Brain [JOURNAL]
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200 papers
GLP1R expression and parkinson's disease and related disorders in GLP-1RA-treated type 2 diabetes.
Woo KA, Jang Y, Kim HJ … +1 more , Park PJ
Brain · 2026 Apr · PMID 41967915 · Publisher ↗
Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, r...
Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, raising the possibility of biologically meaningful heterogeneity. We tested whether interindividual differences in systemic GLP1R expression are associated with PDRD risk among adults with type 2 diabetes initiating GLP-1RAs. We conducted an electronic health record (EHR)-based new-user cohort study in the National Institutes of Health All of Us Research Program, focusing on adults with type 2 diabetes aged 50 years or older who initiated a GLP-1RA between 2005 and 2023 and had no prior PDRD or Alzheimer's disease and related dementias (ADRD). Systemic GLP1R expression was genetically proxied by a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score dichotomized at the cohort median. Follow-up ended at the earliest of incident PDRD, death, or October 1, 2023. Hazard ratios were estimated using multivariable Cox proportional hazards models adjusting for baseline covariates, and incidence rates and rate differences per 1,000 person-years were estimated using Poisson models. Prespecified sensitivity analyses excluded early outcome events and short drug exposure; an exploratory analysis evaluated incident ADRD. The cohort included 7,039 initiators (3,520 high vs 3,519 low genetic score; mean age 61.7 ± 8.4 years; 59.8% female; mean follow-up 3.8 ± 3.1 years). Compared with the low-score group, the high-score group had a lower hazard of incident PDRD (hazard ratio 0.78; 95% confidence interval 0.62 to 0.98) and a lower incidence rate (rate difference -1.36 per 1,000 person-years; 95% confidence interval -2.51 to -0.20). Associations were consistent across sensitivity analyses. No association was observed for incident ADRD (hazard ratio 1.02; 95% confidence interval 0.81 to 1.28). These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among GLP-1RA-treated adults with type 2 diabetes. Systemic GLP1R-mediated pathways may be relevant to interindividual differences in observed PDRD risk, and genetic instruments for GLP1R expression may inform hypotheses for future PDRD trial design.
The Wnt5a-PKCδ-GluA1 axis controls synapse-specific plasticity in HIV-1 gp120-induced pain pathogenesis.
Chen X, Spurgat M, Liu X … +5 more , Maurelli M, Dibua A, Sha C, Wollmuth LP, Tang SJ
Brain · 2026 Apr · PMID 41967910 · Full text
Imbalance of excitatory and inhibitory neuronal activity (E/I imbalance) plays a critical role in pain pathogenesis. Recent studies have identified a novel form of E/I imbalance in the spinal dorsal horn (SDH) of animal...
Imbalance of excitatory and inhibitory neuronal activity (E/I imbalance) plays a critical role in pain pathogenesis. Recent studies have identified a novel form of E/I imbalance in the spinal dorsal horn (SDH) of animal models of HIV-associated pain, manifesting as increased spontaneous excitatory postsynaptic current (sEPSC) frequency in excitatory neurons alongside decreased sEPSC frequency in inhibitory neurons and hence termed neural circuitry polarization (NCP). However, how the opposite forms of synaptic plasticity in NCP is coordinated in the pain neural circuit is unclear. Here, we show that in the SDH of a mouse model of HIV-associated pain, potentiation of excitatory synapses on excitatory neurons (ESE) and depression of excitatory synapses on inhibitory neurons (ESI) employ distinct mechanisms to support their expression. We found the increase of sEPSC frequency in excitatory neurons induced by HIV1 gp120 was mediated by a postsynaptic mechanism, whereas decrease of sEPSC frequency in inhibitory neurons by a presynaptic mechanism. Our studies showed that pharmacological inhibition of calcium-permeable AMPA (CP-AMPA) receptors selectively attenuated potentiation of ESE without significantly affecting ESI depression. We also observed that GluA1 was upregulated in excitatory but not inhibitory neurons, indicating selective CP-AMPA receptor formation in excitatory neurons. Furthermore, we identified a new pain-related signaling pathway in ESE: Wnt5a-PKCδ-GluA1. We elucidated that the GluA1 upregulation and ESE potentiation were controlled by neuronal Wnt5a signaling via protein kinase C delta (PKCδ). Our findings reveal that ESE and ESI in the SDH of HIV pain models use distinct synaptic and molecular mechanisms to support their expression in NCP, demonstrating specialized regulatory pathways for the plasticity of excitatory synapses targeting different neuron types during the pain pathogenesis.
