and cognitive outcomes suggestive of LATE-NC. This approach offers a cost-effective strategy for clinical trial stratification and precision medicine for AD therapeutics.
In vivo tau in epilepsy reflects clinical severity and immune- and ageing-related proteomic changes.
Hong SB, Shin YW, Moon J … +6 more , Park KI, Jung KY, Cho K, Choi H, Chu K, Lee SK
Brain · 2026 Apr · PMID 42032827 · Publisher ↗
Tau pathology plays a central role in a number of neurodegenerative diseases, but its presence and relevance in epilepsy remain incompletely understood. Emerging evidence suggests that epilepsy may promote tau accumulati...
Tau pathology plays a central role in a number of neurodegenerative diseases, but its presence and relevance in epilepsy remain incompletely understood. Emerging evidence suggests that epilepsy may promote tau accumulation, yet whether this occurs in vivo, independent of comorbid dementia or amyloid pathology, is unclear. In this study, we combined [18F]flortaucipir (FTP) PET imaging with high-throughput plasma proteomics to characterise regional tau deposition and its clinical and molecular correlates in non-demented epilepsy patients. We enrolled 75 epilepsy patients and 47 age- and sex-matched healthy controls, collecting detailed clinical data, EEG features, and plasma samples for SOMAscan proteomic profiling, and plasma p-tau217, total tau, and amyloid-β measurement. A subset underwent FTP PET and [18F]florbetaben (FBB) PET imaging. Regional standardised uptake value ratios (SUVRs) were quantified using the AAL3 brain atlas. Compared to controls, epilepsy patients exhibited globally elevated FTP uptake across cortical regions, particularly in the lateral and medial frontal, lateral parietal, and lateral occipital brain areas, while FBB SUVRs showed nonsignificant differences. Exploratory analyses highlighted EEG slowing, multifocal discharges, and continued seizure activity during adolescence as clinical features associated with higher FTP SUVRs. In lateralised epilepsy, asymmetry indices tended to favour the hemisphere with the seizure onset zone. Plasma proteomic analysis identified 473 differentially expressed proteins in epilepsy, enriched in pathways related to immune activation, metabolism, and cytoskeletal remodelling. Protein expression associated with regional tau SUVRs again emphasised immune pathways as well as mitochondrial dysfunction; and suggested distinct mechanisms of tau accumulation in a region-specific manner. Furthermore, using the OrganAge algorithm, we found accelerated biological ageing in epilepsy patients across several organs, including the brain, heart, and muscle. While brain age gaps showed the strongest positive correlation with tau, the heart, pancreas, and muscle age gaps also showed correlations with regional brain tau, suggesting a link between systemic ageing and brain tau accumulation. Together, these findings suggest that epilepsy is associated with widespread elevated tau tracer signal that relates to EEG abnormalities, clinical disease burden, and immune- and ageing-related proteomic signatures. Our results raise the possibility that tau accumulation contributes to key aspects of epilepsy pathophysiology and may have relevance for biomarker development and future therapeutic targeting.
GABAB receptors in glial cells: from physiological regulation to pathological implications.
Wang J, Xu L, Shen Q … +1 more , Tang Y
Brain · 2026 Apr · PMID 42028856 · Publisher ↗
The GABAB receptor, a metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid, is essential for the proper functioning of inhibitory neurons. Previous studies have shown that GABAB receptors are pri...
The GABAB receptor, a metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid, is essential for the proper functioning of inhibitory neurons. Previous studies have shown that GABAB receptors are primarily expressed at presynaptic or postsynaptic membranes of inhibitory or excitatory neurons, where they play a critical role in regulating synaptic signaling. Interestingly, a growing body of evidence indicates that GABAB receptors are also expressed in various types of glial cells and can significantly influence their functions, ultimately contributing to the regulation of multiple processes in the central nervous system. In this review, we first summarize the structure of GABAB receptors and their common downstream signaling pathways in neuronal and glial cells. We then highlight recent research progresses about how GABAB receptors in different glial cell types participate in regulating various important physiological processes, such as excitatory/inhibitory balance, synaptic pruning, and myelination. Furthermore, we provide a comprehensive overview of the significant roles played by glial GABAB receptors in the pathogenesis of neurological disorders, including epilepsy, inflammatory diseases, Alzheimer's disease, major depressive disorder, cerebrovascular diseases, and multiple sclerosis. Accumulating evidence indicates that glial GABAB receptors play a pivotal role in both health and disease, highlighting their potential as therapeutic targets for a variety of neurological conditions. By comprehensively outlining the multiple physiological and pathological processes mediated by GABAB receptors in brain glial cells, this review seeks to broaden the functional scope of glial cells and enhance the comprehension of neuron-glia crosstalk.
