Acta Neuropathologica最新文献

{"title":"Complementary use of the DNA methylation-based tumor classification by the Bethesda v3 classifier in routine diagnostics: evaluation in a series of 516 cases","authors":"Charlotte Brandenburg,&nbsp;Tatjana Starzetz,&nbsp;Niklas Woltering,&nbsp;Akash Kumar,&nbsp;Marco Münzberg,&nbsp;Katharina J. Wenger,&nbsp;Karl H. Plate,&nbsp;Omkar Singh,&nbsp;Kenneth D. Aldape,&nbsp;Leonille Schweizer","doi":"10.1007/s00401-026-03079-2","DOIUrl":"10.1007/s00401-026-03079-2","url":null,"abstract":"<div><p>DNA methylation-based tumor classification has become an essential tool in neuropathological diagnostics, yet a subset of central nervous system (CNS) tumors remains unclassifiable using current approaches. The performance of machine learning-based classifiers across varying case complexity is not fully defined. We evaluated the Bethesda Classifier v3 (Bv3) in both straightforward and diagnostically challenging CNS tumor specimens. We first applied Bv3 to 195 CNS tumor samples that were successfully classified using the Heidelberg Classifier v12.8 (Hv12.8; <i>n</i> = 195). We then compared Bv3 classifications in a retrospective cohort of diagnostically challenging, unclassifiable cases by Hv12.8 (<i>n</i> = 321). Both cohorts have been re-evaluated to identify the integrated histomolecular diagnoses according to the WHO CNS5 (2021) classification, hereafter referred to as the final WHO2021 diagnosis. Misclassification was defined as cases with Bv3 scores ≥ 0.9 that did not match the final WHO2021 diagnosis. In the straightforward cohort, Bv3 correctly classified 189/195 cases (97%). In the challenging cohort, Bv3 classified 180/321 previously unclassifiable cases (56%). 13/321 (4%) cases were misclassified by Bv3, of which 7/13 (54%) were labeled as ganglioglioma. Among glioblastomas, 79% were correctly identified, including tumors with lower DNA concentration and lower tumor purity. Bv3 assigned HGAP (High-Grade Astrocytoma with Piloid features) with a score ≥ 0.9 in three cases, which were not concordant with the final WHO2021 diagnosis. The Bethesda Classifier v3 demonstrates robust performance across both straightforward and diagnostically challenging CNS tumor specimens and represents a valuable complementary machine learning tool in routine neuropathological diagnostics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975259","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":"Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy","authors":"Philippe Codron,&nbsp;Marion Miranda,&nbsp;Maelle Garnier,&nbsp;Shiyang He,&nbsp;Julien Gouju,&nbsp;Julien Cassereau,&nbsp;Pascal Leblanc,&nbsp;Franck Letournel","doi":"10.1007/s00401-026-03086-3","DOIUrl":"10.1007/s00401-026-03086-3","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as <i>peripheral pathology.</i> The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03086-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975334","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":"A new era of genome-wide association studies in the field of Alzheimer’s disease and overlapping co-pathologies: lessons learned from a neuropathology-centered approach","authors":"Celeste Laureyssen,&nbsp;Dietmar Rudolf Thal,&nbsp;Kristel Sleegers","doi":"10.1007/s00401-026-03085-4","DOIUrl":"10.1007/s00401-026-03085-4","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) and overlapping pathologies represent a growing worldwide health concern. With the first disease-modifying treatments on the rise, it becomes increasingly important to move research in this area forward. Genetic research is excellent at discovering novel contributors to disease mechanisms, which has been demonstrated by the discovery of over 75 disease loci associated with AD. However, classical large-scale genome-wide association studies (GWAS) use cohorts of individuals that have been assigned a case or a control status based on a clinical diagnosis. For AD, this can result in bias due to the complex nature of the disease profile. More specifically, on the neuropathological level, AD is multifaceted with co-morbid pathological lesions being the norm rather than the exception. Together with the substantial preclinical phase, this can lead to the introduction of type I and type II errors. An alternative to using large-scale clinical cohorts is to shift toward studying individuals