Rigidity in Parkinson's disease.
Suppa A, Zampogna A, Vivacqua G … +8 more , Falletti M, Asci F, Marinelli L, Trompetto C, Currà A, Hallett M, Obeso JA, Rothwell J
Brain · 2026 Apr · PMID 41967903 · Publisher ↗
Rigidity, along with bradykinesia and tremor, is recognised as one of the core motor symptoms fundamental to the clinical diagnosis of Parkinson's disease. Despite its diagnostic relevance, rigidity has received comparat...
Rigidity, along with bradykinesia and tremor, is recognised as one of the core motor symptoms fundamental to the clinical diagnosis of Parkinson's disease. Despite its diagnostic relevance, rigidity has received comparatively less systematic investigation than other motor symptoms, resulting in gaps in our understanding of its phenomenology, neurophysiological correlates, and response to therapeutic interventions such as deep brain stimulation. This narrative review aims critically to examine and clarify the current conceptual ambiguities, assessment strategies, and pathophysiological underpinnings associated with rigidity in Parkinson's disease. We begin by discussing the wide range of phenomena described by the term "rigidity" in neurological and non-neurological fields and highlight the inconsistencies that arise in its clinical interpretation. We review and compare the clinical and instrumental approaches that are currently used to assess rigidity, emphasising their respective strengths, limitations, and contributions to a more precise characterisation of rigidity in Parkinson's disease. We end with a summary of molecular, neuroimaging and neurophysiological insights into the pathophysiology of rigidity. In sum, we seek to consolidate existing knowledge, underscore unresolved questions, suggest new solutions for existing gaps with the hope of providing a conceptual and methodological foundation to guide future clinical and experimental research in the field.
DRD1-driven infantile dystonia: towards a mechanism-informed framework for GPCR receptoropathies.
Kayhan G, Tany R, Maroofian R … +17 more , Serdaroğlu E, Kurumiya E, Tran DP, Wakasugi-Masuho H, Thomsen M, Salayev K, Kaiyrzhanov R, Badalova S, Guliyeva U, Kareem A, Bauer P, Zifarelli G, Houlden H, Lohmann K, Kitao A, Mulayim MF, Masuho I
Brain · 2026 Apr · PMID 41966088 · Publisher ↗
Despite remarkable advances in human genomics, most rare disorders remain undiagnosed, mechanistically obscure, and without effective treatments. In this study, we establish DRD1, encoding the dopamine D1 receptor (D1R),...