Imaging progenitor cell differentiation during central nervous system remyelination using an MRI gene reporter.
Brechbühl EES, Hill MFE, Chen CZ … +7 more , Gaitsch HF, Ros S, Porcu L, Wright AJ, Reich DS, Franklin RJM, Brindle KM
Brain · 2026 Apr · PMID 42028852 · Publisher ↗
Demyelination, the loss of the myelin sheath from around otherwise intact axons, occurs in several diseases, most notably multiple sclerosis (MS). Demyelinated axons that are not remyelinated are vulnerable to irreversib...
Demyelination, the loss of the myelin sheath from around otherwise intact axons, occurs in several diseases, most notably multiple sclerosis (MS). Demyelinated axons that are not remyelinated are vulnerable to irreversible degeneration and therefore therapies that enhance remyelination have been sought. However, there remains a paucity of suitable outcome measures to assess their efficacy. Magnetic Resonance Imaging (MRI) is a non-invasive imaging modality that is used both preclinically and clinically for the assessment of anatomy and tissue function. Here we describe an MRI technique for following the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes during the spontaneous regenerative process of remyelination in vivo. OPCs were transduced in situ with a lentiviral vector expressing an organic anion transporting polypeptide (OATP1A1) under the control of the differentiation-specific Myelin Basic Protein (MBP) promoter. OATP1A1 mediates cell uptake of a gadolinium-based MRI contrast agent (Primovist), allowing detection of the cells in T1-weighted MR images. Uptake of the contrast agent is restricted to MBP-expressing cells, which is most highly expressed during myelin sheath formation, thereby allowing progenitor-mediated, and potentially oligodendrocyte-mediated, remyelination to be monitored non-invasively in vivo using MRI. These findings provide the foundation for the development of direct methods for assessing the efficacy of pro-remyelination therapies.
Cause, consequence, or synergy: the role of T-cell infiltration across neurodegenerative diseases.
Cullinane PW, Nelvagal H, Wong C … +12 more , Curless T, Baranauskiene G, Jurkeviciene J, Farin Z, Pimparkar S, Bechtawi M, Chiraki N, de Pablo Fernandez E, Brandner S, Warner TT, Lim YM, Jaunmuktane Z
Brain · 2026 Apr · PMID 42028849 · Publisher ↗
Abstract loading — click title to view on PubMed.
The impact of the COVID-19 pandemic on the incidence and clinical profiles of Guillain-Barré syndrome in Japan.
Suichi T, Misawa S, Ukita S … +4 more , Shibuya K, Ogushi M, Sato Y, Kuwabara S
Brain · 2026 Apr · PMID 42025320 · Publisher ↗
Since the coronavirus disease 2019 (COVID-19) pandemic began in 2020, several studies from various countries have described changes in the epidemiology of Guillain-Barré syndrome (GBS); however, it remains unclear whethe...
Since the coronavirus disease 2019 (COVID-19) pandemic began in 2020, several studies from various countries have described changes in the epidemiology of Guillain-Barré syndrome (GBS); however, it remains unclear whether the incidence and clinical profiles were altered by the pandemic. This study aimed to elucidate the impact of the COVID-19 pandemic on the epidemiology and clinical profile of GBS in Japan. We conducted a nationwide survey on the incidence of GBS between 2017 and 2022, encompassing the pre-pandemic [2017‒2019] and pandemic [2020‒2022] periods. Questionnaires were sent to the neurology and paediatrics departments at hospitals throughout Japan. A primary questionnaire was used to estimate the number of patients and incidence, and a second questionnaire was administered to collect detailed clinical information. The annual number of newly diagnosed GBS cases and their incidence were estimated at 1,885 (95% confidence interval [CI], 1,766‒2,004) and 1.49 (95% CI, 1.40‒1.58) per 100,000 population, respectively, during the pre-pandemic, 1,603 (95% CI, 1,463‒1,743) and 1.28 (95% CI, 1.17‒1.39) per 100,000 population during the pandemic periods; the relative risk for GBS incidence during the pandemic period was 0.91 (95% CI, 0.83‒0.99; 9% reduction). Detailed clinical profiles were available for 2,623 patients (1,420 during the pre-pandemic period and 1,203 during the pandemic period). Compared with patients in the pre-pandemic period, those diagnosed during the pandemic period were older (median age, 56 years vs. 53 years; P = 0.02), had a higher proportion of cases without antecedent infectious episodes (38.2% vs. 24.5%; P < 0.0001), longer time to reach nadir (median, 8 days vs. 7 days; P = 0.0418), and higher frequency of the demyelinating subtype of GBS (37.8% vs. 32.6%; P = 0.0068). No significant differences were observed in the outcomes at 6 months post-onset. The Japanese national registry data showed a markedly reduced number of Campylobacter-related enteritis cases following the pandemic. This study demonstrated a decrease in the overall incidence of GBS during the earlier phase of the COVID-19 pandemic in Japan. The increased number of GBS cases without infectious episodes or demyelinating subtypes during the pandemic period may be caused by reduced exposure to conventional infectious triggers of GBS, such as C. jejuni and increased asymptomatic COVID-19-related demyelinating GBS.