where the disease diagnosis has been neuropathologically confirmed, or cohorts where an endophenotype is used which can directly reflect ongoing pathological processes in vivo. Such endophenotypes could entail biofluid or imaging-based biomarkers, but the most undiluted signal is obtained when employing neuropathological data. These data typically represent the presence or absence of a lesion or reflects the semi-quantitative burden of pathological features. Here, we review what this shift toward more detailed phenotypes has already contributed to the field by investigating the genetic background of AD hallmark lesions as well as commonly observed co-pathologies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03085-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975274","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":"Concurrent substitutions H3 S28C or S31C/Y in H3 K27-altered diffuse midline gliomas may represent mutation bias, apart from being a source of potential diagnostic pitfall. Scientific commentary on: “H3K27ME3 loss in diffuse midline gliomas lacking H3K27M or EZHIP expressions, a potential diagnostic pitfall!”","authors":"Margarita Zaytseva,&nbsp;Ludmila Papusha,&nbsp;Alexander Druy","doi":"10.1007/s00401-026-03083-6","DOIUrl":"10.1007/s00401-026-03083-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923244","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":"Molecular programs in human locus coeruleus link APOE and neuromelanin to Alzheimer’s vulnerability","authors":"Bernard Mulvey,&nbsp;Heena R. Divecha,&nbsp;Madhavi Tippani,&nbsp;Svitlana V. Bach,&nbsp;Rahul Bharadwaj,&nbsp;Ishbel Del Rosario,&nbsp;Sarah E. Maguire,&nbsp;Ryan A. Miller,&nbsp;Aaron J. Salisbury,&nbsp;Atharv Chandra,&nbsp;Beau A. Oster,&nbsp;Kelsey D. Montgomery,&nbsp;Sang Ho Kwon,&nbsp;Haya A. Algrain,&nbsp;Alexis R. Papariello,&nbsp;Louise A. Huuki-Myers,&nbsp;Joel E. Kleinman,&nbsp;Leonardo Collado-Torres,&nbsp;Thomas M. Hyde,&nbsp;Shizhong Han,&nbsp;Stephanie C. Hicks,&nbsp;Daniel R. Weinberger,&nbsp;Stephanie C. Page,&nbsp;Kristen R. Maynard,&nbsp;Keri Martinowich","doi":"10.1007/s00401-026-03073-8","DOIUrl":"10.1007/s00401-026-03073-8","url":null,"abstract":"<div><p>The locus coeruleus (LC) is a small noradrenergic nucleus in the dorsal pons that sends widespread projections across the brain to regulate sleep, arousal, and cognition. LC neurons show early accumulation of phosphorylated tau (pTau) and are particularly vulnerable to degeneration in Alzheimer’s disease (AD). AD is also associated with loss of neuromelanin (NM) pigmentation in LC neurons, and NM-sensitive neuroimaging predicts clinical severity and future disease progression. To better understand molecular vulnerability of the LC, we generated spatially resolved transcriptomics data on LC tissue sections from 33 neurotypical middle-aged human brain donors, stratified by AD risk factors including sex, African or European ancestry, and <i>APOE</i> haplotype (E4 risk or E2 protective allele carriers). Comparing across <i>APOE</i> haplotypes, we identify reduced astrocytic gene expression proximal to LC neurons in E4 carriers, in addition to ancestry-specific differences in LC gene expression. Cell-resolution in situ sequencing further demonstrated that <i>APOE</i> differences in LC regional gene expression were partially driven by astrocytes, with more marked haplotype effects in donors of European ancestry. Quantifying gene expression as a factor of local NM content, we find that higher <i>APOE</i> gene expression correlates with reduced NM, and that NM-associated genes are enriched for aging-related pathways. Using the in situ data to analyze NM content in individual LC neurons validated NM associations with expression of <i>APOE</i>, norepinephrine metabolism genes, and genes involved in autophagy. Together, these data suggest that AD risk factors modulate LC vulnerability via molecular processes intrinsic to both noradrenergic neurons and local astrocytes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923243","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":"Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts","authors":"Sibylle de Bertier,&nbsp;Maria-Del-Mar Amador,&nbsp;Claire Guissart,&nbsp;Tomoko Miki,&nbsp;Séverine Boillée,&nbsp;Christian S. Lobsiger,&nbsp;Delphine Bohl,&nbsp;Anne-Laure Fauret-Amsellem,&nbsp;Adrien