Despite remarkable advances in human genomics, most rare disorders remain undiagnosed, mechanistically obscure, and without effective treatments. In this study, we establish DRD1, encoding the dopamine D1 receptor (D1R), as a monogenic cause of an infantile-onset dystonia syndrome, for which pharmacological responsiveness may vary depending on the underlying molecular mechanism. Across three unrelated families, eight affected individuals exhibited generalised dystonia, axial hypotonia, and cognitive impairment and carried homozygous pathogenic missense DRD1 variants. Live-cell biosensor assays revealed that patient-derived DRD1 variants disrupt receptor integrity through mechanistically diverse failures, such as trafficking deficits and impaired agonist-induced activation-ultimately converging on a collapse of D1R-mediated signalling. In line with standard clinical practice and informed by these mechanistic insights, we initiated a trial of levodopa/carbidopa in two individuals in the index family with a partial-loss-of-function variant, which was associated with improvement in voluntary motor function and cognitive engagement. Moreover, in live-cell assays, we demonstrated that Mevidalen-a selective DRD1-positive allosteric modulator currently in clinical development-substantially improved signaling in patient-derived mutants in vitro, supporting a potential future mechanism-aligned therapeutic avenue. To broaden the clinical implications of our findings, we performed a structural interpretation of DRD1 variation in 807,162 individuals and identified 29 rare predicted deleterious missense variants in heterozygous carriers. These variants clustered within evolutionarily conserved transmembrane domains and signaling motifs, providing a basis for pathogenicity assignment and variant prioritization in clinical and research settings. Building on these insights, we developed a structure-informed pharmacological experimental framework that stratifies DRD1 variants according to molecular dysfunction and matches them with mechanistically aligned therapeutic strategies-namely, orthosteric agonists, pharmacological chaperones, allosteric modulators, and readthrough compounds. This in vitro approach enabled functional rescue of otherwise intractable variants, suggesting a potentially actionable molecular architecture across diverse genotypes, which remains to be tested clinically. Together, these findings identify biallelic DRD1 variants as a cause of infantile dystonia and support the potential for mechanism-informed therapeutic exploration, while emphasizing that clinical responsiveness may vary across individuals. More broadly, our integrated genomics-structure-pharmacology framework provides a proof-of-concept approach to functionally stratify G protein-coupled receptor (GPCR) variants, exemplified here by DRD1, and prioritise testable, mechanism-based therapeutic hypotheses for future evaluation.
LSD1 splicing is regulated by the long non-coding RNA MALAT1 and orchestrates stress resilience in mammals.
Paplekaj A, Romito E, Forastieri C … +13 more , Toffolo E, Briguglio S, Pelucchi P, Mosca E, Chiodi A, Viatore M, Bonasoni MP, Santunione AL, Pirani F, Maggioni E, Brambilla P, Battaglioli E, Rusconi F
Brain · 2026 Apr · PMID 41965120 · Publisher ↗
Psychiatric disorders often arise from the interaction between genetic predisposition and chronic psychosocial stress, yet the molecular programs determining resilience versus susceptibility remain incompletely understoo...
Psychiatric disorders often arise from the interaction between genetic predisposition and chronic psychosocial stress, yet the molecular programs determining resilience versus susceptibility remain incompletely understood. Building on evidence that the transcriptional corepressor LSD1 links environmental stress to neuronal gene regulation, we investigated whether isoform-specific regulation of LSD1 splicing contributes to stress adaptation. Using a mouse model of chronic social defeat stress, we analyzed LSD1 microexon E8a splicing in the hippocampus of resilient and susceptible animals. RNA-seq was performed after the last stress session to capture genome-wide transcriptional responses during the window of LSD1 splicing regulation. Comparative analyses with published LSD1 knockdown, LSD1 ChIP-seq and chronic stress datasets were conducted. Hippocampal samples from suicide victims were analyzed to assess translational relevance. Analysis of LSD1 splicing dynamics revealed that resilient mice, but not susceptible animals, retained the ability to reiterate acute stress-induced exon E8a skipping after repeated stress exposure, preserving the capacity to upregulate the enzymatically active ubLSD1 isoform in the hippocampus. In susceptible mice this inducible splicing response was absent. Mechanistically, splicing regulation involved the long non-coding RNA MALAT1, which controls the neurospecific splicing factor nSR100, a regulator of LSD1 exon E8a inclusion. Reduced MALAT1 expression in susceptible mice coincided with marked overactivation of stress-responsive genes revealed by RNA-seq. Approximately 15% (86 of 595) of genes deregulated in susceptible versus resilient hippocampi overlapped with transcripts modulated by LSD1 knockdown in an independent neuronal system. Of these, 25 were direct LSD1 ChIP-seq targets. ESR1 emerged as a regionally divergent upstream regulator associated with susceptibility. The MALAT1-nSR100-LSD1 axis represents a regulatory pathway modulating stress adaptation. Downregulation of ubLSD1 and MALAT1 in the hippocampus of suicide victims recapitulates the molecular phenotype observed in stress-susceptible mice, linking disruption of this pathway to pathological behavioral outcomes.
