Annals of Neurology最新文献

{"title":"Chronological Diagnostic Algorithm Predicting Neuropathology in Parkinsonism.","authors":"Daisuke Ono, Hiroaki Sekiya, Alexia R Maier, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson","doi":"10.1002/ana.78193","DOIUrl":"https://doi.org/10.1002/ana.78193","url":null,"abstract":"<p><strong>Objective: </strong>Pre-mortem diagnosis of parkinsonism is often challenging due to atypical presentations, overlapping syndromes, and co-pathologies. This study aimed to develop a machine learning-based algorithm predicting neuropathology in parkinsonism using chronological clinical presentations, which has previously been underexplored.</p><p><strong>Methods: </strong>Clinical information was automatically abstracted from medical records of the Mayo Clinic Brain Bank using fine-tuned Generative Pre-trained Transformer 4 models. Patients who developed parkinsonism within 3 years of disease onset were included. Six machine learning models were trained with age, sex, family history, and 197 clinical presentations paired with onset information to predict neuropathologic diagnoses, including co-pathologies.</p><p><strong>Results: </strong>Among 7,825 donors, 949 met inclusion criteria, representing 9 neuropathologic categories: Lewy body disease (LBD; n = 128), LBD with Alzheimer's disease (AD; n = 136), progressive supranuclear palsy (PSP; n = 303), PSP with AD (n = 56), PSP with LBD (n = 27), multiple system atrophy (MSA; n = 120), corticobasal degeneration (CBD; n = 99), AD (n = 43), and frontotemporal lobar degeneration (FTLD; n = 37). The CatBoost algorithm achieved an area under the receiver operating characteristic curve of 0.83 across the 9 diagnostic categories at 3 years after onset. Important predictors included age at onset, restricted eye movement, and tremor. The model remained robust to incomplete data, requiring only 23 of 200 parameters for reliable predictions with an area under the curve of 0.80. The algorithm was implemented into a user-friendly program providing diagnostic probabilities with visualizations of parameter contributions.</p><p><strong>Interpretation: </strong>This neuropathology-confirmed diagnostic algorithm provides a cost-effective and interpretable screening tool for parkinsonism, bridging biomarker testing and molecular-targeted therapies. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454891","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":"Astrocytic Mitochondria Transplantation Rescues Neuron Loss and Dendritic Injuries in Acute Cerebral Ischemic Stroke Mouse Model by Flexibly Regulating Mitochondria Dynamics.","authors":"Ning Bian, Jianing Shen, Linwei Tian, Jinghui Li, Lu Yang, Bo Yuan, Shulin Li, Yuyu Niu, Lu Zhao, Jingkuan Wei","doi":"10.1002/ana.78197","DOIUrl":"https://doi.org/10.1002/ana.78197","url":null,"abstract":"<p><strong>Objective: </strong>Cerebral ischemic stroke causes neuronal oxygen/energy deprivation, disrupting mitochondrial function including reduced membrane potential and bioenergetics, exacerbating neuronal injury. Mitochondrial defects are, therefore, a central neuropathological node and potential therapeutic target. Previous studies have shown that mitochondria transplantation rescued infarction in cerebral ischemic stroke. However, interactions between transplanted and endogenous mitochondria remain unclear. Here, we proposed astrocytic mitochondria as the optional donor for mitochondria transplantation in ischemic stroke treatment because of their ischemic resistance.</p><p><strong>Methods: </strong>We transplanted mitochondria derived from astrocytes into an ischemic stroke cell and mouse model to investigate the feasibility and mechanisms of astrocytic mitochondria transplantation for ischemic cerebral stroke. We assessed the uptake of transplanted mitochondria by neurons, their impact on endogenous mitochondrial dynamics (fusion/fission), mitochondrial functions, neuronal dendritic structure, neuronal survival, and mice motor function.</p><p><strong>Results: </strong>Transplanted astrocytic mitochondria were successfully taken up by neurons, and within neurons, they flexibly regulated endogenous mitochondrial dynamics. This intervention rescued the stroke-induced reduction in mitochondrial membrane potential and oxidative phosphorylation capacity. Consequently, it significantly decreased neuronal dendritic injuries and cell death. These cellular improvements translated into alleviated motor deficits in the stroke model.