Brain [JOURNAL]
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200 papers
White matter lesions disrupt cholinergic pathways important for cognition in Parkinson's disease.
Carli G, Brown T, Michalakis F … +8 more , Biddix A, Roytman S, Vangel R, Van Hout A, Kanel P, Scott P, Albin RL, Bohnen NI
Brain · 2026 May · PMID 42117428 · Publisher ↗
White matter lesions are associated with cognitive impairment in Parkinson's disease, but the underlying neurobiological mechanisms remain unclear. One hypothesis is that strategically located white matter lesions disrup...
White matter lesions are associated with cognitive impairment in Parkinson's disease, but the underlying neurobiological mechanisms remain unclear. One hypothesis is that strategically located white matter lesions disrupt long-range white-matter pathways crucial for cognitive functioning, particularly cholinergic projections from the basal forebrain, contributing to cognitive decline. Using volumetric measures of basal forebrain nuclei (T1 MRI proxy for brain cholinergic projection nuclei), quantitative white matter lesions assessments (fluid-attenuated inversion recovery MRI), and a presynaptic cholinergic marker ([18F]-FEOBV PET), we tested a mechanistic model of white matter lesions effects on basal forebrain cholinergic projections and nuclei, and how these disruptions relate to cognition. We analysed data from 127 mid to advanced-stage patients with Parkinson's disease without dementia. Periventricular and deep white matter lesion burdens were quantified with the UBO Detector pipeline. Cognitive function was assessed across five domains using z-scores from a control group matched for age and education. Voxel-wise analyses examined associations between white matter lesion burden and cholinergic synaptic density, followed by mediation analyses testing whether cholinergic alterations mediated the relationship between white matter lesions and cognition, while correcting for sex, levodopa equivalent dose, and disease duration. Voxel-wise analyses revealed that higher periventricular lesions burden was associated with reduced [18F]-FEOBV uptake in an insular-limbic-frontal-cingulum cluster, while deep lesions showed more topographically limited associations that disappeared after adjusting for periventricular burden. Periventricular lesions affected lateral and external Ch4 cholinergic projection pathways (81%-88% of patients), more frequently than deep white matter lesions (25%-47% of patients), except for the external capsule, which was equally affected by both. Cognitive performance (global cognition, memory, executive function, and attention) was associated with both periventricular lesion burden and [18F]-FEOBV uptake within the insular-limbic-frontal-cingulum cluster, as well as with basal forebrain volume. Mediation analyses indicated that periventricular lesions had a direct effect on cortical terminal integrity ([18F]-FEOBV) and an indirect, presumably retrograde degeneration effect via basal forebrain atrophy. The effect of periventricular lesions on insular-limbic-frontal-cingulum cholinergic terminal density was a strong mediator of the association between lesion burden and cognitive performance. A weaker mediation effect via the basal forebrain emerged for global cognition, whereas mediation was more robust for memory and executive functioning. Our findings indicate that periventricular white matter lesions contribute to cognitive vulnerability in Parkinson's disease without dementia through impacts on basal forebrain cholinergic projections. White matter lesion burden may represent a mechanistically meaningful biomarker for predicting cognitive trajectories and informing targeted interventions in Parkinson's disease.
King's stages of amyotrophic lateral sclerosis: an 18F-FDG-PET study of brain connectivity.
