Brain最新文献

{"title":"PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids.","authors":"Tijana Ljubikj,Mayte Z Mars,Astrid T van der Geest,Channa E Jakobs,Nils Bessler,Vanessa Donega,Xynthia P R M van den Oetelaar,Marina de Wit,R Jeroen Pasterkamp","doi":"10.1093/brain/awaf340","DOIUrl":"https://doi.org/10.1093/brain/awaf340","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of upper and lower motor neurons and progressive muscle wasting. Accumulating evidence indicates a role for non-neuronal cells in ALS pathogenesis, but their exact role and mechanism-of-action remain incompletely understood. A hexanucleotide (GGGGCC) repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS (C9-ALS) and a frequent cause of frontotemporal dementia (FTD). Several lines of experimental evidence support a role for the immune system and microglia in C9-ALS/FTD, and, depending on experimental settings and species used, both reduced and increased microglial activity have been reported. To further study microglia in C9-ALS/FTD in the context of a complex, three-dimensional disease environment, we developed cerebral organoids that innately develop microglia derived from induced pluripotent stem cells (iPSCs) of C9-ALS/FTD patients and controls. Here we show reduced cellular complexity and transcriptional changes in C9 neural organoid-derived microglia (C9-oMGs), involving phagocytic, lysosomal and immune response pathways. The release of inflammatory cues from C9-ALS/FTD organoids is decreased and LAMP1 expression in C9-oMGs is reduced. Functional analysis using live imaging reveals impaired phagocytosis by C9-oMGs and reduced engulfment of the post-synaptic protein PSD-95 by C9-oMGs in organoids. Finally, our transcriptomics analysis identifies a PU.1 (encoded by SPI1) regulon as the most strongly downregulated transcription factor network in C9-oMGs. Viral overexpression of PU.1 rescues phagocytosis and gene expression defects in C9-microglia. Overall, our data demonstrate reduced microglial functions in a complex cellular disease environment and identify PU.1 as a potential target for restoring microglia changes in C9-ALS/FTD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"79 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced striatal dopamine transmission as a transdiagnostic substrate of psychomotor retardation.","authors":"Ian Lam Leong,Tsz Huen Ng,Kunal Sen,Ella Burchill,Harry Costello,James B Badenoch,Jan Coebergh,Robert A McCutcheon,Akshay Nair,Michael Browning,Quentin J M Huys,Glyn Lewis,Andrew Lees,Anthony S David,Jonathan P Rogers","doi":"10.1093/brain/awaf335","DOIUrl":"https://doi.org/10.1093/brain/awaf335","url":null,"abstract":"Psychomotor retardation, defined as generalised slowing of movement and speech, is a feature of several neurological and psychiatric disorders. In this review, we discuss the hypothesis that reduced striatal dopaminergic transmission is a transdiagnostic substrate for psychomotor retardation underlying the motor features of conditions such as Parkinson's disease, drug-induced parkinsonism, neuroleptic malignant syndrome, catatonia and depression. We examine the evidence across clinical, epidemiological, neuroimaging, laboratory and therapeutic studies. Parkinsonian disorders share slowed movement and a reduction in verbal output with catatonia and depression. Bradyphrenia, slowed cognitive processing, also occurs in Parkinson's disease and depression. In addition, there are close epidemiological relationships between depression and Parkinson's disease, and between catatonia and neuroleptic malignant syndrome. Neuroimaging studies also generally support the association of psychomotor retardation with reduced dopaminergic transmission, particularly in the dorsal striatum. Cerebrospinal fluid measurement of homovanillic acid (a dopamine catabolite) yields inconsistent results and is very nonspecific. Parkinson's disease and catatonia generally respond well to dopaminergic medication. In contrast, dopamine antagonists can induce both parkinsonism and catatonia. Our review is limited by the variability in measurement of psychomotor retardation and difficulty distinguishing between cognitive and motor slowing. It is also likely that other neurotransmitters, such as GABA and serotonin, play an important role in psychomotor speed. It is possible that dopaminergic deficits in psychiatric disorders represent functional disruptions, in contrast to the structural damage to the substantia nigra in Parkinson's disease. We propose further research be conducted into the effects of levodopa and dopamine agonists in depression with psychomotor retardation. Alternative neuroimaging methods such as PET sequences with shorter imaging protocols and neuromelanin-MRI should also be explored.