Annals of Neurology最新文献

{"title":"Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks.","authors":"Marta Milà-Alomà, Duygu Tosun, Suzanne E Schindler, Isabella Hausle, Kellen K Petersen, Yan Li, Jeffrey L Dage, Lei Du-Cuny, Ziad S Saad, Benjamin Saef, Gallen Triana-Baltzer, David L Raunig, Janaky Coomaraswamy, Michael Baratta, Emily A Meyers, Yulia Mordashova, Carrie E Rubel, Kyle Ferber, Hartmuth Kolb, Nicholas J Ashton, Henrik Zetterberg, Erin G Rosenbaugh, Martin Sabandal, Leslie M Shaw, Anthony W Bannon, William Z Potter","doi":"10.1002/ana.27285","DOIUrl":"10.1002/ana.27285","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to evaluate the timing of change of Alzheimer's disease (AD) plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP, and NfL) from six different assay platforms, alongside established AD biomarkers, using amyloid and tau positron emission tomography (PET)-based AD progression timelines.</p><p><strong>Methods: </strong>Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 784 individuals with longitudinal amyloid PET and 359 with longitudinal tau PET, were analyzed to estimate the age at amyloid and tau PET positivity, respectively. Longitudinal plasma biomarker measurements were available from 190 individuals with an estimated amyloid PET positivity age and from 70 individuals with an estimated tau PET positivity age. In a subset of 17 clinical progressors, age at tau PET positivity strongly predicted symptom onset, allowing for estimation of symptom onset age. Biomarker trajectories based on time from amyloid or tau PET positivity or symptom onset were modelled using Generalized Additive Mixed models. Time intervals of significant biomarker change and the earliest timepoints at which biomarkers exceeded predefined abnormality thresholds were identified.</p><p><strong>Results: </strong>All plasma biomarkers except NfL became abnormal prior to established thresholds for amyloid and tau PET positivity. Plasma Aβ42/Aβ40 became abnormal very early in both amyloid PET and tau PET timelines, while plasma GFAP became abnormal early in the tau PET timeline. Plasma Aβ42/Aβ40 levels plateaued, whereas plasma p-tau217, p-tau181, GFAP, and NfL levels increased throughout the modeled disease progression. Some variations in the timing of these changes were observed across different biomarker assays.</p><p><strong>Interpretation: </strong>These findings suggest that the plasma Aβ42/Aβ40 may be useful in identifying individuals with very low levels of amyloid pathology, whereas p-tau, GFAP, and NfL may be useful in staging disease progression. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332178","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":"Toward a Universal Map of EEG: A Semantic, Low-Dimensional Manifold for EEG Classification, Clustering, and Prognostication","authors":"Laura Krumm,&nbsp;Dominik D. Kranz,&nbsp;Mustafa Halimeh,&nbsp;Alexander Nelde,&nbsp;Edilberto Amorim,&nbsp;Sahar Zafar,&nbsp;Jin Jing,&nbsp;Robert J. Thomas,&nbsp;M. Brandon Westover,&nbsp;Christian Meisel","doi":"10.1002/ana.27260","DOIUrl":"10.1002/ana.27260","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Prognostication in patients with disorders of consciousness (DOCs) remains challenging because of heterogeneous etiologies, pathophysiologies and, consequently, highly variable electroencephalograms (EEGs). Here, we use EEG patterns that are well-characterizable to create a latent map that positions novel EEGs along a continuum. We asses this map as a generalizable tool to extract prognostically valuable information from long-term EEG, by predicting outcome post-cardiac arrest as a first use case.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Categorizable EEGs across the health-disease continuum (wake [W], sleep [rapid eye movement (REM), non-REM (N1, N2, N3)], ictal-interictal-continuum [lateralized and generalized periodic discharges (LPD, GPD) and lateralized and generalized rhythmic delta activity (LRDA, GRDA)], seizures [SZ], burst suppression [BS]; 20,043 patients, 288,986 EEG segments) are arranged meaningfully in a low-dimensional space via a deep neural network, resulting in a universal map of EEG (UM-EEG). We assess prognostication after cardiac arrest (576 patients, recovery or death) based on long-term EEGs represented as trajectories in this continuous embedding space.