New papers on Brain disorders
122 new papers on brain disorders in the last 7 days, within Brain & mind. These are the 50 Pipette rates most worth reading, with the main result in the authors' own words.
The best of the week
Lifespan EEG Reference Charts Reveal Aperiodic Confounds in Beta-Band Biomarkers Across Neurological and Neuropsychiatric Disorders
In this paper, we establish the first comprehensive lifespan reference charts for beta oscillations (N = 22,094, ages: 1-100 years) using complementary analytic approaches that isolate periodic oscillations from aperiodic background activity.
PreprintClaims a big stepHyperventilation Unmasks Convergent Aperiodic EEG Vulnerability in Seizure Disorder and Schizophrenia
These findings establish the first lifespan reference charts for HV reactivity and reveal a dissociation between oscillatory and aperiodic parameters: aperiodic offset captures shared metabolic vulnerability that transcends diagnostic boundaries and emerges as a candidate transdiagnostic biomarker.
PreprintClaims a big stepNeonatal AAV-SIL1 gene therapy prevents Marinesco-Sjögren syndrome in mice
These findings provide proof-of-principle that AAV-mediated SIL1 gene therapy can prevent the neurological and muscular manifestations of Marinesco-Sjogren syndrome and identify Purkinje cells as a critical cellular target for preventing cerebellar dysfunction.
PreprintSingle-cell atlas of transcriptomic vulnerability across brain disorders
Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological-immune-vascular systems, and identifying potential targets for therapeutic intervention.
Peer-reviewed journalClaims a big stepSomatic mutations and single-nucleus transcriptomics reveal uniquely human properties of neuronal aging
Although somatic single nucleotide variant (SNV) and short insertion/deletion (Indel) mutations accumulate at rates that inversely scale to lifespan in colon cells - leaving diverse mammals with similar end-of-life burdens of mutations - here we show that cerebral cortical neurons accumulate SNVs at annual rates that are remarkably similar across six mammalian species (human, chimpanzee, rhesus macaque, marmoset, ferret, mouse) resulting in >12-fold more mutations in human neurons at the end of life compared to mouse neurons.
PreprintBold claims, read criticallyAn ASXL3–thyroid hormone axis in parvalbumin interneurons controls autism-like behaviors
An intein-based AAV system that reconstitutes full-length ASXL3 normalizes cortical architecture and behavior in Asxl3 +/− mice and drives efficient ASXL3 expression in non-human primate brain, establishing an ASXL3–TH–PV interneuron axis as a targetable pathway in ASD.
Peer-reviewed journalReal-world useSpatiotemporal characterization of Alzheimer disease pathology in living human brain tissue
Here we show that small brain biopsies collected during ventriculoperitoneal shunt surgery can be used to study Alzheimer disease pathology and protein turnover during life.
Peer-reviewed journalSingle-nucleus transcriptome-wide association study of human brain disorders
Applying these models to neuropsychiatric and neurodegenerative disorders reveals thousands of gene–trait associations that are undetectable in bulk tissue analyses and resolves many signals to discrete neuronal, glial and immune cell populations.
Peer-reviewed journalAn automated machine vision-based index for Rett Syndrome provides a generalizable framework for modeling rare disease therapeutics
These results establish an objective, high-resolution severity index for RTT and a generalizable framework for preclinical phenotyping in a rare disease.
PreprintLifespan EEG reference charts disentangle alpha-band alterations in neurological and neuropsychiatric disorders
These findings demonstrate that aperiodic components can mask underlying oscillatory changes, and that 1/f adjustment is essential for interpreting alpha dynamics in clinical populations.
PreprintReal-world useDementia Language Models: a generalizable and controllable representation of cognitive impairment
We introduce Dementia Language Models (DLMs)--a generalizable and controllable representation of cognitive impairment through language--alongside an evaluation framework for establishing their validity and clinical grounding.
PreprintBold claims, read criticallyReal-world useMultimodal imaging maps spinal glymphatic transport in health and its disruption after injury
These findings define major determinants of spinal glymphatic transport and show that accelerated tracer propagation after SCI does not indicate effective clearance.
PreprintA neurocognitive speech taxonomy for voice biomarkers of Alzheimer's disease
We developed and validated a scalable and interpretable framework, the Neurocognitive Speech Taxonomy (NST).
PreprintReal-world useIntegrating multiparametric imaging and electrophysiology reveals thalamic pathology
By integrating measurements spanning tissue pathology, intracranial electrophysiology, and clinical phenotype, this study establishes a framework for characterizing pathological network nodes in focal epilepsy.