Default mode network failure across the Alzheimer's disease spectrum.
Corriveau-Lecavalier N, Dicks E, Martin PR … +15 more , Wiste HJ, Gunter JL, Kamykowski MG, Senjem ML, Schwarz CG, Botha H, Graff-Radford J, Machulda MM, Fields JA, Boeve BF, Lowe VJ, Knopman DS, Petersen RC, Jack CR, Jones DT
Brain · 2026 Apr · PMID 42019008 · Publisher ↗
Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages i...
Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.
Collapse of feed-forward inhibition underpins hyperexcitability in GABAA gain-of-function epilepsy.
McKenzie CE, Aung KP, Dos Santos AB … +20 more , Mao M, Spyrou J, Bryson A, Wong R, Lin SXN, Bleakley LE, Palmqvist J, Guzulaitis R, Kan ASH, Liao VWY, Soh MS, Gomez CD, Larsen V, Petersen AMN, Absalom NL, Møller RS, Chebib M, Perrier JF, Ahring PK, Reid CA
Brain · 2026 Apr · PMID 42017314 · Publisher ↗
Gain-of-function (GOF) variants in GABAA receptors are increasingly recognised as a cause of severe developmental and epileptic encephalopathies (DEE). However, the mechanisms by which enhanced GABAA receptor activity le...
Gain-of-function (GOF) variants in GABAA receptors are increasingly recognised as a cause of severe developmental and epileptic encephalopathies (DEE). However, the mechanisms by which enhanced GABAA receptor activity leads to neuronal network hyperexcitability remains unclear. We engineered a novel mouse model based on the human GOF GABRB3 p.(Glu77Lys) variant (β3E77K), identified in two individuals diagnosed with DEE, to explore the mechanisms underlying GABAA receptor GOF disease. The phenotypes of β3E77K mice included embryonic lethality consistent with a severe early developmental impact of the GOF GABAA receptor variant. These mice display spike-wave-like discharges that were exacerbated by vigabatrin and ameliorated by valproate matching the clinical observations of GOF GABRB3 patients. β3E77K mice also have increased proconvulsant-induced seizure susceptibility and a broad increase in ECoG spectral power amplitude, indicative of cortical hyperexcitability. Additionally, neurological assessments revealed hypoactivity and weakened grip-strength. Ex-vivo electrophysiological recordings demonstrated increased GABAA receptor-mediated current amplitudes at both excitatory and inhibitory synapses in CA1 hippocampus, consistent with the GOF molecular phenotype previously identified in functional studies. In cortical layer 2/3, inhibitory interneurons showed increased synaptic GABAA receptor-mediated current amplitude, while synapses onto pyramidal neurons exhibited reduced inhibitory currents. Enhanced GABAA receptor-mediated synaptic activity among layer 2/3 interneuron populations caused a use-dependent collapse of feed-forward inhibition resulting in increased pyramidal neuron excitability. Computational modelling supported this disinhibition mechanism, showing that enhanced GABAA receptor synaptic strength between interneurons diminishes inhibitory synaptic conductance onto pyramidal cells. Our findings highlight the critical role of interneuron network dysfunction in driving cortical hyperexcitability caused by GOF GABAA receptor variants. They provide a novel pathogenic mechanism in DEE that could have broader implications for disorders involving dysfunction in GABAergic neurons. The β3E77K mouse also provides a unique preclinical model to test therapeutic strategies in GOF GABAA receptor disease.