Di Pede F, Cabras S, Manera U … +18 more , Vasta R, Zocco G, Minerva E, Matteoni E, De Mattei F, Pellegrino G, Palumbo F, Pascariu D, Callegaro S, Maccabeo A, Polverari G, Martino A, Giuliani A, Moglia C, Calvo A, Chiò A, Pagani M, Canosa A
Brain · 2026 May · PMID 42102258 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. TDP-43 proteinopathy is the neuropathological signature of the disease, and 18F-FDG-PET serves as a marker...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. TDP-43 proteinopathy is the neuropathological signature of the disease, and 18F-FDG-PET serves as a marker of neurodegeneration in vivo. The aim of the present cross-sectional study was to disentangle 18F-FDG-PET correlates of disease severity assessed through the King's staging system, by exploring connectivity changes across motor stages. ALS patients classified as King's stage 1, 2 and 3, who underwent brain 18F-FDG-PET at diagnosis from 2008 to 2022 at the ALS Centre of Turin, were included. A multiple regression analysis to evaluate the relationship between brain metabolism and King's stage was performed. The clusters showing significant results were used as seed regions in an inter-regional correlation analysis (IRCA), performed for each stage. Out of a total of 832 ALS patients, 337 were classified as King's stage 1, 274 as stage 2, and 221 as stage 3. The three groups significantly differed in age at PET, disease duration and total ALSFRS-R score at the time of PET, C9ORF72 status, and the distribution of cognitive categories. We found a decreasing metabolic gradient from King's stage 1 to King's stage 3 in a cluster encompassing motor and cognitive areas. As King's stage increases, we found a decrease of connectivity within the sensorimotor and cognitive areas. The IRCA also showed the connectivity of motor and cognitive regions with temporal and cerebellar regions. The connectivity with temporal regions found in King's stage 1 decreases in King's stage 2 and finally disappears in King's stage 3. The connectivity with the cerebellum occurs in King's stage 2 and decreases in King's stage 3. The changes of connectivity of motor and cognitive areas with temporal and cerebellar regions among different King's stages might reflect the spread of TDP-43 proteinopathy or a compensatory mechanism, respectively. The present study suggests that 18F-FDG-PET imaging of the brain may be integrated with King's staging system to assess the extent of the pathogenic process in the context of clinical trials.
Beyond human-initiated screening: the imperative for fully autonomous brain health surveillance.
Rezaii N, Estiri H
Brain · 2026 May · PMID 42100828 · Publisher ↗
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Clinical prognostic indicators in multiple system atrophy.
Goh YY, Chelban V, Vijiaratnam N … +15 more , Girges C, Sandhu M, Fumi R, Cullinane PW, Mohammad R, Hu MT, Rowe JB, Pavese N, Archibald N, Kobylecki C, Foltynie T, Morris HR, Warner T, Jaunmuktane Z, Houlden H
Brain · 2026 May · PMID 42095271 · Publisher ↗
Multiple system atrophy (MSA) is a neurodegenerative condition causing parkinsonism, cerebellar ataxia and/or dysautonomia. Typical survival is between 6-10 years, but some people die before five or after 15 years. This...
Multiple system atrophy (MSA) is a neurodegenerative condition causing parkinsonism, cerebellar ataxia and/or dysautonomia. Typical survival is between 6-10 years, but some people die before five or after 15 years. This heterogeneity complicates advanced planning and clinical trial stratification. MSA prognostication studies have shown conflicting results, possibly due to diagnostic accuracy or study size. We report results from a study of survival prognostic factors in a cohort of 555 MSA patients (including the largest post-mortem confirmed cohort to date of 254 people) gathered through the Queen Square Brain Bank and the PROSPECT-M-UK multi-centre prospective cohort study. Through PROSPECT-M-UK, 318 clinically diagnosed MSA patients (17 overlapped with the QSBB cohort) were followed up annually over 5 years. The QSBB cohort clinical data was collected through retrospective review of primary and secondary care documentation. Survival analysis was performed using counting process Cox proportionate hazards modelling, Kaplan-Meier log-rank testing and landmark survival analysis to account for guarantee-time bias. Mean onset age in the combined cohort was 58.7±9.0y with median survival of 8.25y (95% CI:7.88-8.63). 28.8% were clinically diagnosed in-life with MSA-P, 23.8% MSA-C, 40.2% mixed and the rest as non-MSA diagnoses. Later disease onset was associated with shorter survival (HR=1.04, P<0.001). The commonest cause of death was respiratory infection (67%) followed by disease related decline (20%). Median survival from indoor wheelchair use, gastrostomy insertion or development of unintelligible speech was consistently <1.5 years (95% CI upper limits<2.4 years), making these reliable late-stage disease markers. Using landmark analysis, at 3 years from onset, negative prognostic factors included recurrent falls, unintelligible speech, use of catheters and of medication for orthostatic hypotension (HR = 1.57, 3.29, 1.76, 3.29;all P<0.05). At 5 years from onset, mobility milestones including walking aid use, outdoor and indoor wheelchair use (HR = 1.70, 1.93, 2.62;all P<0.01) became significant, whilst dysautonomia milestones (catheter and orthostatic support medication use) were no longer significant. Median individual Unified Multiple System Atrophy Rating Scale (UMSARS) progression rate (n=91) was 10.27 (IQR:5.31-14.30) points/year and did not correlate with symptom duration. Higher baseline UMSARS and faster UMSARS progression were negative prognostic factors of survival from baseline review (HR=1.03 and 1.07 respectively, both P<0.001). We show that in-clinic rating scales and clinical milestone assessment can aid MSA prognostication. Importantly, prognostic factors demonstrate time-dependent variability, which may contribute to previous heterogeneity observed in smaller studies. This knowledge is important for patient care and should inform future clinical trial stratification.