Faecal microbiota transplant for Parkinson's disease.
Santens P, Bruggeman A, Laukens D … +1 more , Vandenbroucke RE
Brain · 2026 Apr · PMID 41955275 · Publisher ↗
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The fluidity of fluid biomarker evidence in the clinic.
Vandenberghe R
Brain · 2026 Apr · PMID 41948801 · Publisher ↗
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Reply: Blinding integrity in cross-frequency transcranial alternating current stimulation for hemianopia.
Raffin E, Bevilacqua M, Windel F … +13 more , Menoud P, Salamanca-Giron RF, Feroldi S, Zandvliet SB, Ramdass N, Draaisma L, Vuilleumier P, Guggisberg AG, Bonvin C, Fleury L, Huxlin KR, Beanato E, Hummel FC
Brain · 2026 Apr · PMID 41947402 · Publisher ↗
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Intracranial biomarkers for anterior thalamic deep brain stimulation in epilepsy: a long-term observational study.
Aiello G, Elshahabi A, Stieglitz L … +4 more , Belvedere A, Dubcek T, Polania R, Imbach L
Brain · 2026 Apr · PMID 41934257 · Publisher ↗
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an established treatment for patients with drug-refractory epilepsy (DRE), yet long-term therapeutic outcomes are highly variable and challeng...
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an established treatment for patients with drug-refractory epilepsy (DRE), yet long-term therapeutic outcomes are highly variable and challenging to predict. This variability is compounded by the delayed and gradual effects of DBS, the difficulty of consistent seizure monitoring, and the absence of physiological biomarkers to inform treatment. In this study, we analyzed longitudinal intracranial recordings over a four-year observational period from a cohort of 22 patients with ANT-DBS. Our primary goal is the identification of neurophysiological signatures that could predict and track clinical DBS response. Our results show that DBS-responders and non-responders exhibit distinct ANT spectral trajectories over time, with responders showing a progressive increase in higher frequencies (β₁,γ) and decreased lower-frequency (δ,θ) activity, as compared to non-responders. Notably, these dynamic biomarkers, particularly high-to-low frequency ratios (e.g., β₁/θ), enabled the early discrimination of clinical outcomes. Additionally, we provide evidence of robust circadian and multidien rhythms in ANT local field potentials, with further analyses supporting the feasibility of adaptive stimulation protocols to improve therapeutic outcomes. Together, these findings propose ANT spectral dynamics in outpatient settings as a promising tool for early prediction of therapeutic efficacy and pave the way for biomarker-guided optimization of DBS therapy in epilepsy.
HTLV1-associated myelopathy as a translational model of progressive neurodegeneration.
da Silva MTT, Araujo AQC
Brain · 2026 Apr · PMID 41926707 · Publisher ↗
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and progressive forms of multiple sclerosis (MS) are chronic central nervous system diseases characterized by persistent inflammation and progressive ne...
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and progressive forms of multiple sclerosis (MS) are chronic central nervous system diseases characterized by persistent inflammation and progressive neurodegeneration. Although triggered by distinct upstream events-persistent HTLV-1 infection in HAM/TSP and autoimmune mechanisms in MS, with increasing evidence implicating Epstein-Barr virus (EBV) in MS initiation-both conditions converge on shared inflammatory and neurodegenerative cascades. In HAM/TSP, a hierarchical Tax-MAP3K8-MEK-ERK signaling axis emerges as a proximal disease-defining pathway that promotes Th1 polarization and sustained interferon-driven inflammation, with JAK/STAT functioning predominantly as a downstream amplification loop. Neurodegeneration in HAM/TSP appears largely secondary to chronic virus-driven immune activation, whereas in progressive MS, degenerative mechanisms may evolve alongside compartmentalized, smouldering inflammation within the CNS. Rather than representing strictly "secondary" versus "primary" paradigms, both diseases are better understood along a continuum in which inflammatory, metabolic, and age-related mechanisms interact to sustain axonal loss. Advanced imaging techniques reveal convergent patterns of spinal cord atrophy and microstructural injury. Biomarkers such as proviral load and CXCL10 in HAM/TSP, and neurofilament light chain and GFAP in MS, provide complementary insights into inflammatory burden and neuroaxonal damage. Emerging therapies target immune and glial signaling pathways, including MAPK and JAK/STAT axes, yet disease progression remains only partially controlled. By integrating hierarchical molecular signaling, viral-immune interactions, imaging correlates, and biomarker profiles, this review positions HAM/TSP as a reductionist human model of chronic inflammation-driven neurodegeneration, offering translational insights relevant to progressive MS and other neuroinflammatory disorders.