Machine learning model based on plasma proteomics for the identification of Parkinson's disease.
Adewale B, Chia R, Moaddel R … +35 more , Landeck N, Rasheed M, Alba C, Reho P, Vasta R, Calvo A, Moglia C, Canosa A, Manera U, Snyder A, Lee YJ, Grassano M, Gao C, Zhu M, Brunetti M, Casale F, Arvind K, American Genome Center , Dawson TM, Rosenthal LS, Hall AJ, Pantelyat AY, Ding J, Gibbs JR, Egan JM, Candia J, Tanaka T, Ferrucci L, Chiò A, Narendra DP, Kwan JY, Ehrlich DJ, Dalgard CL, Traynor BJ, Scholz SW
Brain · 2026 Apr · PMID 42015416 · Publisher ↗
Developing reliable biomarkers capable of differentiating Parkinson's disease from other neurological conditions is crucial for both patient care and research. In this study, we leveraged recent advances in high-throughp...
Developing reliable biomarkers capable of differentiating Parkinson's disease from other neurological conditions is crucial for both patient care and research. In this study, we leveraged recent advances in high-throughput proteomic technology and machine learning to develop candidate biomarkers for Parkinson's disease. Using the Olink Explore 3072 assay, we obtained plasma proteomic profiles from 698 study participants, comprising Parkinson's disease cases (n = 149), neurologically healthy controls (n = 230), and participants with other neurological conditions (n = 319). The study cohort was split into Training Set (n = 560) and Test Set (n = 138). We conducted differential protein abundance analysis and pathway enrichment analysis, and subsequently applied the Boruta algorithm to identify differentially abundant proteins that are predictive of Parkinson's disease. To create a diagnostic biomarker panel, we trained a stacking ensemble machine learning (ML) model on the Training Set (n = 118 Parkinson's patients, n = 184 healthy controls, and n = 258 individuals with other neurological disorders) using eleven proteins (APOH, ARG1, CCN1, CXCL1, CXCL8, DDC, GRAP2, IL1RAP, OSM, PRL, and SPRY2) as model features. We used the Shapley Additive Explanations (SHAP) framework and network analysis to evaluate predictive importance and biological relevance of each protein in the ML model. The model demonstrated high accuracy in the held-out Test Set (n = 138) and three external cohorts-the UK Biobank (n = 43,969), the Parkinson's Disease Biomarkers Program (n = 138), and the Parkinson's Progression Markers Initiative (n = 385), with areas under the receiver operating characteristic curve of 0.939, 0.789, 0.909, 0.816, respectively. Additionally, network and pathway analyses helped interpret the model, revealing activity related to inflammatory mediators, ErbB signaling, T-cell receptor signaling, and lipid metabolism. Our findings highlight the potential of plasma protein biomarkers to improve Parkinson's disease diagnosis and deepen biological understanding of this complex neurological disorder. Our model demonstrates high specificity and reliability across multiple independent cohorts, indicating the significant potential of proteomics-based biomarkers and the clinical utility of ML-supported diagnosis in Parkinson's disease care. The model also helps to elucidate potential novel risk factors and pathways associated with Parkinson's disease.
Neuropathological correlates of age and sex differences in 18F-flortaucipir PET.
Coomans EM, Smith R, Pawlik D … +15 more , Oliveira Hauer K, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Tremblay C, Serrano GE, Beach TG, Rozemuller AJ, Pijnenburg Y, van de Giessen E, Kotari V, Pontecorvo M, Shcherbinin S, Hansson O, Ossenkoppele R
Brain · 2026 Apr · PMID 42010343 · Publisher ↗
Among amyloid-positive individuals with symptomatic Alzheimer's disease, older age and male sex have been associated with a lower prevalence of Tau-PET-positivity. Whether Tau-PET-negative older and/or male individuals t...