Bohic,&nbsp;Brainbank Neuro-CEB neuropathology network,&nbsp;Anna-Gaelle Giguet-Valard,&nbsp;Rémi Bellance,&nbsp;Katell Beauvais,&nbsp;Vincent Meininger,&nbsp;Gaelle Bruneteau,&nbsp;François Salachas,&nbsp;Christophe Vial,&nbsp;William Camu,&nbsp;Florence Esselin,&nbsp;Elisa de la Cruz,&nbsp;Emilien Bernard,&nbsp;Danielle Seilhean,&nbsp;Stéphanie Millecamps","doi":"10.1007/s00401-026-03075-6","DOIUrl":"10.1007/s00401-026-03075-6","url":null,"abstract":"<div><p><i>ARPP21</i> has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 <i>ARPP21</i>-linked patients. <i>ARPP21</i> emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support <i>ARPP21</i> as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating <i>ARPP21</i> into the routine genetic testing panels for fALS could improve diagnostic yield.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890459","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":"Oligodendroglial somatic SNCA copy number gains are associated with inclusions and disease onset in multiple system atrophy","authors":"Caoimhe Morley,&nbsp;Ester Kalef-Ezra,&nbsp;Diego Perez-Rodriguez,&nbsp;Zane Jaunmuktane,&nbsp;Christos Proukakis","doi":"10.1007/s00401-026-03077-4","DOIUrl":"10.1007/s00401-026-03077-4","url":null,"abstract":"<div><p>Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy of unknown aetiology with neuronal and oligodendroglial α-synuclein inclusions. We previously reported somatic copy number variants (CNVs), specifically gains of <i>SNCA</i> (encoding α-synuclein) in MSA brains. Here, we expand on this work by combining fluorescent in situ hybridisation for <i>SNCA</i> on nuclei with α-synuclein and SOX10 immunofluorescence, to assess oligodendrocyte-specific <i>SNCA</i> gains and losses, and their relationship with inclusions across differentially affected regions in two MSA subtypes: striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Analysis of 13 SND, 12 OPCA and 15 control brains demonstrated significantly higher somatic <i>SNCA</i> CNVs, both gains and losses, in MSA oligodendrocytes compared with controls (gains: 6.3% vs 2.0%; losses: 12.5% vs 7.4%,<i> p</i> &lt; 0.0001 for both). Oligodendrocyte <i>SNCA</i> gains were high in the preferentially affected regions (putamen in SND, cerebellum in OPCA), where they were associated with a twofold increased presence of α-synuclein inclusions in the same cell (<i>p</i> &lt; 0.0001). Higher gain burden correlated with earlier disease onset (rho = − 0.45,<i> p</i> = 0.03). Oligodendrocyte <i>SNCA</i> losses, conversely, showed less regional predilection, limited association with inclusions and no correlation with onset age. As double-strand DNA breaks have been reported in Lewy body diseases, we used immunofluorescence for γH2AX in a subset of experiments. The proportion of γH2AX-positive cells was significantly higher in MSA than controls overall (4.9% vs 2.5%, <i>p</i> = 0.01), in oligodendrocytes (9.7% vs 2.5%, <i>p</i> = 0.024) and in other cells (3.2% vs 1.1%; <i>p</i> = 0.048). The proportion of γH2AX-positive cells was also higher in preferentially affected regions (6.3% vs 3.5%, <i>p</i> = 0.004) and in inclusion-bearing cells (22.2% vs 14.9%,<i> p</i> = 0.02). These findings define the oligodendrocyte-specific patterns of somatic <i>SNCA</i> CNVs in MSA, support a role for gains in MSA pathogenesis and demonstrate the presence of <i>SNCA</i> losses and DNA double-strand breaks which require further investigation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890465","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":"Correction: Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation","authors":"Julia Konings,&nbsp;Fleur Mingneau,&nbsp;Serhii Chornyi,&nbsp;Cathrin E. Hansen,&nbsp;Rianne T. M. van der Burgt,&nbsp;Tessa G. van Elk,&nbsp;Laura Bolkaerts,&nbsp;Bo Batens,&nbsp;Gábor Tóth,&nbsp;Ingela Lanekoff,&nbsp;Frédéric M. Vaz,&nbsp;Alessio Cardilli,&nbsp;Marie Sels,&nbsp;Susanne M. A. van der Pol,&nbsp;Helga E. de Vries,&nbsp;Martin Giera,&nbsp;Oliver Werz,&nbsp;Sofie Kessels,&nbsp;Sanne G. S. Verberk,&nbsp;Jeroen F. J. Bogie,&nbsp;Merel Rijnsburger,&nbsp;Jerome J. A. Hendriks,&nbsp;Gijs Kooij","doi":"10.1007/s00401-026-03081-8","DOIUrl":"10.1007/s00401-026-03081-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890482","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":"Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden","authors":"Andrea