</p><p><strong>Interpretation: </strong>Astrocytic mitochondria transplantation is an effective therapeutic strategy for ischemic stroke. Its neuroprotective effects stem from the internalization of functional mitochondria into neurons and the subsequent flexibly regulation of endogenous mitochondrial dynamics, restoring bioenergetics and promoting neuronal survival. This approach holds significant promise for treating ischemic stroke and potentially other brain disorders involving mitochondrial dysfunction. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429525","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":"Predominance of Ferroptotic Cell Death Mechanisms in Substantia Nigra Neurodegeneration in Parkinson's Disease.","authors":"Yue Jing Heng, Anusha Jayaraman, Richard Reynolds, Jia Nee Foo","doi":"10.1002/ana.78202","DOIUrl":"https://doi.org/10.1002/ana.78202","url":null,"abstract":"<p><strong>Objective: </strong>The extent of neuronal loss in Parkinson's disease (PD) and the pathogenic processes underlying neuronal dysfunction and loss remain poorly understood. Here, we analyzed the expression of key molecules representing different cell death signaling pathways and their association with Lewy pathology, dopaminergic (DA) neuron loss and stage of PD progression in human postmortem brain tissue.</p><p><strong>Methods: </strong>We performed neuropathological and molecular analyses on 47 postmortem substantia nigra (SN) tissue samples from PD cases and healthy controls to investigate neuronal cell death pathways.</p><p><strong>Results: </strong>An average loss of 54% of dopaminergic neurons was found in the SN of PD cases, which correlated strongly with PD Braak staging. The apoptosis markers, cleaved subunits of caspases 3 and 8, were absent. Levels of the active necroptosis kinase, phosphorylated RIPK3 (pRIPK3), were significantly increased in advanced-stage PD. Although phosphorylated MLKL (pMLKL) levels were not significantly different, both active markers were detected in small numbers of PD neurons by immunofluorescence, suggesting focal necroptotic pathway activation. In contrast, evidence for ferroptosis was more pronounced, particularly in advanced-stage PD. This was supported by significantly increased transferrin receptor 1 (TFR1) protein levels and significantly decreased glutathione peroxidase 4 (GPX4) RNA and protein levels.</p><p><strong>Interpretation: </strong>Our findings implicate ferroptosis, and to a lesser extent necroptosis, in PD neuronal death, with ferroptosis potentially playing a larger role in advanced disease. We propose a \"2-hit\" model where early synucleinopathy-driven insults are amplified in advanced disease by a neuromelanin-iron-driven feedback loop, establishing ferroptosis as the predominant cell death mechanism. This stage-dependent shift provides critical insights into PD pathogenesis and suggests distinct therapeutic windows for neuroprotection. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388822","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 Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.","authors":"Magne Haugland Solheim, Trond Riise, Marianna Cortese, Ola Nakken, Ole-Bjørn Tysnes, Jannicke Igland, Kjetil Bjornevik","doi":"10.1002/ana.78191","DOIUrl":"https://doi.org/10.1002/ana.78191","url":null,"abstract":"<p><strong>Objective: </strong>The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.</p><p><strong>Methods: </strong>We conducted a nested case-control study using nationwide Norwegian registries (2005-2019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10 years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS based on drug prescription patterns.</p><p><strong>Results: </strong>We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3 years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5 years before diagnosis, respectively.