Among amyloid-positive individuals with symptomatic Alzheimer's disease, older age and male sex have been associated with a lower prevalence of Tau-PET-positivity. Whether Tau-PET-negative older and/or male individuals truly do not harbor widespread tau pathology or whether tangle density is below the PET-detection threshold remains unknown. Therefore, we aimed to investigate the neuropathological correlates of age- and sex-differences in Tau-PET in independent PET-only, autopsy-only, and PET-to-autopsy cohorts. In the PET-only cohort, we included amyloid-β-positive participants with MCI or dementia who underwent [18F]flortaucipir-PET (n=672). In the autopsy-only cohort, we included participants with moderate-to-frequent CERAD scores and MCI or dementia with available data on Braak stage and tangle density (n=945). In the PET-to-autopsy cohort, we included participants who underwent antemortem Tau-PET and had undergone a postmortem assessment of Braak staging (n=85) (median PET-to-post-mortem-interval: 2.6 months). A subset additionally had tangle density data available (n=63). Tau-PET SUVr was calculated in a temporal meta-region, and Tau-PET-positivity was defined using a predefined threshold of 1.36 SUVr. Autopsy cases were categorized as Braak 0-IV versus Braak V-VI. In PET-only-analyses (age: 71.9±8.2, 52.8% male), older age and male sex were associated with a lower prevalence of Tau-PET-positivity and lower Tau-PET SUVr (all p<0.05). In autopsy-only-analyses (age: 82.7±7.9, 54.6% male), older age and male sex were associated with a lower prevalence of Braak-V/VI neuropathology (both p<0.05). Among Braak-V/VI autopsy cases (n=598), older age was associated with lower tangle density (β=-0.38, p<0.001). In PET-to-autopsy-analyses (age: 81.7±9.2, 52.9% male), Tau-PET showed excellent specificity for detecting Braak-V/VI neuropathology (100% across age-stratified and sex-stratified models), while the sensitivity decreased at older age (<83y: 92% [95% confidence interval: 80%-100%] vs ≥83y: 42% [23%-62%]) and in males (females: 85% [69%-96%] vs males: 48% [28%-68%]). Older and male participants with Braak-V/VI neuropathology showed both lower Tau-PET SUVr (age: β=-0.46, p=0.003; sex: β=-0.97, p=0.001), and in the same individuals, older participants showed trend-level lower tangle density (β=-0.31, p=0.053). The lack of age/sex-interactions indicate that the relationship between Tau-PET and tangle density is consistent across ages and sexes. Comprehensive and independent PET, autopsy, and PET-to-autopsy analyses demonstrate that the associations of older age and male sex with lower [18F]flortaucipir-PET uptake and positivity rates can be explained by lower tangle densities. [18F]flortaucipir-PET SUVr thus closely reflects tangle density, which accounts for the lower sensitivity of [18F]flortaucipir-PET for detecting low-density Braak-V/VI tau pathology in older individuals and males.
Satellite glial GLRX3 drives ageing-biased neuropathic pain via HMGB1.
Yang Y, Zhao B, Liu X … +6 more , Wei G, Hu Y, Chen J, Wang Y, Huo J, Cao P
Brain · 2026 Apr · PMID 42007893 · Publisher ↗
Chronic neuropathic pain disproportionately affects older individuals, particularly in the context of persistent oxaliplatin-induced peripheral neuropathy (OIPN); however, the molecular mechanisms sustaining this ageing-...
Chronic neuropathic pain disproportionately affects older individuals, particularly in the context of persistent oxaliplatin-induced peripheral neuropathy (OIPN); however, the molecular mechanisms sustaining this ageing-biased chronicity remain elusive. In this study, we integrated age-stratified murine models and a multicentre longitudinal cohort of patients receiving oxaliplatin-based chemotherapy for colorectal cancer to investigate a glia-to-neuron redox circuit in the dorsal root ganglion. Using single-nucleus RNA sequencing and redox proteomics, we identified selective upregulation of the deglutathionylase glutaredoxin-3 (GLRX3) in satellite glial cells in aged mice during the chronic phase of OIPN. This upregulation leads to a pronounced loss of protein S-glutathionylation (PSSG) within the dorsal root ganglion, a pattern absent in young mice and during acute stages. Mechanistically, GLRX3, via its catalytic Cys148 residue, catalyses the deglutathionylation of high-mobility group box 1 (HMGB1) at the Cys106 site. This modification converts HMGB1 into a potent agonist for the toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, triggering neuronal nuclear factor-κB signalling and the subsequent upregulation of transient receptor potential ankyrin 1 and vanilloid 2 channels in PACAP-positive (C1 subtype) peptidergic nociceptors, thereby sustaining long-term mechanical and cold hypersensitivity. Satellite glial cell-targeted knockdown of GLRX3 restored HMGB1 glutathionylation and reversed the pain phenotype specifically in aged mice. In the clinical cohort, advanced age was significantly associated with a higher incidence of chronic neuropathy. Longitudinal serum analysis revealed that systemic levels of PSSG and glutathionylated HMGB1 declined progressively and correlated inversely with pain duration, particularly among older individuals. Furthermore, oral γ-glutamylcysteine or pharmacologic TLR4 blockade (TAK-242) effectively alleviated refractory hypersensitivity in aged models. These findings define the satellite glial GLRX3-HMGB1-TLR4 redox axis as a critical driver of age-biased neuropathic pain. Circulating PSSG represents a novel age-stratified clinical biomarker, and targeting this redox-sensitive pathway offers a promising therapeutic strategy for geriatric and chemotherapy-related neuropathies.
