Brain Pathology最新文献

{"title":"A 67-year-old man with a spinal extramedullary mass.","authors":"Marcella Callea, Francesco Costa, Rosina Paterra, Valeria Barresi","doi":"10.1111/bpa.70105","DOIUrl":"https://doi.org/10.1111/bpa.70105","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70105"},"PeriodicalIF":6.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-derived surgical samples reveal the cellular and molecular signatures of glioblastoma infiltration in distinct radiological zones.","authors":"Olaya de Dios, Juan Romero, María de Los Ángeles Ramírez-González, Beatriz Herranz, Alicia Avis-Bodas, Juliana Manosalva, Diego Megías, Ana Ramos, Juan Manuel Sepúlveda-Sánchez, Ricardo Gargini, Berta Segura-Collar, Gabriel Velilla, Bárbara Meléndez, Pedro González, Luis Jiménez-Roldán, Guillermo García-Posadas, Aurelio Hernández-Laín, Ángel Pérez-Núñez, Pilar Sánchez-Gómez","doi":"10.1111/bpa.70106","DOIUrl":"https://doi.org/10.1111/bpa.70106","url":null,"abstract":"<p><p>Glioblastoma (GBM) is one of the deadliest cancers, largely due to its nearly inevitable recurrence driven by residual tumor cells. Recent evidence suggests that performing supratotal resections that extend into non-contrast-enhancing (nCE) tumor regions may prolong survival. However, tumor infiltration in these areas has not been fully characterized. Our goal was to define the cellular landscape of the GBM periphery and its clinical relevance. To accomplish this, we prospectively collected 161 biopsies from 45 GBM patients. The samples were classified using magnetic resonance imaging (MRI) as either enhancing tumor, nCE tumor, vasogenic edema, or radiologically normal tissue. We performed immunohistochemistry with MIB1 staining to detect proliferative cells and measure cell density. We also performed transcriptional profiling, selecting immune, glial, and vascular markers from single-cell RNA sequencing data. We analyzed the associations with the extent of resection and patient outcomes. Most nCE tumor biopsies displayed neoplastic features, including high cellularity, proliferative markers, and loss of oligodendrocyte signatures. However, some regions labeled as edema by MRI also contained infiltrating tumor cells and were associated with disease progression. Therefore, although MRI-based classification of nCE tumor regions is generally accurate, it underestimates infiltration within edema-labeled areas. Furthermore, in patients who underwent gross-total resection, high peripheral cellularity predicted earlier local recurrence. This suggests that assessing cell density in the periphery can improve recurrence risk prediction. Regarding the tumor microenvironment analysis, immune-related phenotypes were associated with a worse prognosis only after complete resection of the enhancing tumor. Furthermore, our gene panel, particularly the oligodendrocyte markers, provides prognostic insights depending on both biopsy location and resection extent. These findings support the integration of histological and molecular evaluations of the tumor periphery into surgical and therapeutic decision-making processes. This approach offers a path to better patient stratification and outcome prediction in GBM.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70106"},"PeriodicalIF":6.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain viral reservoir seeding and neurological metabolic dysregulation in early-life immunodeficiency virus infection.","authors":"Li Ma, Robert Blair, Yao-Zhong Liu, Xiaolei Wang, Eunice Vincent, Christopher Yu, Lara A Doyle-Meyers, Cissy Zhang, Ahmad Saied, Anne Le, Ronald S Veazey, Qigui Yu, Huanbin Xu","doi":"10.1111/bpa.70104","DOIUrl":"10.1111/bpa.70104","url":null,"abstract":"<p><p>While viral reservoirs establish rapidly in the peripheral and lymphoid tissues in HIV-exposed and infected infants, the timing and consequences of viral seeding in the developing brain remain unclear. Using a neonatal rhesus macaque SIV model, we tracked early brain-associated viral DNA/RNA, neuropathology, and cerebrospinal fluid (CSF) metabolism, and evaluated the impact of early antiretroviral therapy (ART). CSF viral RNA was detectable by 2 days post infection (dpi), mirroring plasma viral load kinetics. In contrast, brain tissue SIV DNA and RNA remained largely undetectable through the first 3 days of infection. Despite this early viral dissemination, we observed no significant neuropathological lesions or CSF proinflammatory cytokine responses during the first week. However, marked CSF metabolic dysregulation emerged by 1 month post infection. Initiating ART early, specifically at 3 dpi, normalized these neurometabolic abnormalities. These findings demonstrate that CSF metabolomic shifts can occur independently of overt neuroinflammation during the early stages of viral seeding. These results support initiating ART as early as possible after perinatal HIV exposure to prevent the brain viral reservoir seeding and limit long-term neurological sequelae.