Mastrangelo,&nbsp;Simone Baiardi,&nbsp;Edoardo Ruggeri,&nbsp;Giuseppe Mario Bentivenga,&nbsp;Claudia Marina Vargiu,&nbsp;Angela Mammana,&nbsp;Marco Sbriccoli,&nbsp;Barbara Polischi,&nbsp;Benedetta Carlà,&nbsp;Sabina Capellari,&nbsp;Piero Parchi","doi":"10.1007/s00401-026-03076-5","DOIUrl":"10.1007/s00401-026-03076-5","url":null,"abstract":"<div><p>Neuropathological validation studies of pathology-specific biomarkers for neurodegenerative diseases are essential but are often limited by long sampling-to-death intervals and the lack of semi-quantitative pathology measures. We assessed the associations of five cerebrospinal fluid (CSF) (Aβ₄₂/Aβ₄₀, p-tau₁₈₁, p-tau₂₁₇, Aβ₄₂/p-tau₁₈₁ and Aβ₄₂/p-tau₂₁₇) and three plasma (p-tau₂₁₇, p-tau₂₁₇/Aβ₄₂ and Aβ₄₂/Aβ₄₀) biomarkers with post-mortem Aβ and tau pathology burden in 250 participants with ante-mortem CSF (<i>n=</i>230) and/or plasma (<i>n=</i>101), affected by prion (<i>n=</i>162) or non-prion diseases (<i>n=</i>88). Aβ and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of Aβ and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5 months for CSF and 1 month for plasma. CSF Aβ₄₂/Aβ₄₀ decreased at the second quartile of Aβ burden (<i>p&lt;</i>0.001), whereas p-tau₁₈₁ (<i>p&lt;</i>0.01) and p-tau₂₁₇ (<i>p&lt;</i>0.001) increased only from the third quartile. CSF Aβ₄₂/Aβ₄₀ achieved its highest accuracy at low/intermediate Aβ burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau₂₁₇ and Aβ₄₂/p-tau₂₁₇ consistently showed higher accuracy than their p-tau₁₈₁ counterparts across Aβ and tau pathology scores. Plasma p-tau₂₁₇ and p-tau₂₁₇/Aβ₄₂ significantly increased in the highest Aβ and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer’s disease neuropathological continuum. CSF Aβ₄₂/Aβ₄₀ best reflects low/intermediate Aβ burden, while CSF p-tau markers are more closely related to high Aβ and intermediate tau load. Plasma markers primarily identify advanced Aβ and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of Aβ deposition.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885962","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":"Seeds from ALS patients homozygous for the SOD1 D90A mutation transmit two types of SOD1 aggregation and motor neuron disease","authors":"Caitlin Henne,&nbsp;Isabelle Sigfridsson,&nbsp;Thomas Brännström,&nbsp;Karin M. E. Forsberg,&nbsp;Stefan L. Marklund,&nbsp;Per Zetterström,&nbsp;Peter M. Andersen","doi":"10.1007/s00401-026-03078-3","DOIUrl":"10.1007/s00401-026-03078-3","url":null,"abstract":"<div><p>Mutations in superoxide dismutase−1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most prevalent mutation, D90A, disease primarily develops in homozygotes. Increasing evidence suggests that prion-like propagation of SOD1 aggregation is the central pathogenic mechanism. Two structurally different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic (Tg) mouse models of ALS. Strain A is formed by most mutants including hSOD1^G85R and homozygous hSOD1^WT Tg mice, whereas homozygous hSOD1^D90A Tg mice form a distinct strain B, but also A. Inoculation of strain A and B seed preparations from Tg mice into lumbar spinal cord of adult hSOD1^G85R mice induced templated spreading hSOD1 aggregation and premature ALS-like disease. Seeds from an ALS patient carrying the hSOD1^G127X truncation mutation likewise transmitted strain A aggregation and disease. In the present study, we investigated whether seeds prepared from spinal ventral horns from six patients homozygous for the hSOD1^D90A mutation could transmit aggregation and disease to adult hSOD1^G85R Tg mice. Despite the extensive degeneration and loss of motor neurons in the long-lived D90A patients, two of the seeds significantly shortened the survival of the Tg mice, one transmitting A and the other B-pattern hSOD1 aggregation. Nine different preparations from four human controls lacked effects. The results demonstrate that two distinct aggregate strains can arise and propagate in homozygous hSOD1^D90A ALS patients, further supporting the hypothesis that prion-like transmission of hSOD1 aggregation is the primary pathogenic mechanism in SOD1-linked ALS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13534153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863014","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}