Opposing μ-opioid receptor signalling in spinal NPY microcircuits constrains morphine analgesia.
Nelson TS
Brain · 2026 Jun · PMID 41999185 · Full text
This scientific commentary refers to ‘Distinct contribution of spinal neuropeptide Y and NPY1R neurons to morphine analgesia’ by Wu (https://doi.org/10.1093/brain/awag077).
This scientific commentary refers to ‘Distinct contribution of spinal neuropeptide Y and NPY1R neurons to morphine analgesia’ by Wu (https://doi.org/10.1093/brain/awag077).
Blood mtDNA markers of mitochondrial subtype and early-onset Parkinson's disease biology.
Grünewald A, Knab F, Zimmermann M … +20 more , Landoulsi Z, Ghelfi J, Hezzaz S, Delcambre S, Zarani M, Copie RG, Röben B, Sharma K, Parchi P, von Thaler AK, Sünkel U, Schulte C, Hauser AK, Klein C, Gasser T, Wissinger B, Brockmann K, May P, Machetanz G, Fitzgerald JC
Brain · 2026 Apr · PMID 41992946 · Publisher ↗
Mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD), integrating both genetic and environmental factors. Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations ar...
Mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD), integrating both genetic and environmental factors. Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations are needed. Emerging evidence suggests that somatic changes to mitochondrial DNA (mtDNA) may reflect early disease-associated processes relevant to PD conversion and clinical manifestation. In this study, we analysed somatic mtDNA major arc deletions as a measure of mitochondrial genome integrity and evaluated 7S DNA abundance as well as copy number as complementary readouts in whole blood (n=776) from a large cohort, including idiopathic and genetic PD patients, individuals at risk, PD converters, patients with primary mitochondrial disease, and healthy controls. This work was complemented by analyses in CSF samples (n=72). Finally, mtDNA measures were integrated with genetic, protein, and clinical data, including mitochondrial polygenic risk scores, alpha-synuclein seeding assays, and serum neurofilament light chain levels. In blood, the strongest effects occurred in PINK1/PRKN-PD (deletions: P<0.0001; 7S DNA: P<0.0001) and early-onset idiopathic PD (7S DNA: P=0.0009-0.0030). Individuals with prodromal signs conferring a high risk for PD also showed increased mtDNA deletions (P=0.0045) and reduced 7S DNA (P=0.0046). In PD converters, these alterations were detectable prior to clinical diagnosis (deletions: P=0.0024; 7S DNA: P=0.0091). In CSF-derived extracellular vesicles, we observed an age-associated increase in mtDNA copy number in healthy controls (R2=0.121, P=0.035) that was absent in idiopathic PD (R2=0.014, P=0.548). Across all PD patients, those with the highest mtDNA deletion burden and lowest 7S DNA exhibited a higher risk of developing cognitive impairment and depression, while also showing a longer time to postural instability (deletions: P=0.0187; 7S DNA: P=0.0281). Integration of mtDNA readouts, mitochondrial polygenic risk scores, alpha-synuclein seeding, and serum neurofilament light chain levels revealed complementary contributions to biological heterogeneity in PD, with receiver operating characteristic analyses showing moderate group-level discrimination using mtDNA measures alone (AUC=0.66) and substantially improved discrimination when combined with alpha-synuclein and neurodegeneration markers (AUC up to 0.96). Alpha-synuclein seeding activity was associated with later age at onset, whereas mtDNA deletion burden showed an inverse association, indicating that these biomarkers capture distinct biological dimensions of PD. MtDNA damage markers, particularly deletion burden, capture mitochondrial dysfunction arising from both genetic and environmental influences and are detectable across early clinical stages of PD. While not serving as stand-alone diagnostic biomarkers, mtDNA measures provide complementary biological information within a multimodal framework and may support patient stratification based on mitochondrial involvement using a minimally invasive approach.