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Classification of out-of-sample EEG match state-of-the-art artificial intelligence algorithms while extending it to the currently largest set of classes across the health-disease continuum (mean area under the receiver-operating-characteristic curve [AUROCs] 1-vs-all classification: W, 0.94; REM, 0.92; N1, 0.85; N2, 0.91; N3, 0.98; GRDA, 0.97; LRDA, 0.97; SZ, 0.87; GPD, 0.99; LPD, 0.97; BS, 0.94). UM-EEG enables outcome prediction after cardiac arrest with an AUROC of 0.86 and identifies interpretable factors governing prognosis such as the distance to healthy states over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>UM-EEG presents a novel and physiologically meaningful representation to characterize brain states along the health-disease continuum. It offers new opportunities for personalized, long-term monitoring and prognostication. ANN NEUROL 2025;98:357–368</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 2","pages":"357-368"},"PeriodicalIF":8.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the Clinical Features that Associate with Progression, Causes, and Outcomes in Patients with Suspected Rapidly Progressive Dementia.","authors":"Yoav D Piura, Nihal Satyadev, Nick Corriveau-Lecavalier, Lindsey A Kuchenbecker, Lauren E Haydu, Michael D Geschwind, Philip W Tipton, Neill R Graff-Radford, Gregory S Day","doi":"10.1002/ana.27297","DOIUrl":"10.1002/ana.27297","url":null,"abstract":"<p><strong>Objective: </strong>To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD.</p><p><strong>Methods: </strong>Patients with suspected RPD were enrolled and followed at Mayo Clinic (Jacksonville, FL; January 2020 to October 2023) and Washington University (Saint Louis, MO; June 2016 to December 2019). Two dementia specialists independently reviewed clinical data and assigned diagnoses. Patients were diagnosed with RPD if they developed dementia within 1 year or incapacitation within 2 years of symptom onset. The associations between clinical features and causes and outcomes were explored via univariate and multivariate comparisons.</p><p><strong>Results: </strong>Of 248 patients with suspected RPD, 185 (74.6%) met criteria for RPD. Patients with RPD were older (62.6 ± 14.5 vs 55.2 ± 18.1 years; p < 0.001), and more frequently diagnosed with Alzheimer's disease or related dementias (OR 3.13, 95% CI 1.40, 7.31) or Creutzfeldt-Jakob disease (OR 4.67, 95% CI 1.38, 15.75). Visual agnosia (15/183; 8.2%), substantial brain atrophy (27/182; 14.8%), and periodic epileptiform discharges (11/151; 7.3%) were exclusively detected in patients with RPD. After controlling for age, intensive care unit admission (OR 4.77, 95% CI 1.61, 14.12), lack of seizures (OR 2.47, 95% CI 1.15, 5.31), abnormal brain magnetic resonance imaging (OR 2.01, 95% CI 0.997, 4.05), and cerebrospinal fluid white blood cell count ≤5 cells/mm³ (OR 3.30, 95% CI 1.60, 6.82) were also independently associated with RPD. Patients with RPD were more likely to die or develop severe dementia (mean time to outcome, 36.1 months; 95% CI 31.2-41.0).</p><p><strong>Interpretation: </strong>Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Brain Stimulation for VPS16-Related Dystonia: A Multicenter Study.","authors":"Tatiana Svorenova, Luigi M Romito, Ahmet Kaymak, Eoin Mulroy, Laura Cif, Elena Moro, Kirsten E Zeuner, Simone Zittel, Jan Niklas Petry-Schmelzer, Doreen Gruber, Liesanne Centen, Alberto Albanese, Miriama Ostrozovicova, Vladimir Han, Veronika Magocova, Kamil Knorovsky, Aurelia Kollova, Barbara Garavaglia, Nico Golfrè-Andreasi, Chiara Reale, Alberto Mazzoni, Giovanna Zorzi, Roberto Eleopra, Vincenzo Levi, Thomas Foltynie, Patricia Limousin, Harith Akram, Ludvic Zrinzo, Francesca Magrinelli, David Murphy, Henry Houlden, Manju A Kurian, Claudio Baiata, Steffen Paschen, Katja Lohmann, Jens Volkmann, Wolfgang Hamel, Michael T Barbe, Martje E van Egmond, Maj Tijssen, Lubos Ambro, Veronika Jurkova, Robert Jech, Petra Havrankova, Juliane Winkelmann, Michael Zech, Matej Skorvanek","doi":"10.1002/ana.27290","DOIUrl":"10.1002/ana.27290","url":null,"abstract":"<p><strong>Objective: </strong>The objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16-related dystonia.</p><p><strong>Methods: </strong>This observational study collected preoperative and postoperative demographic, clinical, stimulation, genetic, neuroimaging, and neurophysiological data of medically refractory DYT-VPS16 patients with implanted DBS in 10 international centers. Motor symptoms and disability outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale Motor (BFMDRS-M) and Disability (BFMDRS-D) scales. A cut-off threshold for considering response to DBS was set at 25% of BFMDRS-M improvement at the last follow-up (FU) compared to baseline.