Circular RNA SCMH1 promotes persistent brain repair via N6-methyladenosine methylation post stroke.
Bai Y, Cai N, Wen L … +8 more , Pang L, Yang Y, Shen L, Zhang Y, Luo Z, Chao J, Han B, Yao H
Brain · 2026 May · PMID 42093648 · Publisher ↗
Circular RNA (circRNA)-based nucleic acid therapeutics exhibits distinct pharmacological advantages including sustained therapeutic effects from single-dose administration, but the molecular basis governing this persiste...
Circular RNA (circRNA)-based nucleic acid therapeutics exhibits distinct pharmacological advantages including sustained therapeutic effects from single-dose administration, but the molecular basis governing this persistence remains mechanistically unresolved. Using single-cell RNA sequencing (scRNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and genetic animal models, we demonstrated that a single dose of exogenous circSCMH1 sustained elevated endogenous circSCMH1 levels in the peri-infarct region. This persistence stems from a self-sustaining loop initiated by exogenous circSCMH1, as confirmed by experiments with a modified circSCMH1 variant (ΔcircSCMH1), which distinguishes endogenous from exogenous sources. Mechanistically, microglial overexpression of the m6A demethylase FTO enhances circSCMH1 biogenesis by suppressing m6A methylation, with YTHDC1 identified as the primary m6A reader protein facilitating this process. Furthermore, YTHDC1 collaborates with Exportin-4 to mediate m6A-dependent nuclear export of circSCMH1, a step critical for its therapeutic efficacy. In Exportin-4-deficient mice, impaired nuclear export abolishes the sustained brain repair induced by circSCMH1, as evidenced by diminished sensorimotor recovery in behavioural tests. These findings elucidate how a single dose of circSCMH1 improves brain repair through a self-sustaining loop that leverages endogenous circRNA biogenesis machinery. Unlike traditional therapies requiring repeated dosing, this approach achieves prolonged therapeutic efficacy, offering substantial translational advantages for stroke treatment.
Paediatric functional seizures: when care models meet clinical reality.
Parikh A, Albert DVF, Yel I … +1 more , Bronson B
Brain · 2026 May · PMID 42093643 · Publisher ↗
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Targeting glutamatergic pathways: genetic insights into comorbid neurodevelopmental disorders.
Glessner JT, Khan ME, Chang X … +14 more , Liu Y, Torkamandi S, Abrams D, Otieno FG, Kim J, Mahesh Y, Lemma M, Mentch F, Li J, Kao C, March ME, Qu H, Connolly J, Hakonarson H
Brain · 2026 May · PMID 42093631 · Publisher ↗
Copy number variants (CNVs) in genes encoding metabotropic glutamate receptors (GRMs) have been previously implicated in attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, invest...
Copy number variants (CNVs) in genes encoding metabotropic glutamate receptors (GRMs) have been previously implicated in attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, investigations of their role in comorbid ADHD patients suffering from coexisting neurodevelopmental disorders (NDDs), such as anxiety and ASD with or without developmental delay remains limited. To assess the enrichment of CNVs in GRM genes and their molecular interaction networks in a large pediatric cohort with ADHD and comorbid NDDs, we analyzed CNV data from 72,626 pediatric participants recruited through the Center for Applied Genomics at Children's Hospital of Philadelphia. The cohort includes 12,472 individuals diagnosed with ADHD (including 7,967 with other NDD comorbid conditions). CNVs were identified using PennCNV and annotated for overlap with GRM genes and their protein-protein interaction (PPI) networks using data from STRING. We evaluated CNV enrichment in ADHD cases with and without comorbid diagnoses, including autism spectrum disorder (ASD), anxiety, and developmental delay. Significant enrichment of CNVs was observed in GRM-interacting networks among ADHD cases with comorbid NDDs. Specifically, 27 genes interacting with primary GRM genes were significantly enriched in CNVs in these individuals with false discovery rate (FDR) < 0.05, compared to ADHD-only cases or disease-free controls. These included key neurodevelopmental genes such as DLG2, NRXN1, SHANK3, and SYNGAP1, which are involved in synaptic signaling and glutamatergic neurotransmission. In contrast, enrichment of GRM network gene CNVs observed in ADHD-only cases was notably less. Our findings support a distinct genetic profile in ADHD cases with comorbid NDDs, marked by CNV enrichment in glutamatergic signaling pathways involving GRM-interacting genes. These results suggest that GRM network disruptions contribute to the complexity of the phenotype spectrum in ADHD patients suffering from comorbid neurodevelopmental phenotypes and highlight a potential pathway for targeted, genetically informed interventions in these patients.