</p><p><strong>Interpretation: </strong>Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429635","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":"Thalamic Stimulation Induced Changes in Network Connectivity and Excitability in Epilepsy","authors":"Nicholas M. Gregg MD,&nbsp;Gabriela Ojeda Valencia MS,&nbsp;Tereza Pridalova MS,&nbsp;Harvey Huang BAS,&nbsp;Vaclav Kremen PhD,&nbsp;Brian N. Lundstrom MD, PhD,&nbsp;Jamie J. Van Gompel MD,&nbsp;Kai J. Miller MD, PhD,&nbsp;Gregory A. Worrell MD, PhD,&nbsp;Dora Hermes PhD","doi":"10.1002/ana.78087","DOIUrl":"10.1002/ana.78087","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single-pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus-ventral anterior nucleus junction. DBS delivered for &gt;1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well-connected seizure networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large-scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748–760</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":"748-760"},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562026","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":"Additive Effects of White Matter Hyperintensity and APOE ε4 Status on Risk of Incident Dementia in Two Large Longitudinal Cohorts","authors":"Adam de Havenon MD, MS,&nbsp;Lauren Littig BA,&nbsp;Santiago Clocchiatti-Tuozzo MD, MHS,&nbsp;Ian P Johnson BA,&nbsp;Sofia Constantinescu BS,&nbsp;Cyprien A Rivier MD,&nbsp;Shufan Huo MD, PhD,&nbsp;William T Kimberly MD, PhD,&nbsp;Teresa Gomez-Isla MD,&nbsp;Yvonne Kim,&nbsp;Eric Stulberg MD,&nbsp;Eric E Smith MD,&nbsp;Jonathan Rosand MD,&nbsp;Guido Falcone MD,&nbsp;Kevin N Sheth MD,&nbsp;Adam M Brickman PhD","doi":"10.1002/ana.78103","DOIUrl":"10.1002/ana.78103","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate whether white matter hyperintensities (WMH) and apolipoprotein E (<i>APOE)</i> ε4 status have an additive or multiplicative effect on the risk of incident all-cause dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study and confirmed findings in the UK Biobank (UKB). The exposures were <i>APOE</i> ε4 status (0 vs. ≥1 allele) and WMH on magnetic resonance imaging (MRI). The primary outcome was incident all-cause dementia. After confirming an additive interaction, we created combined exposure groups: WMH−/ε4−, WMH+/ε4−, WMH−/ε4+, and WMH+/ε4+. Cox proportional hazards models were adjusted for age, sex, race, education, cognition (ARIC only), hypertension, diabetes, and prior stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In ARIC (n = 1,736, mean age 63, 58.8% female, 48.7% non-Hispanic White individuals, median follow-up 18.6 years), the dementia incidence rate was 10.4 (95% CI, 9.2–11.6) per 1,000 person-years. Compared to WMH−/ε4–, adjusted hazard ratios (HRs) for dementia were: WMH−<i>/</i>ε4+, 1.5 (95% CI, 1.1–2.1); WMH+/ε4–, 2.0 (95% CI, 1.4–2.7); and WMH+<i>/</i>ε4<i>+</i>, 3.2 (95% CI, 2.2–4.6). In UKB (n = 40,307, mean age 55, 52.7% female, 97.1% non-Hispanic White individuals, median follow-up 3.2 years), the dementia incidence rate was 0.42 (95% CI, 0.32–0.55) per 1,000 person-years. Adjusted HRs were: WMH−<i>/</i>ε4+, 2.3 (95% CI, 1.2–4.5); WMH+/ε4–, 2.1 (95% CI, 1.0–4.6); and WMH+<i>/</i>ε4<i>+</i>, 6.7 (95% CI, 3.2–13.9).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>WMH burden and <i>APOE</i> ε4 status additively increase dementia risk. These findings support the potential benefit of vascular risk management to reduce WMH and delay dementia onset, even among genetically at-risk individuals. ANN NEUROL 2026;99:656–667</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":"656-667"},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562033","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":"Before Symptoms Begin: Immune Activation in Preclinical ALS","authors":"Adriano Chiò MD, FAAN,&nbsp;Andrea Calvo MD, PhD, FAAN, FEAN","doi":"10.1002/ana.78174","DOIUrl":"10.1002/ana.78174","url":null,"abstract":"&lt;p&gt;For decades, amyotrophic lateral sclerosis (ALS) was conceptualized primarily as a cell-autonomous motor neuron disorder, with immune activation viewed as a secondary epiphenomenon. This framework has been fundamentally revised. Accumulating genetic, molecular, and clinical evidence now positions immune dysregulation, both central and peripheral, as a core determinant of disease vulnerability, progression, and outcome.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Within this evolving paradigm, chronic neuroinflammation has emerged as a central and biologically consequential mechanism in ALS and related neurodegenerative diseases.&lt;/p&gt;&lt;p&gt;Converging evidence has consolidated chronic neuroinflammation as a central and biologically consequential mechanism in neurodegenerative diseases, including ALS. In ALS, sustained activation of microglia and astrocytes generates a persistent inflammatory milieu marked by cytokine dysregulation, oxidative stress, and progressive motor neuron injury.