</p><p><strong>Results: </strong>The cohort consisted of 26 participants (17 men, 65.4%). Age at dystonia onset and surgery was 17.8 ± 10.9 and 35.3 ± 14.8 years, respectively. At the last FU, 102.5 ± 57.3 months (range, 2-216), the mean BFMDRS-M improvement was 41.6 ± 37.3% (26/26 patients) and 34.8 ± 42.6% for the BFMDRS-D (23/26 patients). Most patients (19/26, 73%) were considered responders. Higher motor improvement was associated with stimulation of the ventroposterior portion of the internal globus pallidus. A significant inverse relationship was observed between improvement in BFMDRS-M at last FU, and the presence of spasticity (p = 0.027) and fixed skeletal deformities (p = 0.001) before surgery. Non-responders had a younger age at disease onset and at implantation, shorter disease duration at DBS surgery, and higher baseline BFMDRS scores.</p><p><strong>Interpretation: </strong>DBS was an effective treatment for three-quarters of patients with pathogenic VPS16 variants in our cohort. Mean motor improvement was most pronounced at the 1-year FU, but persisted at the last FU despite disease progression. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332176","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":"AI in Neurology: Everything, Everywhere, All at Once Part 1: Principles and Practice","authors":"Matthew Rizzo MD,&nbsp;Jeffrey D. Dawson ScD","doi":"10.1002/ana.27225","DOIUrl":"10.1002/ana.27225","url":null,"abstract":"<p>Artificial intelligence (AI) is rapidly transforming healthcare, yet it often remains opaque to clinicians, scientists, and patients alike. This review, part 1 of a 3-part series, provides neurologists and neuroscientists with a foundational understanding of AI's key concepts, terminology, and applications. We begin by tracing AI's origins in mathematics, human logic, and brain-inspired neural networks to establish a context for its development. The review highlights AI's growing role in neurological diagnostics and treatment, emphasizing machine learning applications, such as computer vision, brain-machine interfaces, and precision care. By mapping the evolution of AI tools and linking them to neuroscience and human reasoning, we illustrate how AI is reshaping neurological practice and research. We end the review with an overview of model selection in AI and a case scenario illustrating how AI may drive precision neurological care. Part 1 sets the stage for part 2, which will focus on practical applications of AI in real-world scenarios where humans and AI collaborate as joint cognitive systems. Part 3 will examine AI's integration with extensive healthcare and neurology networks, innovative clinical trials, and massive datasets, expanding our vision of AI's global impact on neurology, healthcare systems, and society. ANN NEUROL 2025;98:211–230</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 2","pages":"211-230"},"PeriodicalIF":8.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous Thrombolysis Use before Inter-Facility Transfer for Thrombectomy: Association with Efficacy and Safety Outcomes.","authors":"Pierre Seners, Michael Mlynash, Adrien Ter Schiphorst, Anke Wouters, Nicole Yuen, Caroline Arquizan, Jeremy J Heit, Denis Sablot, Anne Wacongne, Thibault Lalu, Vincent Costalat, Gregory W Albers, Maarten G Lansberg","doi":"10.1002/ana.27303","DOIUrl":"https://doi.org/10.1002/ana.27303","url":null,"abstract":"<p><strong>Objective: </strong>Patients with acute ischemic stroke and large vessel occlusion (LVO) often require transfer from primary stroke centers (PSCs) to thrombectomy-capable centers. This study assessed the efficacy and safety of intravenous thrombolysis (IVT) initiated before inter-hospital transfer.</p><p><strong>Methods: </strong>Data from 2 prospective cohorts of patients with anterior circulation LVO transferred for thrombectomy from a PSC, regardless of whether thrombectomy was eventually attempted at the endovascular-capable center, were analyzed. Efficacy outcomes included good 3-month functional outcome (modified Rankin scale [mRS] = 0-2), excellent functional outcome (mRS = 0-1), and arterial recanalization during transfer. Safety outcomes included any intracerebral hemorrhage (ICH) and symptomatic ICH (sICH) at 24 hours. Propensity score with overlap weighting balanced the covariates between patients treated with IVT versus those without.</p><p><strong>Results: </strong>Of 521 patients, 260 (50%) received IVT before transfer. IVT was withheld mainly due to being outside the 4.5-hour window (58%) or anticoagulant use (21%). Median age was 72 years, 55% were men, and median baseline National Institutes of Health Stroke Scale (NIHSS) was 15. After propensity score with overlap weighting, patients receiving IVT more frequently had good functional outcome (odds ratio [OR] = 2.17, 95% confidence interval [CI] = 1.43-3.30, p < 0.01), excellent functional outcome (OR = 1.99, 95% CI = 1.21-3.25, p < 0.01), and inter-facility recanalization (OR = 5.64, 95% CI = 2.92-10.89, p < 0.01) compared with patients not treated with IVT. Any ICH (OR = 1.14, 95% CI = 0.76-1.70) and sICH (OR = 0.73, 95% CI = 0.36-1.51) rates were similar between groups.