Autologous adipose-derived mesenchymal stromal cells for chronic traumatic brain injury.
Cox CS, Ashley JR, Juranek J … +12 more , Ewing-Cobbs L, Prossin AR, Pedroza C, Chen B, Kosmach S, Duron MC, Scott MC, Bianchi J, Collier A, Olson SD, Schriner JB, Savitz SI
Brain · 2026 May · PMID 42093626 · Publisher ↗
Secondary injury from traumatic brain injury (TBI) leads to a chronic inflammatory process, neurodegeneration, and tissue loss, resulting in poor outcomes. Mesenchymal stromal cell (MSC) treatment can dampen microglial a...
Secondary injury from traumatic brain injury (TBI) leads to a chronic inflammatory process, neurodegeneration, and tissue loss, resulting in poor outcomes. Mesenchymal stromal cell (MSC) treatment can dampen microglial activation and improve TBI outcomes. Our study aimed to assess the impact of autologous adipose-derived MSC treatment in adult patients with chronic TBI using imaging, functional, and neurocognitive outcome measures. Our Phase 1/2a study analyzed safety and treatment effect of 3 intravenous infusions (over 6 weeks) of autologous adipose-derived MSCs (HB-adMSCs) in 24 chronic TBI patients. Outcome measures included functional, neuropsychological, and psychometric testing; multimodal MRI; and PET using [11C]ER176 to measure brain immune cell density. There were no serious treatment-related adverse events. DT-MRI analyses in a priori regions of interest showed that at 6 months after treatment, elevated mean diffusivity volumes (supraMD) were significantly reduced bilaterally in the hippocampus (mean decrease 163.51 mm3, 95% CI -286.55 to -41.51 mm3; P=0.013). A trend for reduced supraMD was observed in the amygdala (mean decrease 113.60 mm3, 95% CI -229.52 to 2.90 mm3; P=0.058); no changes in the insula were observed (P=0.19). Brain-behavior analyses indicated significant interactions between levels in baseline neuropsychological assessments of anxiety and depression and magnitude of supraMD changes in the amygdala and hippocampus, respectively. Macrostructural volumetric changes were not significant in the hippocampus, amygdala, or insula (all P >0.10). PET results showed that HB-adMSC treatment induced significant reductions in brain immune cell density in the right caudate (x,y,z: 12,2,7; T20 = 4.1; P <0.0003), extending into both the right ventral anterior thalamus (x,y,z: 13, -2,11; T20 = 3.6; P < 0.0009) and right nucleus accumbens (x,y,z: 8,9, -3; T20 = 2.5; P < 0.01), and right parahippocampal gyrus (x,y,z: 29, -40, -7; T20 = 3.1; P <0.003). Reductions in measures of depression (P=0.026), fatigue (P=0.008), and pain (P=0.007) 6 months after treatment were also observed. Our study demonstrates autologous adipose-derived MSCs for chronic TBI are safe, have clinically relevant treatment effect sizes in functional and neurocognitive outcome measures, yield significant improvements in specified measures of microstructural integrity (i.e., reduced volume of elevated MD voxels) in brain-based behavior relations, and reduce density of brain immune cells in regions corresponding to pain, fatigue, and depression. These data provide quantitative justification for the sample size of next-phase clinical trials using either functional outcomes or surrogate imaging outcomes.
Neuroinflammation and neurodegeneration trigger a specific splice form of ribosomal protein S24.
Magadi SS, Jonson M, Lucena PB … +20 more , Caliandro MF, Almeida B, Bilalli L, Budinger D, Tsoi A, Ntzouni M, Maqdissi JA, Kaczmarczyk L, Zijlstra JJ, Faketija M, Perkins M, Paul G, Hallbeck M, Ingelsson M, Watts JC, Reichenbach N, Petzold GC, Schieweck R, Heneka MT, Jackson WS
Brain · 2026 May · PMID 42087813 · Publisher ↗
Neuroinflammation, particularly that involving reactive microglia, the brain's resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases (NDs). Multiple studies have reported changes in...