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70104"},"PeriodicalIF":6.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147762929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven thresholds for standardized classification of severe Alzheimer's disease neuropathology using digital neuropathology.","authors":"Ryan K Shahidehpour, Allison M Neltner, Mitchell A Klusty, Cole Corbett, Angelique D Gonzalez, David A Gutman, David W Fardo, Adam D Bachstetter, Cody Bumgardner, Margaret E Flanagan, Peter T Nelson","doi":"10.1111/bpa.70102","DOIUrl":"https://doi.org/10.1111/bpa.70102","url":null,"abstract":"<p><p>Alzheimer's disease neuropathological changes (ADNC)-operationalized with semi-quantitative parameters-represent the consensus-based gold standard for diagnostic evaluation of disease severity. Although useful, ADNC diagnostic frameworks have limitations, particularly in advanced disease stages where pathological severity varies widely within a given diagnostic category. Further, some individuals lacking cognitive impairment are inappropriately categorized as having severe ADNC. In this study, quantitative pathology metrics and alternative tissue sampling schemes were integrated with data about premortem cognitive status, in order to derive clinically informed neuropathologic diagnostic thresholds. Specific goals of the current study were to generate data-driven, standardized diagnostic cut-points, with the most severe stages of ADNC having consistent implications: Braak neurofibrillary tangle (NFT) stage V cases being always impaired (MCI or demented) and Braak NFT stage VI cases being always demented. Utilizing whole-slide imaging and AI-based image analysis, object-based (NFT counts) and pixel-based (phosphorylated tau [pTau] burden) quantifications were compared across neocortical regions in three subsamples of cases from the University of Kentucky ADRC autopsy cohort (n = 329, all with clinical evaluations within 2 years of death). We also compared between HALO- and Aperio-based platform results, and between AT8 and PHF-1 pTau antibodies. Applying refined thresholds enabled reclassification of cases previously misaligned with their digitally determined appropriate status: 17% of cases were thus reclassified. The use of commercially available software, standardized classifier architectures, and interoperable analysis pipelines facilitated scalable and reproducible digital quantification. Cross-institutional validation at University of Texas San Antonio, with the same algorithms applied in both research centers, confirmed near-perfect agreement of pathology counts, underscoring shareability and the feasibility of harmonized digital workflows for collaborative research and diagnostic purposes. These findings support the integration of quantitative digital pathology into standard neuropathological protocols and provide a scalable model for future multi-site studies. Enabling comparisons of analytical platforms, pTau antibodies, and anatomical sampling strategies, an updated workflow demonstrated high reproducibility and consistent clinical-pathological correlations.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70102"},"PeriodicalIF":6.2,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147762952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human brain matters: Navigating the neuropathology of COVID-19.","authors":"Juliana M Nieuwland, Angelica Scaramuzza, Marianna Bugiani, Wilma D J van de Berg, Jinte Middeldorp","doi":"10.1111/bpa.70101","DOIUrl":"https://doi.org/10.1111/bpa.70101","url":null,"abstract":"<p><p>Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide. Although the incidence of severe acute cases has declined, the prevalence of long COVID, also known as post-acute sequelae of COVID-19 (PASC), is rising. The pathological mechanisms underlying severe COVID-19, along with the relationship to neurological disorders and potential risk for