PreprintReal-world useDisruption of a Structural Niche for Otoconia Maintenance May Underlie Common Vestibular Disorders
We propose a new disease model for common vertigo and balance disorders in which disruption of the otoconia-generating and -trafficking epithelial-mesenchymal roof niche leads to displacement and depletion of otoconia.
PreprintBold claims, read criticallyTDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD
Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs).
PreprintReal-world usemTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis
Here we show, using single-cell transcriptomics and cyclic immunostaining across human brain organoids and resected tuber tissue from patients, that loss of TSC2 biases neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell autonomous manner.
Peer-reviewed journalLoss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases
These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.
PreprintLow-rank tensor decompositions reveal coupled spatiotemporal patterns of CSF tracer transport in the human brain
We recover four replicable components, three of which resolve distinct transport pathways capturing CSF--ISF interaction: distribution of tracer in the supratentorial subarachnoid space and cerebral gray and white matter at 24 hours; transient early influx in regions consistent with transport along major cerebral arteries; and tracer influx to ventricular CSF, also called ventricular reflux.
PreprintReal-world useRNA Editing of DEGS1 Links Genetic Risk to Ceramide Dysregulation and Astrocyte Toxicity in ALS
These findings establish a novel regulatory link between RNA editing, sphingolipid metabolism and ALS pathogenesis.
PreprintCirculating extracellular vesicle lipidomics identifies distinct signatures of amyotrophic lateral sclerosis and spinal muscular atrophy
Here, we identify lipidomic signatures of circulating extracellular vesicles (EVs) that distinguish ALS from neurologically healthy controls and related neuromuscular diseases.
PreprintBold claims, read criticallyReal-world useThe value of a family history to distinguish monogenic from polygenic amyotrophic lateral sclerosis
A family history provides limited accuracy for inferring genetic architecture in ALS.
PreprintReal-world useDifferentiating nonfluent/agrammatic and logopenic primary progressive aphasia in Catalan-Spanish bilinguals by applying multilingual multimodal machine learning to connected speech
ConclusionsTaking advantage of recent advances in multilingual multimodal machine learning, we accurately differentiate Spanish-Catalan bilingual individuals with nfvPPA and lvPPA using a largely automated, time-efficient (1-2 minutes), and ecologically valid connected-speech-based approach.
PreprintReal-world useA lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids.
Together, these findings establish HuDeHA as a resource for developmental benchmarking of hippocampus-relevant organoid systems and describe cell-lineage-specific developmental changes in PSEN1 E280A organoids that may inform interpretation of early cellular alterations in fAD.
PreprintBeyond statistical thresholds: Mapping sequential ATN cascade transitions via brain structural topography in Alzheimer’s disease
Using neuroimaging-derived brain network topology, we identify four reproducible subgroups that exhibit distinct biological processes, biomarker signatures, and longitudinal cognitive trajectories.
Peer-reviewed journalBold claims, read criticallyA self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease
Thus, anabolic capacity, rather than activation state, marks microglial resilience in AD, and sustained stimulation of phagocytosis by anti-amyloid antibodies risks biosynthetic exhaustion and self-limiting efficacy.
PreprintSpatial organization of AQP4 water channel expression in the human brain
Here, we use AQP4 gene expression to reconstruct a whole-brain glymphatic-related topography and link it to vascular physiology, glioma, and vulnerability to neurodegenerative diseases.
Peer-reviewed journalSingle molecule detection of Tau seeds in extracellular vesicles from Alzheimer's disease brains
Owing to the high spatial resolution and capability of SMLM to detect sparse epitopes, we identified pathological Tau proteins in individual EVs from AD samples.
PreprintDiagnostic Labels and Measurement Timing Drive Systematic Inconsistency in ADNI Neuroimaging Data
In this paper, we showed that ADNI contains three interacting sources of bias with direct implications for machine learning: (a) diagnostic label inconsistency, (b) technical measurement drift, and (c) longitudinal survivor bias.
PreprintReal-world useThe United States CADASIL Consortium: Baseline Findings from a Natural History Study
This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.
PreprintSpatial multi-omics reveals disease-associated oligodendrocytes and metabolic dysregulation in male Parkinson’s disease mouse models
Spatial multi-omics of Parkinson’s disease mouse models identifies a disease-associated oligodendrocyte state in which IL-33 signalling to microglial ST2 shapes alpha-synuclein clearance, alongside regional lipid and glutamate metabolic disruption.