Neuroinflammation, particularly that involving reactive microglia, the brain's resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases (NDs). Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein-synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggests functional ribosome specialization through variation in their protein composition. Among RPs, S24, encoded by RPS24 in humans and Rps24 in mice, is unique as its transcripts undergo alternative splicing to produce protein variants with different C-terminal sequences that are differentially expressed across tissues and cell types. Understanding heterogeneous RP expression patterns across brain regions and cell types could reveal mechanisms underlying selective vulnerability in NDs and provide new biomarkers for neuroinflammatory responses. To identify RP expression patterns across brain regions in neurons, astrocytes, and microglia we analyzed cell type-specific translating mRNAs from mice. To investigate Rps24 isoform-specific expression, we performed cell type-resolved transcript analysis and developed antibodies specific for the S24-PKE protein variant encoded by mRNA isoform Rps24c. We examined Rps24c/S24-PKE expression in brains from mouse models of aging and neurodegeneration, as well as in human postmortem tissue from patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This work revealed distinct RP expression patterns across brain regions and between neurons, astrocytes, and microglia, including neuron-enriched RPs Rpl13a and Rps10. Analysis of RP paralogs revealed complex expression relationships with their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Across brain regions and cell types, Rplp0 and Rpl13a, commonly used normalization references, showed heterogeneous expression, raising important methodological considerations for gene expression studies. Rps24 isoforms exhibited striking cell type-specific expression patterns. Rps24c was predominantly expressed in microglia and was increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. Using S24-PKE-specific antibodies, we verified increased expression of this protein variant in brains with AD, PD, and HD, and in relevant mouse models. These findings establish heterogeneous RP expression as a feature of brain cell types which may enable cell type-specific translation regulation via specialized ribosomes. This work also identifies Rps24c/S24-PKE as a potential novel marker for neuroinflammation and neurodegeneration and provides new tools for monitoring these responses.
Of time, space, and closed-loop deep brain stimulation.
Hart MG
Brain · 2026 May · PMID 42084458 · Publisher ↗
Abstract loading — click title to view on PubMed.
A chicken-or-egg dilemma resolved: autoantibodies initiate neurodegeneration.
Di Liberto G, Irani SR
Brain · 2026 May · PMID 42084457 · Full text
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Burst suppression: a default brain state associated with loss of network complexity.
Doorn N, Hassink GC, Frega M … +1 more , van Putten MJAM
Brain · 2026 May · PMID 42083472 · Publisher ↗
Burst suppression (BS) is a highly stereotyped EEG pattern observed across a wide range of clinical contexts, from general anesthesia and postanoxic coma to neonatal encephalopathy. Despite its consistent appearance, BS...
Burst suppression (BS) is a highly stereotyped EEG pattern observed across a wide range of clinical contexts, from general anesthesia and postanoxic coma to neonatal encephalopathy. Despite its consistent appearance, BS comprises two distinct forms with markedly different implications. BS with identical bursts (IBS) is almost exclusively seen in patients with severe, irreversible encephalopathy and is consistently associated with poor neurological outcome. In contrast, heterogeneous BS (HBS) can appear in reversible conditions such as anesthesia. The mechanisms that give rise to these divergent forms remain elusive. Existing theories impose disease-specific processes on otherwise healthy networks, but such models fail to explain why BS emerges across diverse etiologies and disregard the clinically critical distinction between IBS and HBS. We combined clinical, experimental, and computational approaches to identify shared mechanisms underlying BS. We analyzed EEG recordings from patients with a severe postanoxic encephalopathy (n = 33) and from patients undergoing general anesthesia (n = 10). These clinical observations were compared with activity recordings from human induced pluripotent stem cell-derived neuronal networks (n = 29) and rodent cortical cultures (n = 10), and simulations of biophysically grounded neuronal network models. Purely excitatory, low-complexity networks, both in vitro and in silico, spontaneously generated activity virtually indistinguishable from pathological IBS. Introducing inhibitory neurons, modular network structure, or diverse external inputs progressively increased signal complexity and produced HBS-like or continuous activity resembling physiological EEG. Our findings suggest that BS, and particularly IBS, reflects a default dynamic state of simplified excitatory networks that emerges when biological complexity is lost. Different clinical conditions may compromise distinct mechanisms-inhibition, connectivity, or afferent input-yet converge on the same underlying activity pattern. While IBS reflects near-complete loss of complexity, HBS indicates partial preservation. This unified framework explains how diverse etiologies converge on BS and highlights identical forms as signatures of severely reduced network complexity.