neurodegeneration, remain poorly understood. The aim of this narrative review is to summarize neuropathological features described in postmortem human COVID-19 brains (n = 352). Furthermore, analysis of biofluids and neuroimaging from PASC patients underline long-term changes in the proteome and CNS response following the infection. Postmortem brain studies from severe COVID-19 patients highlight disruption of the fluid-brain barriers and vascular dysregulation defined by endothelial inflammation and disruption, hemorrhages, and hypoxic-ischemic damage. Neuroinflammation, including astrogliosis, microglia nodules and infiltration of adaptive immune cells, has been reported in the olfactory bulb, medulla oblongata, midbrain and cerebellum. Neuronal damage was demonstrated in the hippocampus, midbrain and cerebellum in severe COVID-19 and protein aggregation was observed in the midbrain and entorhinal cortex. Neuropathological burden and elevated blood and/or cerebrospinal fluid (CSF) levels of proinflammatory cytokines (e.g. IL-6) and neuro-axonal proteins (e.g. NfL) correlated with severity of anosmia, memory deficits, and cerebellar ataxia. Elderly patients and/or patients with underlying neurological diseases were more susceptible and had worsened symptoms. Potential disease mechanisms underlying neurological symptoms observed in severe COVID-19 are vascular and fluid-brain barrier abnormalities, chronic neuroinflammation, persistent axonal damage and protein aggregation. In PASC patients, an altered biofluid proteome with increased neuronal proteins and pro-inflammatory cytokines was observed. The pathological burden in affected brain regions may contribute to manifestations such as anosmia, memory deficits, and cerebellar ataxia.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70101"},"PeriodicalIF":6.2,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147762993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New perspectives on VEGF signalling in Alzheimer's disease.","authors":"Cherelle E G Emery, Seth Love, J Scott Miners","doi":"10.1111/bpa.70100","DOIUrl":"https://doi.org/10.1111/bpa.70100","url":null,"abstract":"<p><p>Vascular endothelial growth factor (VEGF) signalling mediates pleiotropic effects within the brain, encompassing angiogenesis, neuronal survival, and immune signalling. There is growing interest in the role of VEGF signalling in the pathophysiology of Alzheimer's disease (AD). The generation of single-cell brain atlases and recent large multi-omic studies, including analysis of CSF and bloods alongside post-mortem brain tissue, have provided novel insights into the role of VEGF signalling in AD. Disruption of the VEGF-A/VEGFR2 signalling pathway, due in part to elevated soluble VEGFR1 expression may contribute to pathogenic angiogenesis, BBB leakiness, and neuronal loss in AD. Induction of VEGF-B/VEGFR1 signalling in microglia suggests that dysregulated VEGF-mediated immune cell signalling is a further influence on AD pathogenesis. A reduction in expression of the 'protective' VEGFR3 and co-receptors neuropilin 1 and 2 has also been recently linked to cognitive decline in AD. In large clinical studies, lower VEGF-A levels in CSF and serum, raised soluble VEGFR1in CSF and elevated PlGF in CSF and serum, are predictive of more rapid cognitive decline and accelerated Alzheimer's disease neuropathological change (ADNC). This review discusses findings from recent multi-omic studies of large clinical and neuropathological studies that prompt reconsideration of the nature of VEGF signalling in AD and shed light on some of the complexities and previous conflicts within the field.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70100"},"PeriodicalIF":6.2,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between TMEM106B C-terminal fragment aggregation, age, and TDP-43 or tau pathology.","authors":"Albert Acewicz, Sylwia Tarka, Michał Grzegorczyk, Radosław Rzepliński, Teresa Wierzba-Bobrowicz, Tomasz Stępień","doi":"10.1111/bpa.70090","DOIUrl":"https://doi.org/10.1111/bpa.70090","url":null,"abstract":"<p><p>Transmembrane protein 106B (TMEM106B) is a lysosomal glycoprotein whose genetic polymorphisms contribute to the severity of neurodegenerative disorders associated with TDP-43 pathology. Recent studies have revealed that TMEM106B can form amyloid filaments composed of C-terminal fragments (CTFs) in the human brain. In the present study, we explored the relationships between