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency.","authors":"Felix Distelmaier,Julia Corral-Sarasa,Laura Jiménez-Sánchez,María Elena Díaz-Casado,Melanie Rohmann,Annette Seibt,Diran Herebian,Sander H J Smits,Juliane Münch,Ertan Mayatepek,Jörg Breitkreutz,Ralf A Husain,Sergio López-Herrador,Pilar González-García,Luis C López","doi":"10.1093/brain/awaf334","DOIUrl":"https://doi.org/10.1093/brain/awaf334","url":null,"abstract":"Primary coenzyme Q (CoQ) deficiency is a mitochondrial disorder with variable clinical presentation and limited response to standard CoQ10 supplementation. Recent studies suggest that 4-hydroxybenzoic acid (4-HBA), a biosynthetic precursor of CoQ, may serve as a substrate enhancement treatment in cases caused by pathogenic variants in COQ2, a gene encoding a key enzyme in CoQ biosynthesis. However, it remains unclear whether 4-HBA is required throughout life to maintain health, whether it offers advantages over CoQ10 treatment, and whether these findings are translatable to humans. Here, we demonstrate that lifelong 4-HBA supplementation in a murine model carrying the pathogenic Coq2A252V variant is well tolerated and prevents the onset of mitochondrial encephalopathy. In contrast, withdrawal of 4-HBA leads to progressive neurological decline. Notably, while conventional CoQ10 supplementation transiently ameliorated cardiac dysfunction, it failed to prevent fatal neurological deterioration. Guided by these preclinical findings, we initiated a first-in-human individual therapeutic trial with 4-HBA in a 3-year-old boy with genetically confirmed primary CoQ10 deficiency due to compound heterozygous pathogenic COQ2 variants. The patient presented with a Leigh-like syndrome characterized by bilateral brain lesions, developmental delay, muscular hypotonia, failure to thrive, lactic acidosis, and steroid-resistant nephrotic syndrome. Despite high-dose oral CoQ10 supplementation, clinical response had been minimal. Prior to clinical application, patient-derived fibroblasts were treated in vitro with 4-HBA, resulting in a marked increase in endogenous CoQ10 levels. Following the initiation of oral 4-HBA treatment, the patient experienced rapid and sustained remission of proteinuria, improved renal hyperfiltration, and a gradual increase in serum CoQ10 concentrations. No adverse effects were observed during a six-month follow-up. Clinically, the patient showed notable improvements in motor skills, language acquisition, cognitive alertness, and overall development, accompanied by significant gains in growth and nutritional status. Clinical recovery was also reflected by improved scores on the Newcastle Paediatric Mitochondrial Disease Scale. These findings support 4-HBA as a promising targeted metabolic treatment for COQ2-related CoQ deficiency and highlight the need for further clinical investigation.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct cerebellar networks underpin clinical improvement in adolescent Tourette disorder.","authors":"Giuseppe A Zito,Therese-Marie Sartoris,Cyril Atkinson-Clement,Prasanthi Jegathesaan,Benoît Béranger,Andreas Hartmann,Virginie Czernecki,Clement Tarrano,Charlotte Rosso,Pierre Burbaud,Emmanuel Roze,Cecile Gallea,Yulia Worbe","doi":"10.1093/brain/awaf332","DOIUrl":"https://doi.org/10.1093/brain/awaf332","url":null,"abstract":"Adolescence is frequently called the second brain maturation period. In Tourette disorder (TD), the clinical trajectory of tics and associated psychiatric co-morbidities vary significantly across individuals during the transition from adolescents to adulthood. In this study, we aimed to identify patterns of resting-state functional connectivity that differentiate adolescents with TD from their neurotypical peers, and to monitor symptom-specific functional changes over time. We employed multivariate analysis based on support vector machine (SVM) to predict patterns of resting-state functional connectivity in 64 adolescents with TD and 61 sex- and age-matched healthy controls (HC). 