GluN2A-NMDA receptors mediate the effect of BDNF on network hyperexcitability in hippocampal neurons.
De Luca P, Mele M, Napoli F … +3 more , Mshelia P, Costa RO, Duarte CB
Brain · 2026 May · PMID 42083468 · Publisher ↗
Brain-derived neurotrophic factor (BDNF) modulates synaptic plasticity via activation of TrkB receptors and plays a key role in epileptogenesis, though its molecular mechanisms remain incompletely understood. Here, we ex...
Brain-derived neurotrophic factor (BDNF) modulates synaptic plasticity via activation of TrkB receptors and plays a key role in epileptogenesis, though its molecular mechanisms remain incompletely understood. Here, we examined how BDNF-TrkB signaling regulates synaptic GluN2A-containing NMDA receptors (NMDARs) and impacts network synchronization in cultured hippocampal neurons. BDNF increased synaptic surface expression of GluN2A-NMDARs in rat hippocampal synaptoneurosomes and cultured neurons in a time- and protein synthesis-dependent manner. Mechanistically, we identified a signaling cascade involving hnRNPK, Pyk2, and protein kinase C (PKC) as critical for this effect. Knockdown of hnRNPK or Pyk2, PKC inhibition, or expression of a phosphorylation-deficient Pyk2 mutant prevented BDNF-induced GluN2A synaptic accumulation. Pyk2 phosphorylation at Y402 was required for both basal and BDNF-induced GluN2A expression. Multielectrode array recordings demonstrated that BDNF and GluN2A-NMDARs contribute to enhanced network activity following stimulation. In vivo, BDNF-TrkB signaling mediated increased synaptic GluN2A expression in the hippocampus of rats subjected to the pilocarpine model of temporal lobe epilepsy, confirming a TrkB-dependent mechanism. These findings reveal a BDNF/TrkB-PKC-Pyk2-hnRNPK pathway that regulates GluN2A synaptic expression and neuronal excitability, offering new insights into the molecular basis of synaptic plasticity and epilepsy.
Genotype-structure-phenotype correlations define divergent natural history in early-onset spastic paraplegia type 4.
Alecu JE, Schierbaum LM, Tam A … +20 more , Quiroz V, Bernardi K, Yang K, Roller JR, Döbler-Neumann M, Rattay TW, González-Salazar C, Zehr EA, Skorohodovs D, Rong J, Carty S, Battaglia N, Lee S, Moon J, Christie M, Roll-Mecak A, França MC, Schüle R, Schöls LJ, Ebrahimi-Fakhari D
Brain · 2026 May · PMID 42083457 · Publisher ↗
Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onse...
Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onset complex disease. Robust genotype-phenotype correlations and detailed natural history data are lacking, limiting clinical trial readiness. We analyzed 206 patients with genetically confirmed SPG4 enrolled across seven international centers, complemented by high-quality literature-derived cases. Deep phenotyping included standardized motor scales, spasticity ratings, developmental milestones, and patient-reported outcomes. We developed an extended essentiality-mapping framework to classify SPAST missense variants by integrating in silico pathogenicity predictions, evolutionary constraint, physicochemical residue connectivity, and variant enrichment within the human spastin hexamer structure. Plasma neurofilament light chain (pNfL) using was quantified using Simoa in 26 patients and 101 controls. We identified 136 distinct SPAST variants, including 10 novel variants. Variant class segregated strongly by inheritance, with de novo cases enriched for missense variants and inherited cases showing a variety of variant classes with enrichment for truncating variants. Longitudinal analysis revealed two latent trajectories: a rapidly progressive severe subgroup enriched for de novo missense variants, and a biphasic moderate subgroup enriched for inherited truncating variants. Patient stratification integrating spastin essentiality mapping (missense variants affecting essential, neutral, or context-dependent residues) with established genetic modifiers (biallelic pathogenic variants or modifier variants in trans) classified patients into predicted severe and moderate subgroups with divergent age at onset and clinical disease progression. The severe subgroup showed early developmental delays, rapid loss of ambulation, and declining quality of life, while the moderate subgroup displayed delayed but accelerating disease progression. pNfL levels were elevated in both subgroups, most pronounced in severe early disease. This study provides the most detailed natural history of SPG4 to date and introduces a biologically informed stratification framework that links variant class and location to divergent clinical trajectories. These data establish clinically meaningful benchmarks and offer a genotype-based framework to improve anticipatory care and optimize trial design for SPG4.