</p><p><strong>Interpretation: </strong>IVT before transfer was associated with improved recanalization and functional outcomes without increasing safety risks but is used in only 50% of patients. Expanding IVT criteria, including treatment beyond 4.5 hours and in anticoagulated patients, should be explored. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323950","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":"Pediatric RNS Lead Migration: Wandering Eyes or Electrode?","authors":"Charuta Joshi MBBS, MSCS,&nbsp;Daniel Veltkamp MD,&nbsp;Cathleen Dodez BBA,&nbsp;Aaron E. L. Warren PhD,&nbsp;Deepa Sirsi MD,&nbsp;Afsaneh Talai MD,&nbsp;Rana Said MD,&nbsp;Angela Price MD","doi":"10.1002/ana.27273","DOIUrl":"10.1002/ana.27273","url":null,"abstract":"&lt;p&gt;Neuromodulation with responsive neurostimulation (RNS, NeuroPace, Mountain View, CA) is increasingly being used off-label in pediatric drug-resistant epilepsy (pDRE).&lt;/p&gt;&lt;p&gt;A 7-year-old boy, with RNS depth electrodes targeting bilateral thalamic centromedian nucleus (CM); developed paroxysmal bilateral esotropia (left &gt; right) 52 weeks after initial implantation. Esotropia worsened over 3 weeks and was discovered to be caused by a ventrally migrated left CM electrode.&lt;/p&gt;&lt;p&gt;Bilateral CM implantation of narrowly spaced (3.5 mm) 13.6 mm RNS electrodes was achieved using direct magnetic resonance imaging (MRI) visualization and Robotic Surgical Assistant (ROSA) guidance after extensive presurgical evaluation. The RNS battery was housed over the right parietal region, with the left CM electrode inserted via a 2.5 mm left frontal burr hole. A lead protector sheath covered the electrode and was secured with a “dogbone” titanium cranial plate provided by NeuroPace. A 50% seizure reduction was achieved after 6 months, and stepwise charge density increases were well tolerated without adverse effects. At 40 weeks, the mother reported increased seizures and at 50 weeks, “tilting head to one side” and drifting of the left eye; which seemed to be “floating around.” This was initially attributed to a refractive error. At 52 weeks, the family reported an episode of eyes “going in all directions” and occasional loss of vision. Urgent head computed tomography (CT) was initially reported as unchanged. The patient displayed left head tilt and intermittent right head turn. Neurologic examination, notable for intermittent esotropia (left &gt; right; see Fig 1A) with normal mental status, pupillary response, and full eye excursions directed localization hypothesis to the midbrain. CT images were re-examined with co-registration to preoperative MRI and ROSA coordinates, confirming an 8 mm ventral and medial migration of the left CM electrode into the midbrain (see Fig 1A).&lt;/p&gt;&lt;p&gt;Comparison to anatomic atlases using Lead-DBS software,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; including previously published atlases of brainstem tractography&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; and histology&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; (see Fig 1B), revealed that the left CM tip had crossed the midline and was located within the medial longitudinal fasciculus (MLF), immediately adjacent to the oculomotor nucleus and approximately 3 mm anterior to the periaqueductal gray area.&lt;/p&gt;&lt;p&gt;Within a few minutes of disabling RNS stimulation, the eye movements normalized. During surgical admission for left CM electrode repositioning, the abnormal eye movements were reproduced (medial deviation L &gt; R, non-reproducible downward deviation without pupil changes) with stimulation of the 3 deepest left CM electrode contacts, but not with the remaining 4 right CM or the most superficial left CM contact. Intraoperative exposure revealed distal migration of the left CM electrode sheath protector from under the securing “dogbone","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 2","pages":"354-356"},"PeriodicalIF":8.