57 TD patients participated twice, at a time interval of 15 months. Based on the results of the multivariate analysis, we implemented a general linear model testing within-group differences in resting-state functional connectivity over time, as well as their correlation with changes in severity of tics, depressive, obsessive-compulsive (OCD) and attention deficit and hyperactivity (ADHD) symptoms. SVM significantly discriminated TD from HC with above-chance accuracy, specificity and sensitivity. The most discriminative connections were prefrontal, striatal and cerebellar networks. Between the visits, adolescents with TD showed decreased functional connectivity between the vermis 3 and the bilateral supplementary motor area, and between the vermis 4,5 and the occipital cortex. The correlation analysis evidenced that (i) an improvement between the visits in the severity of tics was associated with increased connectivity between the pre-supplementary motor cortex, anterior cingulate and inferior frontal gyrus; (ii) an improvement of ADHD was associated with decreased connectivity of the anterior cingulate cortex with the inferior temporal cortex; (iii) an improvement of OCD correlated with decreased cerebellar (lobule 8 and vermis 8, 9) connectivity with fronto-polar, superior temporal and superior frontal cortices, and increased cerebello-parietal connectivity, as well as fronto-parietal and fronto-frontal connectivity; and (iv) an improvement of depressive symptoms correlated with decreased connectivity of the cerebellum (lobule 4, 5 and vermis 6) with the precuneus. Our findings support pathophysiological models of TD in which aberrant patterns of functional connectivity are related to specific comorbidities, that may evolve differently throughout adolescence. Resting-state functional connectivity may provide unique endophenotypes with developmental changes potentially linked to the modification of severity of comorbid conditions. Distinct regions of the cerebellum and its connectivity with various frontal cortical regions emerge as candidate biomarkers to monitor, and possibly predict, the clinical trajectory of TD symptoms, offering insights into disorder pathogenesis and likely guide clinical decision-making.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"308 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex.","authors":"Sofia Avalos-Alais,Maciej Jedynak,Anthony Boyer,Blandine Chanteloup-Forêt,Cristiana Pinheiro,Christopher C Cline,Sara Parmigiani,Yasser Alemán-Gómez,Patric Hagmann,Corey J Keller,Olivier David, ","doi":"10.1093/brain/awaf317","DOIUrl":"https://doi.org/10.1093/brain/awaf317","url":null,"abstract":"The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48,797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age 24±13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution - higher resolution in the LPFC in the hemisphere of interest and lower elsewhere - maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (p-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92±0.09, mean R² = 0.93±0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26±0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior DLPFC demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (eg. 0.21±0.01 vs 0.15±0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16±0.02) and hippocampus (0.12±0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"14 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Right hemisphere language network plasticity in aphasia.","authors":"Peter E Turkeltaub,Kelly C Martin,Alycia B Laks,Andrew T DeMarco","doi":"10.1093/brain/awaf308","DOIUrl":"https://doi.org/10.1093/brain/awaf308","url":null,"abstract":"The role of the right hemisphere in aphasia recovery has been controversial since the 19th century. Imaging studies have sometimes found increased activation in right hemisphere regions homotopic to canonical left hemisphere language regions, but these results have been questioned due to small sample sizes, unreliable imaging tasks, and task performance confounds that affect right hemisphere activation levels even in neurologically healthy adults. Several principles of right hemisphere language recruitment in aphasia have been proposed based on these studies: that the right hemisphere is recruited primarily by individuals with severe left hemisphere damage, that transcallosal disinhibition results in recruitment of right hemisphere regions homotopic to the lesion, and that increased right hemisphere activation diminishes to baseline levels over time. It is debated whether engagement of language homotopes reflects upregulation of weakly