TMEM106B, age, TDP-43, and tau aggregates, and their roles in neurodegeneration. We used immunohistochemistry with an antibody against CTFs of TMEM106B on postmortem human brain fragments (amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia) from patients with and without TDP-43/tau pathology at different ages (6-94 years) and with different neurological conditions (subacute sclerosing panencephalitis, Alzheimer's disease, frontotemporal lobar degeneration, and neurologically healthy subjects). Our results revealed that TMEM106B CTF fibrillization is a common, nonspecific, diffuse, and age-dependent phenomenon (appearing after >52 years of age) that affects neurons and neuroglia (most numerous in astrocytes and oligodendrocytes) and broad neuroanatomical regions (most severe in the temporal cortex). We did not find TMEM106B CTF aggregates in young subjects with TDP-43/tau pathology (with subacute sclerosing panencephalitis), but we revealed differences in TMEM106B CTF fibrillization between Alzheimer's disease without TDP-43 pathology, frontotemporal lobar degeneration with TDP-43 pathology, and older healthy subjects without TDP-43/tau pathology. Our results suggest that TMEM106B CTF aggregation is an age-dependent phenomenon and may have a weak association with TDP-43 or tau pathology, shedding new light on the complex relationships among TMEM106B, TDP-43, and tau and the unclear role of TMEM106B fibril formation in the neurodegeneration process.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70090"},"PeriodicalIF":6.2,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RE: Comments on cIMPACT-NOW Update 11","authors":"Henning Leske,&nbsp;Richard Doughty,&nbsp;Pitt Niehusmann","doi":"10.1111/bpa.70061","DOIUrl":"10.1111/bpa.70061","url":null,"abstract":"&lt;p&gt;We read with great interest cIMPACT-NOW Update 11, in which the consortium provides diagnostic recommendations for glioblastoma, IDH-wildtype (GBM); diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (pHGG); and posterior fossa ependymal tumors. The authors are to be commended for addressing unresolved challenges identified since the release of the 5th edition of the WHO Classification of Tumours of the Central Nervous System (WHO CNS5, 2021). While the update offers valuable guidance, we would like to comment on several aspects that would benefit from clarification, closer alignment with WHO CNS5, and refined wording to avoid diagnostic ambiguity in routine practice.&lt;/p&gt;&lt;p&gt;WHO CNS5 specifies an age of “≥55 years” in the absence of &lt;i&gt;IDH1&lt;/i&gt; p.R132H immunoreactivity, classic GBM histology, non-midline location, and no history of a pre-existing lower-grade glioma as sufficient for a GBM diagnosis. The repeated use of “&gt;55 years” in Update 11—implying a shift from ≥55 to ≥56 years—appears to be a typographical inconsistency, which should be confirmed by the authors [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;WHO CNS5 also recommends that ATRX-negative tumors should undergo additional molecular testing to exclude &lt;i&gt;IDH1&lt;/i&gt;/&lt;i&gt;2&lt;/i&gt; and/or H3 alterations, regardless of age. Update 11 highlights H3 p.K28me3 immunostaining as a practical method to exclude diffuse midline glioma, H3 K27-altered (DMG)—useful not only for H3 p.K28M-mutant cases, as mentioned by the authors, but also for those driven by &lt;i&gt;EZHIP&lt;/i&gt; overexpression or &lt;i&gt;EGFR&lt;/i&gt; sequence alterations, as retained nuclear expression virtually excludes DMG.&lt;/p&gt;&lt;p&gt;The committee's recommendation that &lt;i&gt;TERT&lt;/i&gt;-promoter mutations in IDH-wildtype astrocytic gliomas with low-grade histology should not, in isolation, define GBM is prudent to prevent overtreatment in a subset of cases, particularly given recently characterized tumors such as adult-type diffuse high-grade glioma, IDH-wildtype, subtype F (HGG-F) with less aggressive clinical behavior. However, the suggestion that some tumors with “higher-grade features that do not meet histologic criteria for glioblastoma” be diagnosed descriptively (not elsewhere classified, NEC) introduces ambiguity. It remains unclear whether such cases with absence of necrosis and vascular proliferation—despite high mitotic activity and isolated &lt;i&gt;TERT&lt;/i&gt;-promoter mutation—do not justify a GBM diagnosis.