Peer-reviewed journalBrain Landscape In Situ Crosslinking Mass Spectrometry (BLIS-XL-MS) Enables Global Analysis of Protein Structural Remodeling in the Brain
Here we present Brain Landscape In Situ Crosslinking Mass Spectrometry (BLIS-XL-MS), an experimental and computational framework for analyzing protein and protein-complex remodeling in brain tissue.
PreprintCell-type specific transcriptional risk scores and longitudinal multiple sclerosis outcomes
Cell-line specific transcriptional risk scores were associated with MS outcomes in two independent cohorts.
PreprintLitBench: A Benchmark for Retrieval-Grounded Multi-Paper Evidence Synthesis in Epilepsy
ConclusionsNo system was reliable across every axis tested: accuracy fell as competing papers were added, interpretation-requiring facts were harder than stated ones, two-paper synthesis was rarely achieved, and only some systems recognized absent evidence.
PreprintReducing Neutrophil Sialic Acid Residues Alleviates Cerebral Hypoperfusion in Alzheimer's Models
Conclusions: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD.
PreprintReal-world useKMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics
These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.
PreprintMolecular subgroups of ALS patients with distinct survival outcomes identified through plasma proteomics
Using the Olink Explore HT, we profiled [~]5400 plasma proteins in ALS patients (n = 235) from the ALSrisc Study at Karolinska Institutet, Sweden, and applied consensus clustering, which revealed three patient subgroups significantly differing in survival outcome.
PreprintReal-world useP2X7 receptor antagonism potentiates seizure-suppressive effects of anti-seizure medications in human resected epileptic brain tissue
When co-administered, however, P2X7R antagonists significantly enhanced the anti-seizure efficacy of carbamazepine and lorazepam.
PreprintReal-world useCentenarians maintain cognition by resisting amyloid-β or decoupling it from tau propagation
However, the majority of the centenarians maintained high cognitive performance until death, and they appeared to be protected against cognitive decline through two distinct mechanisms: 44% were resistant to amyloid-beta accumulation, while 28% harbored substantial amyloid-beta pathology but resisted downstream p-tau propagation.
PreprintRestoring Aquaporin-4 alleviates molecular and motor phenotypes in zQ175 mouse model of Huntington disease
In summary, restoration of AQP4 enhances glymphatic transport and is associated with reduced proteopathic, neuroinflammatory and neurodegenerative phenotypes in zQ175 HD mice.
PreprintPerformance of protein panels is inflated across many biomarker studies
Through simulation and real-world proteomic data, we demonstrate that typical pipelines are broadly susceptible to this issue, producing inflated performance estimates, poor generalization, and excess false positives.
PreprintExtracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease
Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.
PreprintCentenarians maintain cognition by resisting amyloid-β or decoupling it from tau propagation
However, the majority of the centenarians maintained high cognitive performance until death, and they appeared to be protected against cognitive decline through two distinct mechanisms: 44% were resistant to amyloid-beta accumulation, while 28% harbored substantial amyloid-beta pathology but resisted downstream p-tau propagation.
PreprintSmartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration
DiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing.
PreprintReal-world useSmartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration
DiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing.
PreprintReal-world useA bipolar disorder-associated ultra-rare AKAP11 protein-truncating variant attenuates stimulus-dependent PKA activation and induces anxiety- and depression-related behaviors in mice
Together, our study presents a clinically relevant and genetically precise mouse model that provides mechanistic insight into how ultra-rare PTVs may contribute to psychiatric disorder pathogenesis, and a platform for testing rational therapeutics.
PreprintLaromestrocel preserves brain volume and cognitive function in Alzheimers disease by inhibiting neuroinflammation
Together these results show that long-lasting anti-neuroinflammatory effects of laromestrocel mitigate AD brain inflammation and are associated with markedly reduced brain tissue destruction and improved clinical function.
PreprintBold claims, read criticallyReal-world useChanges in Neural Dynamics of Brain Activity and Connectivity Independently Predict Post-Stroke Aphasia Recovery
Early recovery was independently predicted by acute and subacute activity and connectivity, whereas later improvement was predicted by activity alone.
PreprintReal-world useSleep Health in Lennox-Gastaut Syndrome impacts both Individuals with LGS and their Caregivers
These findings underscore the dual impact of LGS-related sleep disturbances on patients and caregivers, and highlight the need for comprehensive, family-centered approaches to sleep health.
PreprintReal-world useEasy to readAntonyms: A Performance Metric to Assess Word-Finding Difficulty in Multiple Sclerosis
Among 660 patients, Antonyms demonstrated better criterion validity than traditional language tasks (e.g., animal generation, Boston Naming Test).
PreprintReal-world use