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annals of Neurology: Volume 98, Number 1, July 2025","authors":"","doi":"10.1002/ana.26985","DOIUrl":"https://doi.org/10.1002/ana.26985","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26985","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal Fluid Metabolome in Central Nervous System Infections: A Study of Diagnostic Accuracy.","authors":"Steven L Staal, Sabine E Olie, Michel van Weeghel, Bauke V Schomakers, Frédéric M Vaz, Diederik van de Beek, Matthijs C Brouwer","doi":"10.1002/ana.27291","DOIUrl":"https://doi.org/10.1002/ana.27291","url":null,"abstract":"<p><strong>Objective: </strong>To assess the diagnostic accuracy of metabolites in cerebrospinal fluid (CSF) for central nervous system (CNS) infections.</p><p><strong>Methods: </strong>Patients were derived from three prospective cohort studies in the Netherlands. All studies included adults suspected of a CNS infection who underwent a diagnostic lumbar puncture. Metabolomics was performed on CSF using ultra-high-performance liquid chromatography with tandem mass spectrometry on a discovery and validation cohort. Metabolite quantification was the index test; a microbiologically confirmed diagnosis was the reference standard.</p><p><strong>Results: </strong>In total, 343 episodes were included, of whom 170 (50%) had a CNS infections and 173 (50%) episodes had other diagnoses. CNS infections included bacterial meningitis in 88 (26%), viral meningoencephalitis in 50 (15%), and other CNS infections in 32 (9%) episodes. Other diagnoses consisted of CNS autoimmune disorders in 21 (6%), other neurological diseases in 84 (24%), and systemic infections in 68 (20%) episodes. A distinct metabolomic profile was observed in CSF of CNS infections, particularly bacterial meningitis. Glucose, glycerate, 1.3-diphosphoglyceric acid, pyruvate, lactate, taurine, and alpha-ketoglutarate had the highest diagnostic accuracy (area under the curve 0.87 to 0.95). Combinations further improved diagnostic accuracy, resulting in models that outperformed both individual metabolites and CSF leukocytes. Episodes with CSF leukocytes between 5 and 1,000 cells per mm³ showed similar results.</p><p><strong>Interpretation: </strong>CSF metabolites demonstrate high diagnostic accuracy for CNS infections, particularly bacterial meningitis. Combinations further improve the diagnostic performance, exceeding that of CSF leukocytes alone. These findings highlight the potential of cerebrospinal fluid metabolites to improve diagnostic accuracy in clinical practice. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315649","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":"Blood α-Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies.","authors":"George T Kannarkat, Rebecca Zack, R Tyler Skrinak, James F Morley, Roseanne Davila-Rivera, Sanaz Arezoumandan, Katherine Dorfman, Kelvin Luk, David A Wolk, Daniel Weintraub, Thomas F Tropea, Edward B Lee, Sharon X Xie, Ganesh Chandrasekaran, Virginia M-Y Lee, David Irwin, Rizwan S Akhtar, Alice S Chen-Plotkin","doi":"10.1002/ana.27288","DOIUrl":"10.1002/ana.27288","url":null,"abstract":"<p><strong>Objective: </strong>Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBDs), including Parkinson's disease (PD), and dementia with Lewy bodies (DLB) disease. Although evidence exists for aSyn \"strains,\" conformations with distinct biological properties, biomarkers for PD versus DLB are lacking. Here, we used monoclonal antibodies selective for two different in vitro aSyn species - termed strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma.</p><p><strong>Methods: </strong>Using these antibodies, we characterized specific aSyn species in human specimens from neurologically normal individuals and individuals with LBD using enzyme-linked immunosorbent assay (ELISA), Western blot, and immunohistochemistry. We also characterized aSyn species immunoprecipitated from brain lysate or plasma with these antibodies using seed amplification assays (SAAs) and a cellular model.</p><p><strong>Results: </strong>Surprisingly, levels of strain A and B aSyn species were higher in plasma from individuals with PD compared to DLB in 2 independent cohorts. Lower levels of plasma aSyn strain A species predicted a faster rate of cognitive decline in individuals with PD. Furthermore, strain A and strain B aSyn species were undetectable in CSF, and their levels in brain versus plasma did not correlate. Moreover, plasma aSyn species isolated by aSyn strain antibodies could template aSyn fibrillization, and they could seed formation of aSyn inclusions in cells.</p><p><strong>Interpretation: </strong>Our findings suggest that circulating plasma aSyn strains may impact LBD clinical presentation, particularly cognition. The enrichment of these aSyn species in plasma but not CSF also suggests a potential source outside the brain. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}