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This glia-driven cascade provides a mechanistic bridge between aging, genetic susceptibility, and selective neuronal vulnerability, reinforcing the view that neuroinflammation is not a passive bystander but an active determinant of disease onset and progression.&lt;/p&gt;&lt;p&gt;Microglia are indispensable for central nervous system (CNS) homeostasis through immune surveillance, synaptic remodeling, and clearance of cellular debris. In ALS, however, prolonged microglial activation becomes maladaptive, fostering chronic neuroinflammation and accelerating neurodegeneration. The long-standing M1/M2 polarization framework is now widely recognized as an oversimplification. Contemporary transcriptomic and single-cell analyses instead reveal a continuum of microglial activation states that are dynamic, context-dependent, and temporally evolving.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In ALS, microglia frequently adopt disease-associated transcriptional programs characterized by suppression of homeostatic gene networks and upregulation of pathways governing phagocytosis, lipid metabolism, and innate immune signaling, consistent with a stage-dependent shift from compensatory neuroprotection to overt neurotoxicity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Beyond the CNS, peripheral immune mechanisms are increasingly acknowledged as integral components of ALS pathobiology. Perturbations across multiple immune compartments, including T lymphocytes, natural killer (NK) cells, monocytes/macrophages, neutrophils, mast cells, complement pathways, and humoral immunity, have been implicated in disease susceptibility and progression.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Nevertheless, a persistent conceptual challenge remains distinguishing primary immune drivers from secondary inflammatory responses to neurodegeneration.&lt;/p&gt;&lt;p&gt;Among adaptive immune pathways, regulatory T cells (Tregs) have emerged as particularly salient modulators of disease trajectory. Tregs preserve immune tolerance by restraining excessive inflammatory sig","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":"588-590"},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148577","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 99, Number 3, March 2026","authors":"","doi":"10.1002/ana.78188","DOIUrl":"https://doi.org/10.1002/ana.78188","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78188","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147562735","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":"Tenecteplase Versus Alteplase for First-Pass Reperfusion in Basilar Artery Occlusion Stroke Thrombectomy","authors":"Dylan N. Wolman MD,&nbsp;Rahul R. Karamchandani MD,&nbsp;Sina Hemmer MD,&nbsp;Tyler M. Bielinski MS,&nbsp;Nitin Goyal MD,&nbsp;Jeremy B. Rhoten BSN, MHA,&nbsp;Mahesh V. Jayaraman MD,&nbsp;Christian T. Sidebottom MD,&nbsp;Bradley A. Gross MD,&nbsp;Alhamza R. Al-Bayati MD,&nbsp;Mohamed F. Doheim MD,&nbsp;Matthew K. Tobin MD, PhD,&nbsp;Anoop Chinthala BS,&nbsp;Avi Gajjar BS,&nbsp;Justin Mascitelli MD,&nbsp;Matthew R. Webb MD,&nbsp;Jan-Karl Burkhardt MD,&nbsp;Kyle W. Scott MD,&nbsp;Visish Srinivasan MD,&nbsp;Daniel Tonetti MD,&nbsp;Manisha Koneru MD,&nbsp;David J. Altschul MD,&nbsp;Dhrumhil Vaishnav MBBS,&nbsp;Sumeet Multani MD,&nbsp;Thana Theofanis MD,&nbsp;William J. Ares MD,&nbsp;Je Yeong Sone MD,&nbsp;Ramin Zand MD,&nbsp;Sasan Bahrami MD,&nbsp;Jiang Li MD, PhD,&nbsp;Gary Defilipp MD,&nbsp;Dale Strong BS,&nbsp;Radmehr Torabi MD,&nbsp;Krisztina Moldovan MD,&nbsp;Clemens M. Schirmer MD, PhD,&nbsp;Alexandra R. Paul MD,&nbsp;Bradley N. Bohnstedt MD,&nbsp;Raul G. Nogueira MD,&nbsp;Philipp Hendrix MD, PhD","doi":"10.1002/ana.78102","DOIUrl":"10.1002/ana.78102","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The first-pass effect (FPE), defined as excellent reperfusion after a single attempt, is associated with improved outcomes in large vessel occlusion stroke. We evaluated whether intravenous tenecteplase (TNK) compared with alteplase (TPA) increases the likelihood of FPE in basilar artery occlusion (BAO).