active right hemisphere processors in a bihemispheric language network, versus recruitment of new processors into the network. We address these issues in 76 chronic left hemisphere stroke survivors with ongoing or prior aphasia and 69 neurologically healthy older adults using a semantic decision fMRI paradigm that elicits reliable and strongly left-lateralized individual-participant language activation and adapts to require effortful performance irrespective of participant ability levels. Right hemisphere activation was greater in stroke survivors than controls, and related to younger age, left-handedness, and higher education. Right hemisphere activation magnitude was modest compared to left hemisphere activation. In contrast to prior proposals, right hemisphere activation was unrelated to lesion size and greater with longer time-since-stroke. Right ventral inferior frontal and mid-anterior temporal regions were weakly engaged in language processing in controls and co-activated with their homotopic left hemisphere counterparts. Lesions to those left hemisphere counterparts resulted in greater homotopic activation that contributed to naming and word reading outcomes. In contrast, the right dorsal inferior frontal cortex was not engaged during language processing in controls and did not co-activate with its left hemisphere counterpart. It exhibited the largest group-level difference in activation for stroke survivors relative to controls due to complex lesion-activation interactions, but the activation was unrelated to the aphasia outcomes tested here. In sum, right hemisphere language homotopes are recruited in some chronic left hemisphere stroke survivors, consistent with both upregulation of weakly active processors in a bihemispheric language network and new recruitment of the dorsal inferior frontal gyrus into the network. These findings clarify the mechanisms of, and constraints on, right hemisphere language network plasticity after left hemisphere stroke.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"31 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A human striatal-midbrain assembloid model of alpha-synuclein propagation.","authors":"Hoang-Dai Tran,Min-Kyoung Shin,Xin Yi Yeo,Sangyong Jung,Muhammad Junaid,Su Bin Lim,Jungmo Kim,Hyun Goo Woo,Charlotte R Denman,Run-Run Han,Minju Kim,Dongju Jeon,Haerim Kim,Yeo Jin Kim,Ji Young Mun,Eun Jeong Lee,Sang Myun Park,Bernd Kuhn,Gordon W Arbuthnott,Junghyun Jo","doi":"10.1093/brain/awaf326","DOIUrl":"https://doi.org/10.1093/brain/awaf326","url":null,"abstract":"Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cells (hPSCs)-derived neural organoids have provided improved access to study PD etiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modeling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present and the neurons such as dopaminergic (DA) neurons and GABAergic neurons were electrophysiologically active in the hSMAs. hSMA development in the presence of increased α-syn from SNCA overexpression, induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to DA neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to pathological form in human patients, was accumulated in midbrain area of hSMAs. Treatment with protein aggregation inhibitor (Anle138b) and autophagy inducer (Rapamycin) reduced α-syn aggregation, indicating potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modeling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"71 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo self-assembled siRNAs ameliorate neurological pathology in TDP-43-associated neurodegenerative disease.","authors":"Jianhao Wu,Jingwei Guo,Jiaxi Wu,Junzhu Song,Jiawei Xu,Yingqi Lin,Chunhui Huang,Chunxiang Shi,Jiawei Li,Caijuan Li,Yizhi Chen,Wei Wang,Jiale Gao,Qin Zhou,Yuanpei Zhang,Shihua Li,Xiao-Jiang Li,Chen-Yu Zhang,Xi Chen,Sen Yan","doi":"10.1093/brain/awaf330","DOIUrl":"https://doi.org/10.1093/brain/awaf330","url":null,"abstract":"Abnormal accumulation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Small interfering RNAs (siRNAs) targeting TDP-43 offer potential therapeutic strategies for these diseases. However, efficient and safe delivery of siRNAs to the central nervous system (CNS) remains a critical challenge. Here, we present a synthetic biology-based approach that leverages endogenous small RNA processing machinery to self-assemble siRNA-encapsulating small extracellular vesicles (sEVs) and utilizes the host's natural circulatory system