Frequency-specific and spatiotemporal dynamics of β-γ phase-amplitude coupling in Parkinson's disease.
Loehrer PA, Yassine S, Weber I … +9 more , Sanner V, He S, Pogosyan A, Chen L, Witt L, Fink GR, Pedrosa DJ, Timmermann L, Tan H
Brain · 2026 Mar · PMID 41920885 · Publisher ↗
Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscill...
Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscillation is coupled to the phase of a slower brain oscillation, is implicated in various higher-order cognitive functions and was shown to be pathologically altered in neurological and psychiatric disease. In Parkinson's disease (PD), the coupling between gamma amplitude (50-150 Hz) and beta phase (13-35 Hz) is exaggerated. Enhanced β-γ PAC was found in the subthalamic nucleus and various cortical sources and shown to be responsive to dopaminergic therapy and deep brain stimulation (DBS). Therefore, exaggerated β-γ PAC has been proposed to be a disease marker and a potential target for brain circuit interventions. Despite these promising findings, a significant knowledge gap remains, as the spatial and frequency-specific dynamics of β-γ PAC and its association with motor symptoms and therapy remain elusive. To address this knowledge gap, we employed high-density electroencephalography (EEG) with source localisation techniques for patients with PD at rest. We highlight three key findings: (1) a frequency-specific increase in high β (23-35 Hz)-γ PAC within and between sources of the cortical motor network, (2) a link between elevated high β-γ PAC and bradykinesia and rigidity when OFF medication, but not tremor, and (3) a medication-induced reduction in high β-γ PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides novel insights into the pathophysiology of PD as an oscillopathy and identifies high β-γ PAC as a potential marker of Parkinsonian symptoms and treatment effects. This has important implications for invasive as well as non-invasive therapeutic strategies as high β-γ PAC targeting might hold greater promise than targeting β-γ PAC per se.
Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.
Kwan JY, Lantz CI, Korobeynikov VA … +22 more , Snyder A, Huang X, Haselhuhn T, Dore KN, Madruga A, Danielian LE, Schindler AB, Chia R, Rasheed M, Crook J, Szabo M, Portley M, Sherer CM, King MC, Huang TH, Kosa P, Bielekova B, Ward ME, Grunseich C, Shneider NA, Traynor BJ, Narendra DP
Brain · 2026 Mar · PMID 41911331 · Publisher ↗
Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical de...
Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.
Long-read sequencing and the evolving landscape of facioscapulohumeral muscular dystrophy diagnosis.
Giardina E, Strafella C
Brain · 2026 May · PMID 41906865 · Publisher ↗
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Synapse-associated neuropathological markers in Alzheimer disease.
Barrantes FJ
Brain · 2026 Mar · PMID 41906816 · Publisher ↗
Abnormal amyloid β and microtubule-associated protein are two intimately related proteinopathies central to the pathophysiology of Alzheimer disease (AD). Both are often accompanied by cholesterol dysmetabolism and/or al...