Impaired reward-based learning but preserved motor invigoration in chronic stroke.
Sporn S, Herrojo Ruiz M, Fathana R … +3 more , Zich C, Bestmann S, Ward N
Brain · 2026 May · PMID 42081374 · Publisher ↗
Reward provides a feedback signal that modulates behaviour through several mechanisms, including invigorating performance and learning of action-outcome associations to guide future choices. After stroke, the ability to...
Reward provides a feedback signal that modulates behaviour through several mechanisms, including invigorating performance and learning of action-outcome associations to guide future choices. After stroke, the ability to utilise reward feedback can be impaired, which may limit the benefits of rehabilitation approaches that use reinforcement. One possibility is that stroke causes a global impairment of reward processing, leading to both reduced invigoration and diminished learning from feedback. Alternatively, reward processing may be selectively disrupted, such that either invigoration or the ability to update beliefs from reward feedback is disproportionately affected. To test these competing hypotheses, we recruited forty chronic stroke survivors and thirty age-matched healthy controls to complete a probabilistic reversal learning task with both their strong (non-paretic/dominant) and weak (paretic/non-dominant) limb. On each trial, participants reached to one of two targets associated with different reward probabilities that changed unpredictably over time, requiring continued monitoring of outcomes and adaptation of choice behaviour. Stroke survivors showed reduced reward-based learning compared to controls, expressed as lower overall choice accuracy and a greater tendency to switch responses after rewarded trials (i.e., lower win-stay rates), particularly when using the weak upper limb. Control analyses confirmed that these selective impairments were not explained by general motor impairment or cognitive deficits. To identify the putative computations underlying these behavioural differences in reward-based learning we used an established model of hierarchical Bayesian inference, the Hierarchical Gaussian Filter (HGF). The HGF characterises learning dynamics as trial-by-trial updating of an agent's beliefs about action-outcome probabilities and their change over time (environmental volatility). Compared to healthy controls, stroke survivors were slower to update their beliefs about action-reward contingencies, an effect most pronounced for the weak upper limb, whereas updating beliefs about environmental volatility remained intact. Reward-based invigoration was also preserved: stronger trial-by-trial predictions about action-reward contingencies were associated with faster movement times, with comparable slopes of this association across groups, indicating that motivational drive was maintained in patients despite overall slower performance. This behavioural dissociation between preserved motivational invigoration but impaired probabilistic reward-based learning highlights a key translational opportunity: to leverage intact motivational pathways to enhance rehabilitation intensity and compliance, and to develop adaptive feedback strategies that compensate for impaired reward learning. Harnessing these complementary approaches could strengthen recovery outcomes and support greater long-term independence after stroke.
Alzheimer's disease subtyping approaches and the role of co-pathologies.
Gawor K, Statz K, Schaeverbeke J … +1 more , Thal DR
Brain · 2026 May · PMID 42081371 · Publisher ↗
Alzheimer's disease (AD) is characterized by amyloid-β plaques and abnormal phosphorylated tau protein-containing neurofibrillary tangles, yet it shows marked heterogeneity in clinical presentation, neuroanatomical invol...
Alzheimer's disease (AD) is characterized by amyloid-β plaques and abnormal phosphorylated tau protein-containing neurofibrillary tangles, yet it shows marked heterogeneity in clinical presentation, neuroanatomical involvement, and progression rate. This variability challenges the traditional view of AD as a single disease entity and has prompted efforts to define patient subgroups with shared characteristics who might benefit from targeted treatment strategies. Here, we provide a cross-disciplinary overview of current subtyping strategies. We describe both traditional stratification approaches, including those based on clinical AD syndromes, neuropathological staging, and age of onset, as well as emerging data-driven methods that utilize clinical information, neuroimaging, omics data, and multimodal data integration. Subtypes derived using these data-driven methods overlap to some extent with hypothesis-driven classifications but also uncover additional axes of heterogeneity, including distinct anatomical patterns and molecular signatures. Furthermore, we highlight that most AD patients exhibit co-pathologies such as transactive response DNA-binding protein 43, α-synuclein, or cerebrovascular changes, which are often overlooked in existing stratification systems, despite their potential to affect atrophy patterns and progression rate and, hence, influence subtype interpretation. Finally, we outline future directions for developing unified stratification frameworks that link clinical features with underlying biology, including co-pathologies, aiming to enhance diagnostic precision and enable future personalized therapeutic interventions.