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 163 consecutive BAO patients treated with intravenous TNK or TPA within 4.5 h of last known well across 14 U.S. stroke systems (January 2020–August 2024). Patients with early reperfusion (<i>n</i> = 27) or aborted procedures (<i>n</i> = 3) were excluded. Multivariable ordinal and logistic regression identified predictors of FPE (expanded Thrombolysis in Cerebral Infarction [eTICI] 2c–3) and modified FPE (mFPE, eTICI 2b–3), and FPE/mFPE association with 90-day outcomes (modified Rankin Scale [mRS] 0–3).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FPE occurred in 55 of 133 patients (41.4%) and was more frequent with TNK than TPA (51.7% vs 32.9%, <i>p</i> = 0.029). TNK was independently associated with higher odds of FPE (adjusted odds ratio [aOR] 2.37, 95% confidence interval [CI] 1.13–4.98, <i>p</i> = 0.023) and mFPE (aOR 2.74, 95% CI 1.20–6.25, <i>p</i> = 0.017). Both FPE and mFPE were independently associated with ambulatory outcomes at 90-days (FPE: aOR 2.94, 95% CI 1.18–7.33, <i>p</i> = 0.021; mFPE: aOR 5.11, 95% CI 1.81–14.43, <i>p</i> = 0.002). TNK compared with TPA did not show an independent association with functional outcome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>In this multicenter BAO cohort, TNK increased the odds of achieving FPE compared with TPA. As FPE strongly predicted functional recovery, these findings suggest TNK may confer a reperfusion advantage with potential clinical benefit, although a direct outcome effect was not demonstrated. ANN NEUROL 2026;99:692–704</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":"692-704"},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601450","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":"The Epidemiology of Primary Lateral Sclerosis: Results from a Population-Based Cohort","authors":"Rosario Vasta,&nbsp;Enrico Matteoni,&nbsp;Giorgio Pellegrino,&nbsp;Antonio Canosa,&nbsp;Umberto Manera,&nbsp;Francesca Palumbo,&nbsp;Maurizio Grassano,&nbsp;Sara Cabras,&nbsp;Alessandra Maccabeo,&nbsp;Fabrizio D'Ovidio,&nbsp;Gabriele Mora,&nbsp;Salvatore Gallone,&nbsp;Elisa D'Angelo,&nbsp;Letizia Mazzini,&nbsp;Fabiola De Marchi,&nbsp;Cristina Moglia,&nbsp;Adriano Chiò,&nbsp;Andrea Calvo","doi":"10.1002/ana.78105","DOIUrl":"10.1002/ana.78105","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>In this population-based study, we described the epidemiology of primary lateral sclerosis (PLS) in northern Italy and compared the clinical characteristics of patients with PLS to those with predominant upper motor neuron (PUMN) involvement and classic amyotrophic lateral sclerosis (ALS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients from the PARALS registry diagnosed with probable or definite PLS between 2007 and 2021 were included. Crude annual incidence rates were calculated, along with age- and sex-specific rates. A survival analysis was performed to identify prognostic factors at diagnosis. Covariates included sex, age at onset, site of onset, diagnostic delay, forced vital capacity (FVC), change in ALS Functional Rating Scale (ΔFRS), and change in body mass index (ΔBMI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 57 PLS patients (2.7%) were included, with a crude incidence rate of 0.084 per 100,000 person-years. Compared to PUMN and classic ALS, PLS patients were younger (median onset age 63.5 years, interquartile range [IQR] 54.9–70.4) and predominantly female (male-to-female ratio 0.58). Bulbar onset occurred in 11 cases (19.3%), all of whom later developed spinal symptoms. At censoring, 38 patients (66.7%) were still alive (median survival 8.3 years, IQR 5.7–12.3), corresponding to a point prevalence of 0.89 per 100,000. Survival was significantly associated with age at onset (hazard ratio [HR] 1.17, 95% confidence interval [CI]: 1.05–1.33, <i>p</i> = 0.001), male sex (HR 4.41, 95% CI: 1.24–15.6, <i>p</i> = 0.02), and FVC at diagnosis (HR 0.95, 95% CI: 0.93–0.98, <i>p</i> = 0.006).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>PLS was confirmed to be rarer than other ALS phenotypes. Patients had a higher age at onset than previously reported and a female predominance. Sex, age at onset, and respiratory function were key prognostic factors. ANN NEUROL 2026;99:606–613</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 3","pages":"606-613"},"PeriodicalIF":7.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627116","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}