to transport siRNAs. Specifically, we engineered liver cells to express and package TDP-43-targeting siRNAs into rabies virus glycoprotein (RVG)-tagged sEVs, which are released into circulation and cross the blood-brain barrier to deliver siRNAs to the CNS. In a mouse model of TDP-43 pathology induced by stereotactic injection of mutant TDP-43 (M337V) virus, treatment with in vivo self-assembled TDP-43 siRNAs (IVSA-siR-TDP43) effectively reduced TDP-43 accumulation, leading to significant improvements in motor function and neuropathology. Additionally, an adeno-associated virus (AAV)-based delivery system was utilized to produce IVSA-siR-TDP43, demonstrating sustained therapeutic effects in TDP-43-associated neurodegeneration. These findings highlight a novel, effective, and minimally invasive gene therapy platform for addressing TDP-43 pathology in ALS and FTLD, offering a promising avenue for future clinical applications.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"31 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin intraneural phosphorylated α-synuclein is a highly specific biomarker for early Parkinson's disease.","authors":"Vincenzo Donadio,Alex Incensi,Giovanni Rizzo,Allessandro Furia,Salvatore Bonvenga,Enrica Olivola,Marco Piatti,Francesco Ventruto,Veria Vacchiano,Cecilia Delprete,Martin Ingelsson,Nicola Modugno,Ronald Postuma,Roberto Cilia,Rocco Liguori","doi":"10.1093/brain/awaf313","DOIUrl":"https://doi.org/10.1093/brain/awaf313","url":null,"abstract":"An early diagnosis of Parkinson's disease (PD) represents a challenge and novel accurate biomarkers are therefore urgently needed. Detection of phosphorylated α-synuclein (p-α-syn) in skin nerve fibers has shown promise as such a marker. However, its accuracy for the identification of PD among patients with early signs of parkinsonism has not been thoroughly explored. In this blinded, multicenter, prospective and follow-up study, 151 patients diagnosed with early-stage parkinsonism (<18 months duration) were enrolled at three tertiary movement disorders centers. Clinical scales were performed and initial diagnoses were reassessed at 18 and 46 months follow-up visits. Skin biopsy, with analysis for neuronal and glial p-α-syn deposits, and olfactory testing were performed at the baseline visit and repeated in 44 patients at the 18 months visit. After the follow-up period, a final diagnosis was reached in 140 patients: PD (n=101; 67% of all screened patients), tauopathies (n=22; 15%), multiple system atrophy (n=5; 3%), vascular parkinsonism (n=4; 3%), essential tremor (n=3; 2%), dystonic tremor (n=2; 1%) and no neurological illness (n=3, 2%). Eleven patients did not fit any clinical criteria and were therefore classified as undefined. Baseline skin intraneural p-α-syn showed a robust diagnostic accuracy (81% sensitivity and 100% specificity) for identifying PD. Importantly, in 30 out of 44 patients not diagnosed with PD until the follow-up intraneural p-α-syn was positive already at baseline. Moreover, the analyses showed a large degree of consistency over time, as the same results at baseline and follow-up were obtained in 42 (96%) of the tested patients. Finally, although olfactory testing at baseline showed a more abnormal score in PD compared to the other groups, its predictive accuracy was more modest (72%). In conclusion, given its high sensitivity, specificity and reproducibility, skin intraneural p-α-syn could become a valuable tool for diagnosing PD at early stages, potentially years before the diagnostic criteria are met, and for differentiating PD from atypical parkinsonism. In contrast, olfactory function, although more impaired in PD than in non-PD patients, only seems to have a more limited diagnostic accuracy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"15 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The postdoc paradox: a career without a path.","authors":"Jonathan Pansieri,Sandy Figiel,David Menassa,Vito A G Ricigliano,Meral Seferoglu,Serena Borrelli,Natalia Szejko,Sara Samadzadeh,Vinícius Boldrini,Luis Zarco,Edgar Patricio Correa-Díaz,Valeria Pozzilli,Silvia Marenna,Edgar Carnero Contentti,Emine Rabia Koc,Gloria Dalla Costa,Adriana Casallas-Vanegas,Christos Bakirtzis,Sanja Gluscevic,Abdulkadir Tunç,Enrique Gomez Figueroa","doi":"10.1093/brain/awaf314","DOIUrl":"https://doi.org/10.1093/brain/awaf314","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"43 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}