Abnormal amyloid β and microtubule-associated protein are two intimately related proteinopathies central to the pathophysiology of Alzheimer disease (AD). Both are often accompanied by cholesterol dysmetabolism and/or altered transport of this neutral lipid in carriers of the APOEε4 (apolipoprotein E gene epsilon 4 allele), a causal gene for early-onset (familial) AD and the most important genetic risk factor for late-onset AD. Age, the principal risk factor for sporadic AD, together with comorbidities such as cardiovascular diseases, diabetes, and chronic inflammation converge on synapses to generate cognitive synaptopathies. The latter probably constitute the early and asymptomatic manifestations of AD and other dementias, preceding neuronal loss, disruption of neuronal networks, and the appearance of severe -particularly mnemonic- cognitive impairments. Here, I assess how key biomolecules stemming from synapses can be used as neuropathological markers to identify early signs of AD synaptopathy before overt clinical symptoms. In particular, the review dissects how molecular constituents of the synapse can be analysed by blood plasma proteomics and other state-of-the-art methods for the early diagnosis of cognitive impairment onset and prognosis of evolution. Finally, possible avenues for therapeutic interventions to ameliorate risk factors and comorbidities of AD are reviewed.
Quantitative pathology and APOE genotype reveal dementia risk and progression in Lewy body disease.
Nelvagal HR, Chiraki N, Curless T … +16 more , Cullinane PW, Rockliffe A, Pimparkar S, Kawamura H, Ollerenshaw S, Elahi I, Brandner S, Wu L, Real R, Ryten M, Hardy J, De Pablo Fernandez E, Warner TT, Morris HR, Lim YM, Jaunmuktane Z
Brain · 2026 Mar · PMID 41889331 · Publisher ↗
Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology includi...
Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials.
Interplay between genetic and environmental risk factors in multiple sclerosis: what have we learned?
Jacobs BM, Vandebergh M, Maltby VE … +2 more , Dobson R, Kreft KL
Brain · 2026 Mar · PMID 41889330 · Publisher ↗
Genome-wide association studies (GWAS) have identified over 230 genetic variants associated with susceptibility to multiple sclerosis (MS) and one genome-wide significant variant associated with progression of MS. Enviro...
Genome-wide association studies (GWAS) have identified over 230 genetic variants associated with susceptibility to multiple sclerosis (MS) and one genome-wide significant variant associated with progression of MS. Environmental risk factors, such as vitamin D deficiency and obesity, have also been implicated in MS pathogenesis. Statistical approaches building on these genetic data, such as Mendelian randomization and colocalization, have established putative causal links between environmental risk factors and MS risk, most notably for vitamin D and body mass index. However, studies have thus far revealed limited statistically significant interactions between host genetics and environmental factors beyond the Major Histocompatibility Complex. Epigenetics - the study of non-nucleotide alterations to DNA such as DNA methylation or histone acetylation - might provide a mechanistic framework for understanding how environmental and genetic factors interact in MS. Environmental factors, such as Epstein-Barr virus (EBV) infection, vitamin D deficiency, and smoking, are associated with epigenetic modifications at key MS-related genomic loci, altering the expression of MS risk genes in a cell-type specific manner. Transcriptomics have identified significant pathways via which genetic risk is realised, potentially providing targets for intervention. This review synthesizes current evidence on gene-environment interactions in the context of MS GWAS findings, evaluates the strengths and limitations of various study methodologies, and discusses the challenges in elucidating the interplay between genetics and environmental factors. We propose potential strategies for future research to advance our understanding of the biological mechanisms underlying MS susceptibility in at-risk individuals.
SCN2A variants are associated with familial and sporadic hemiplegic migraine.
Riant F, Thompson CH, Wafa SMA … +13 more , Fenton TA, DeKeyser JM, Abramova TV, Desai RR, Gazal S, Moulin T, Chaigne D, Kort L, Corpechot M, Tournier-Lasserve E, Ben-Shalom R, George AL, Ducros A
Brain · 2026 Mar · PMID 41885191 · Publisher ↗
Familial hemiplegic migraine (FHM) is a severe autosomal dominant subtype of migraine with aura, characterized by transient motor weakness during attacks. Known genes (CACNA1A, ATP1A2, SCN1A, PRRT2) account for fewer tha...