&lt;/p&gt;&lt;p&gt;The statement that isolated &lt;i&gt;EGFR&lt;/i&gt; amplification or +7/−10 signature alone is not sufficient for a GBM diagnosis in patients &lt;40 years is reasonable, but somewhat rigid. It should be stressed that these are expert recommendations intended to guide pathological practice. However, since the authors also note that diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (pHGG) as one of the major differential diagnoses can occur “in adults up to 70 years of age,” this rule of thumb may be adapted to local resources and shou","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 3","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to comments on cIMPACT-NOW update 11","authors":"Pieter Wesseling,&nbsp;David N. Louis","doi":"10.1111/bpa.70047","DOIUrl":"10.1111/bpa.70047","url":null,"abstract":"<p>The associated commentary acknowledges that cIMPACT-NOW update 11 addresses areas of significant diagnostic uncertainty and that it provides important interim guidance for CNS tumor classification. The commentary also provides a set of comments and suggestions. In this context, it is important to understand that cIMPACT-NOW update 11 (like all cIMPACT-NOW updates) presents consensus recommendations from multiple experts in the field, with the opinions often following lengthy discussions and the weighing of different possibilities. These debates included whether other recommendations should be provided on particular topics; however, for the paper, the consensus opinions were part of cIMPACT-NOW update 11, but topics that did not yield consensus decisions were not included. Some of these latter, open-ended issues were brought up in the associated commentary. We trust that deliberations for the 6th edition of the WHO Classification of CNS Tumors, which begin in late 2025, will discuss some of these topics again, and the associated commentary provides another set of comments to inform such discussions.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 3","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13051917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's disease and mixed pathologies as a hidden contributor to fatal hypothermia: A large-scale forensic autopsy-based study","authors":"Shojiro Ichimata,&nbsp;Koji Yoshida,&nbsp;Ryo Tanaka","doi":"10.1111/bpa.70051","DOIUrl":"10.1111/bpa.70051","url":null,"abstract":"<p>There is a paucity of autopsy-based studies providing detailed neuropathological characteristics of fatal hypothermia cases, particularly in trauma-associated cases. Hence, this study investigated 2054 serial autopsy cases in which histopathological examination of all organs, including the brain, could be performed. We identified 168 cases (75 female and 93 male patients) of fatal hypothermia and examined the clinical and neuropathological characteristics in these cases. Patients aged ≥65 years constituted 80% of the cohort (135 cases). Cognitive impairment (CI) was identified in 39% of cases with available clinical histories, and approximately half of these cases were presumed to have developed hypothermia while wandering, based on clinical history and the circumstances of discovery. Alzheimer's disease was the most commonly identified pathology, affecting 40% of the total and approximately two-thirds of patients aged ≥80 years. CI caused by multiple pathologies, especially two, was more frequently observed than by a single pathology. The most common manner of exposure to cold temperatures was accidents (120 cases), including 35 cases with multiple traumatic injuries, most likely resulting from falls. In these cases, the trauma was considered the primary cause of immobility, leading to subsequent exposure to cold environments. Importantly, 30 (86%) of these trauma-associated cases showed one or more neuropathological conditions, and CI was documented in 13, with four presumed to have fallen while wandering. Notable neuropathological manifestations were also observed in eight of the 33 cases of patients aged less than 65 years. Our results demonstrate that neurodegenerative diseases, especially Alzheimer's disease, are underlying conditions in fatal hypothermia in the elderly and in relatively younger individuals, suggesting that they may contribute to its onset. These findings highlight the necessity for comprehensive neuropathological examination in all forensic autopsy cases of hypothermia.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 3","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145629935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}