Sex-specific genetic drivers of memory, executive functioning and language in older adults.
Eissman JM, Regelson AN, Walters S … +42 more , Archer DB, Durant A, Mukherjee S, Lee ML, Choi SE, Scollard P, Trittschuh EH, Mez J, Kang M, Bush WS, Kunkle BW, Naj AC, Gifford KA, Bilgel M, Kuzma AB, Cuccaro ML, Cruchaga C, Pericak-Vance MA, Farrer LA, Wang LS, Schellenberg GD, Vardarajan BN, Mayeux R, Haines JL, Jefferson AL, Kukull WA, Keene CD, Saykin AJ, Thompson PM, Martin ER, Albert MS, Johnson SC, Engelman CD, Ferrucci L, Bennett DA, Barnes LL, Schneider JA, Resnick SM, Sperling RA, Crane PK, Hohman TJ, Dumitrescu L
Brain · 2026 Apr · PMID 41989867 · Publisher ↗
We previously published a sex-specific genetic analysis of memory performance, a strong endophenotype of Alzheimer's disease (AD), whereby we identified numerous sex-specific genetic loci, candidate genes, and biological...
We previously published a sex-specific genetic analysis of memory performance, a strong endophenotype of Alzheimer's disease (AD), whereby we identified numerous sex-specific genetic loci, candidate genes, and biological pathways associated with late-life memory performance. Here, we expand on this work by conducting a sex-specific, cross-ancestral genetic analysis of three cognitive domains related to cognitive change in AD: memory, executive functioning, and language. This analysis was comprised of 10 aging and AD cohorts, including 33,918 older adults with a mean age of 73 years old, 57% females and 59% cognitively unimpaired. First, we evaluated SNP-based heritability across all three cognitive domains, both with baseline performance and longitudinal cognitive decline, and determined that the heritability across all measures was comparable across sexes. Next, we conducted cross-ancestry, genome-wide meta-analyses across the 10 cohorts, identifying three novel genome-wide significant loci relating to cognition in a sex-specific manner. First, we identified a locus (rs13387871), associated with female-specific language decline, and functional annotation suggested VRK2 as a candidate gene of interest; VRK2 is a published candidate gene for multiple neuropsychiatric traits, especially those involving language ability. Then we identified two sex-specific loci among individuals with cognitive impairment. The first locus was associated with male-specific memory decline (rs12501200), and functional annotation suggested DCHS2 as a gene of interest; notably DCHS2 is a published candidate gene for AD age-at-onset and tau pathology burden. Finally, among cognitively impaired individuals, we identified a sex-interaction with baseline executive functioning (rs1380012), and functional annotation suggested AGA as a candidate gene of interest. We additionally identified numerous biological pathways associated with sex-specific AD-related cognitive performance, including regulation of meiosis, fatty acid synthesis, and chromatin silencing. Our comprehensive genetic analysis of memory, executive functioning, and language performance highlighted genetic loci, genes, and biological pathways that relate to sex-specific cognitive change in both preclinical and clinical AD.
Dissociating executive prefrontal substrates following capsulotomy in obsessive-compulsive disorder.
Zhao Y, Cui H, Zhang Y … +7 more , Chen R, Manssuer L, Li H, Zhang J, Liu W, Sun B, Voon V
Brain · 2026 Apr · PMID 41989106 · Publisher ↗
Obsessive-compulsive disorder (OCD) is characterized by widespread executive function impairments linked to disrupted fronto-striatal circuits. Ablative therapies such as capsulotomy show promise efficacy in treatment-re...