The cascade to pathogenicity in autoantibody-mediated CNS diseases.
Montini F, Wing E, Herman M … +4 more , Pittock SJ, Lopez S, Flanagan EP, Irani SR
Brain · 2026 May · PMID 42081370 · Publisher ↗
The discovery of pathogenic neuroglial-surface directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognise...
The discovery of pathogenic neuroglial-surface directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognised, diseases. Annual descriptions of novel CNS-targeting antibodies create a continuous stream of new conditions in which to evaluate distinct phenotypes, specific tumour associations and immunotherapy responses. Alongside this clinical growth, increasing basic knowledge has highlighted origins and mechanisms underlying disease causation, most comprehensively interrogated in the well-established autoantibody-mediated conditions of autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The corresponding most common 'big six' autoantigens are LGI1, the NMDA receptor, CASPR2, IgLON5, in forms of AE, AQP4 and MOG. Each of these autoantigens associates with a homogenous set of basic clinical features, across age, sex, tumour associations and ethnicities, coupled with partly distinctive profiles of triggers and predispositions, paradigms of immune tolerance escape in the periphery, how cells and autoantibodies gain access to the CNS and discrete mechanisms by which the CNS autoantibodies induce neuroglial dysfunction. These observations lead us to reconstruct a proposed chronological series of events as the "cascade to pathogenicity", which together culminate in a rare CNS disease. By extension, we hypothesize elucidating the underlying biology of each condition will present differing precision medicine approaches to optimize patient care. Despite distinctions, there are also clinical and biological overlaps between these diseases, collectively creating opportunities to compare and contrast their individual features. Here, in each condition, we review current knowledge regarding the similarities and differences between the triggering events, underlying immunological processes and pathogenic mechanisms of autoantibodies. In some instances, we identify scientific clues which drive hypothetical pathways of pathogenesis and, for others, highlight striking observations which aim to generate hypothesis-driven next steps. Our aim is to construct a model across the major autoantibody-mediated CNS diseases to highlight distinct components of cascades to pathogenicity which may offer targeted therapeutic approaches to improve patient outcomes, and identify key areas and questions for future research.
Combining SMN2 splicing modifiers with HDAC6 inhibition improves spinal muscular atrophy outcomes.
Osseni A, Slika R, Coudert L … +13 more , Conjard-Duplany A, Weill L, Belotti E, Siopi E, Gangloff YG, Sapaly D, Bendris S, Clerc Z, Bruneteau G, Vuillerot C, Leblanc P, Charbonnier F, Schaeffer L
Brain · 2026 May · PMID 42068140 · Publisher ↗
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by SMN gene defects. It leads to motor neuron death and muscle weakness. Without treatment, most affected children don't survive past age two. Recen...
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by SMN gene defects. It leads to motor neuron death and muscle weakness. Without treatment, most affected children don't survive past age two. Recently, new gene therapies help SMA children survive, but treated patients now face ongoing muscle atrophy and functional deficits, creating a novel clinical presentation. Over the last years, treatments of various animal models of neuromuscular disorders have shown the ability of inhibitors of the non-conventional histone deacetylase 6 (HDAC6) to reduce muscle atrophy. This study examines HDAC6 inhibition's impact on muscle cell differentiation and tests in vivo if combining it with new standard SMA treatments improves muscle and overall condition in SMA mice. Here, we report that HDAC6 controls myotube formation and maturation in vitro. In particular, HDAC6 inhibition increases the size of SMA patients-derived muscle primary myotubes. In vivo, when combined with ASOs inducing exon-7 inclusion in SMN2 RNA, HDAC6 systemic inhibition strongly improved muscle strength, mass, function, and longevity of SMA-like mice model. These findings provide evidence that selective inhibition of HDAC6 improves myogenic progression. Hence, HDAC6 inhibitors are good candidates to ameliorate persisting symptoms of SMA patients treated with the new standard of care.
The consequences of MDMA use are not easily disentangled from other drug use or lifestyle factors.
Basedow LA
Brain · 2026 Apr · PMID 42057714 · Publisher ↗
Abstract loading — click title to view on PubMed.
Is nociception necessary for pain?
van Rysewyk S
Brain · 2026 Apr · PMID 42057712 · Publisher ↗
Abstract loading — click title to view on PubMed.
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