Familial hemiplegic migraine (FHM) is a severe autosomal dominant subtype of migraine with aura, characterized by transient motor weakness during attacks. Known genes (CACNA1A, ATP1A2, SCN1A, PRRT2) account for fewer than 20% of genetically diagnosed cases. To identify novel genetic contributors to FHM, we performed whole-genome linkage analysis and partial exome sequencing in a four-generation pedigree. A candidate ion channel gene (SCN2A) was subsequently screened in six additional pedigrees with multiple affected members and in a cohort of 594 unrelated probands with familial or sporadic hemiplegic migraine without mutations in known FHM genes. Functional consequences of identified variants were assessed using heterologous expression and automated patch clamp recording. The neurophysiological impact of SCN2A dysfunction was investigated using computational neuron models. We identified a heterozygous missense mutation (c.4438A>G, p.Lys1480Glu) in SCN2A, encoding the neuronal voltage-gated sodium channel NaV1.2, which co-segregated with the FHM phenotype. Additional SCN2A variants (c.769T>A, p.Phe257Ile, and c.3955C>G, p.Arg1319Gly) were found in a second family and a sporadic case, respectively. All variants were absent from the gnomAD database. All ten individuals carrying a SCN2A variant experienced typical hemiplegic migraine attacks beginning in childhood. Two children heterozygous for p.Phe257Ile also had self-limited infantile seizures during the first year of life. None of the affected individuals exhibited permanent cerebellar ataxia, intellectual disability, or recurrent febrile coma. Functional studies revealed altered voltage-dependent and kinetic properties in all three variants that elicited abnormal action potential firing in a computer model of a neuron, supporting their pathogenicity. These findings implicate SCN2A dysfunction in both familial and sporadic hemiplegic migraine, expanding the genetic landscape of migraine and the phenotypic spectrum associated with SCN2A variants.
Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer's disease.
Young CB, Sheng J, Winer JR … +7 more , Cody K, Sai I, Carlson ML, Younes K, Insel PS, Schultz AP, Mormino EC
Brain · 2026 Mar · PMID 41885175 · Full text
Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical...
Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared to other biomarker-defined clinically unimpaired groups given that identifying those at highest risk for decline is critical for informing prevention trials and understanding early disease mechanisms. In this longitudinal study, we examined tau PET, MRI, cognitive, and functional data from 395 clinically unimpaired participants, ages 65 to 85 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study. Participants had 2-5 flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Change in regional and voxelwise tau patterns, atrophy, cognition, and functioning were examined. Longitudinal trajectories from A+TCortical+ (n=34) were compared to preclinical Alzheimer's disease with elevated tau PET signal in medial temporal lobe only (A+TMTL+, n=102), preclinical Alzheimer's disease without significant tau (A+TMTL-, n=210), and those without amyloid or tau (A-TMTL-, n=49). Cortical tau accumulation was fastest in A+TCortical+ (0.018-0.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+, and A+TMTL- groups (0.010-0.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = -0.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048-0.182 points per year; Mini-Mental State Examination = -0.189-0.006 points per year). In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration, and have faster cognitive and functional decline than other preclinical Alzheimer's disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer's disease without subtyping may be disproportionately influenced by this small, high-risk subgroup.
The emotional cost of caring: amygdala lesions reduce the aversiveness of affective empathy.
Zhao S
Brain · 2026 May · PMID 41885173 · Full text
This scientific commentary refers to ‘Empathy motivation is preserved following amygdala damage’ by Scheffer . (https://doi.org/10/1093/brain/awag074).
This scientific commentary refers to ‘Empathy motivation is preserved following amygdala damage’ by Scheffer . (https://doi.org/10/1093/brain/awag074).
The prevalence of Lewy body pathology across nine international community-based cohorts.
Gibson LL, Suemoto CK, Attems J … +20 more , Abner EL, Corrada MM, Gomez-Isaza L, Grinberg LT, Kapasi A, Jicha GA, Kawas C, Keene CD, Kovacs GG, Latimer CS, Leite REP, Montine T, Myllykangas L, Neltner AM, Troncoso J, Walker KA, Walker R, Wang SJ, Aarsland D, Nelson PT
Brain · 2026 Mar · PMID 41885166 · Publisher ↗
Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to pro...
Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer's disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88-2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30-30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67-1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology-specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.
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