Obsessive-compulsive disorder (OCD) is characterized by widespread executive function impairments linked to disrupted fronto-striatal circuits. Ablative therapies such as capsulotomy show promise efficacy in treatment-refractory OCD, yet their effects on executive neural substrates remain poorly understood. This study explores how OCD and capsulotomy influence executive prefrontal function. Twenty-three post-capsulotomy OCD patients, thirty OCD controls, and thirty-two health controls (HC) were recruited in the study. Post-capsulotomy patients were recruited at least 6 months following surgery to allow for post-operative stabilization. Participants completed three executive function tasks assessing distinct cognitive domains: the Extra-Dimensional Intra-Dimensional (EDID) task testing set-shifting, the N-back task testing working memory and flanker task measuring conflict processing. The EDID and N-back tasks were administered during concurrent task-based fMRI, while the flanker task provided only behavioral measures. In the EDID task, OCD capsulotomy patients demonstrated greater post-error flexibility towards ID versus ED shifting relative to both OCD controls and healthy controls, despite exhibiting more ED errors. OCD controls showed less shifts after errors compared to HC, which was not revealed in the capsulotomy group. OCD patients showed less neural differentiation between ED versus ID in lateral and mesial prefrontal regions relative to HC. Capsulotomy was associated with decreased pre-supplementary motor area activity to ED shifts compared to HC, indicating impairments in neural reactivity to ED shifting. No evidence supported the influence of capsulotomy in the n-back or the flanker task. Specifically, both OCD groups showed impaired working memory performance at high memory load along with dysfunction in the whole frontoparietal network. In the flanker task, impairment in dissociating congruent and incongruent conditions were found in both OCD groups but not in the HC group. These findings suggest capsulotomy specifically remediates error-monitoring and behavioral flexibility through mesial prefrontal remodeling, while leaving working memory and conflict processing deficits intact. This dissociation implies that cognitive flexibility may represent a state-dependent process amenable to intervention, whereas working memory and conflict processing impairments may reflect trait markers of OCD vulnerability. These results have clinical implications on relative safety profile of capsulotomy and patient selection for precision neuromodulation.
Calcitonin gene-related peptide induces headache attacks in people with idiopathic intracranial hypertension.
Yiangou A, Do TP, Mollan SP … +8 more , Thaller M, Mitchell JL, Mugo CW, Tsermoulas G, Hill LJ, Lucas SJE, Ashina M, Sinclair AJ
Brain · 2026 Apr · PMID 41989095 · Publisher ↗
Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology. Idiopathic intracranial hypertension (IIH) headache phenotype is now understood to be typically migraine-like, but it is unclear wheth...
Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology. Idiopathic intracranial hypertension (IIH) headache phenotype is now understood to be typically migraine-like, but it is unclear whether CGRP directly provokes IIH headaches or alters intracranial pressure (ICP) dynamics. We conducted a randomised, double-blind, placebo-controlled, two-way crossover trial to address this. Twenty women with IIH and no prior migraine were randomly assigned to receive a 20-min continuous intravenous infusion of CGRP (1.5 μg/min) or placebo (isotonic saline). The primary outcome was the difference in the proportion of participants who developed a provoked headache attack between CGRP and placebo during the 12 h observation after infusion. Secondary outcomes included the area under the curve (AUC) for headache intensity from -10 min to 12 h, the timing and duration of headache features, and baseline-adjusted changes for vital signs, cerebrovascular haemodynamics and ICP. Seventeen participants with mean (SD) age 26.7 (6.4) years completed both visits. Twelve (71%) participants developed a typical IIH headache attack with migraine-like features after CGRP compared with three (18%) after placebo (risk difference 53%; 95% CI, 26-79; P = 0.004). The AUC-10min-12h for headache intensity was higher after CGRP than after placebo (P = 0.016). The mean ICP remained unchanged, whereas ICP amplitude increased significantly after CGRP (P = 0.005). Vital signs and cerebrovascular haemodynamics AUC-10min-90min were significantly altered after CGRP (increased: heart rate (P < 0.001), tissue oxygenation index (P = 0.041), oxygenated haemoglobin (P < 0.001) and decreased: mean arterial pressure (P = 0.010), middle cerebral artery blood velocity (P = 0.006)). CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude, as a measure of intracranial compliance, without altering mean pressure. These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population.
Data-driven modelling of tau pathology reveals distinct progressive supranuclear palsy subtypes.
Cullinane PW, Parmera JB, Nelvagal H … +24 more , Curless T, Paras Chajed L, Wrigley S, Sifontes Valladares W, Burrows M, Ebanks K, Wu L, Binding LP, Anton J, Revesz T, Real R, Vaughan DP, Jabbari E, Morris HR, Brandner S, Young AL, Hoti G, Ma Y, Bechtawi M, Chiraki N, de Pablo-Fernández E, Lim YM, Warner TT, Jaunmuktane Z
Brain · 2026 Apr · PMID 41974128 · Publisher ↗
Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathol...
Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology.
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