Acta Neuropathologica最新文献

{"title":"Correlative ultrastructural mapping of Lewy pathology reveals regional diversity in Parkinson’s and dementia with Lewy bodies","authors":"Notash Shafiei,&nbsp;Daria Proniakova,&nbsp;Marija Simjanoska,&nbsp;Anniken Mathea Rafnum Sjødal,&nbsp;Daniel Stähli,&nbsp;Lukas van den Heuvel,&nbsp;Marta Di Fabrizio,&nbsp;Eve Aaron,&nbsp;Sandor Kasas,&nbsp;Mathis Solal Krause,&nbsp;Mallory Wittwer,&nbsp;Julika Radecke,&nbsp;Henning Stahlberg,&nbsp;Wilma D. J. van de Berg,&nbsp;Amanda J. Lewis","doi":"10.1007/s00401-026-03039-w","DOIUrl":"10.1007/s00401-026-03039-w","url":null,"abstract":"<div><p>Lewy body diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are defined by neuronal accumulation of misfolded α-synuclein (α-Syn), yet the ultrastructural diversity of these inclusions across brain regions and disease contexts remains unclear. Here, we applied large-scale correlative light and electron microscopy (CLEM) to map α-Syn pathology across cortical regions (entorhinal cortex, ENT; anterior cingulate cortex, AC; hippocampal CA2 region) and substantia nigra (SN) in clinically and pathologically confirmed PD and DLB donors. We identified pronounced regional heterogeneity in Lewy pathology, with cortical inclusions showing diverse maturation stages at the ultrastructural level, ranging from low-density fibrils interspersed with organelles to highly compact fibrillar inclusions. In the SN of DLB donors, we observed the full range of classical nigral LB morphologies previously described in PD. We additionally characterized diverse neuritic α-Syn pathologies in DLB and identified a distinct population of electron-dense, degenerating, α-Syn-positive cortical neurons not previously reported. Importantly, we found no significant difference in LB ultrastructure between PD and DLB in either cortical or nigral pathology. In contrast, quantitative analysis of &gt; 10,000 mitochondria revealed disease- and region-specific signatures of altered mitochondrial homeostasis. PD showed increased mitochondrial density and enlargement in the SN, whereas DLB showed increased mitochondrial density only in the ENT. Mitochondrial enlargement was exclusive to PD. These findings indicate that LB ultrastructure alone does not distinguish PD from DLB; instead, region-specific mitochondrial phenotypes may better reflect disease identity and regional susceptibility. Overall, we provide a high-resolution framework for human Lewy pathology in PD and DLB, revealing that ultrastructural responses to α-Syn pathology are driven primarily by neuronal identity and regional vulnerability. Our results highlight the need for disease- and region-specific models that capture human phenotypes to advance mechanistic understanding and therapeutic targeting of synucleinopathies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03039-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410023","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 Pick fold in tau filaments from human MAPT mutants","authors":"Chao Qi,&nbsp;Sofia Lövestam,&nbsp;Jenny Shi,&nbsp;Alexey G. Murzin,&nbsp;Sew Peak-Chew,&nbsp;Thomas T. Warner,&nbsp;Harro Seelaar,&nbsp;Patrick W. Cullinane,&nbsp;Zane Jaunmuktane,&nbsp;John C. van Swieten,&nbsp;Sjors H. W. Scheres,&nbsp;Michel Goedert","doi":"10.1007/s00401-026-03049-8","DOIUrl":"10.1007/s00401-026-03049-8","url":null,"abstract":"<div><p>Mutations in <i>MAPT</i>, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Pick’s disease and filaments made of three-repeat tau in nerve cells. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from the brains of individuals with <i>MAPT</i> mutations D252V, G272V, S320F and ΔG389-I392. The two-layered Pick fold was present in the brains of individuals with mutations D252V and ΔG389-I392 who had also abundant tau inclusions in glial cells. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272–341 rotated by 20–25° with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V and S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03049-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409950","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":"CTE-type tau filaments in Alzheimer’s disease with co-morbid LATE-NC","authors":"Jaimin K. Rana,&nbsp;Emile S. Pinarbasi,&nbsp;Martin G. Fernandez,&nbsp;Vikas Navratna,&nbsp;Kyle S. Conway,&nbsp;Andrew P. Lieberman,&nbsp;Sami J. Barmada,&nbsp;Shyamal Mosalaganti","doi":"10.1007/s00401-026-03052-z","DOIUrl":"10.1007/s00401-026-03052-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03052-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395478","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":"Annexin A11 and TDP-43: core players in neurodegeneration","authors":"Courtney L. Smith,&nbsp;John L. Robinson,&nbsp;Edward B. Lee","doi":"10.1007/s00401-026-03043-0","DOIUrl":"10.1007/s00401-026-03043-0","url":null,"abstract":"<div><p>Annexin A11 (ANXA11) is a Ca²⁺-dependent phospholipid-binding protein that has recently emerged as a key player in neurodegeneration. Rare pathogenic <i>ANXA11</i> variants were initially identified in cases of amyotrophic lateral sclerosis (ALS). Since then, ANXA11 has been linked to a broader spectrum of related neurodegenerative diseases. Two independent studies demonstrated that ANXA11 co-aggregates with TDP-43 in all cases of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C, with cryo-EM revealing heteromeric ANXA11–TDP-43 filaments. These discoveries support the direct pathological interaction between the two proteins as an important feature of FTLD-TDP type C. We also described secondary ANXA11 pathology in related neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE), and more rarely in ALS and FTLD-TDP types A and B. ANXA11 and TDP-43 co-aggregates are also a feature of a FTLD-TDP associated with primary lateral sclerosis. These advances have renewed interest in ANXA11 as a major player in ALS/FTLD pathogenesis in both genetic and sporadic neurodegenerative diseases. In this review, we summarize ANXA11 pathology across genetic and sporadic cases, highlighting its heterogeneous overlap with TDP-43 pathology. We synthesize current knowledge of ANXA11’s physiological roles in phase separation, membrane repair, and RNA granule dynamics, integrating emerging evidence on how disruption of these processes may promote pathological aggregation and toxicity. Finally, we outline priorities for future research, with particular emphasis on elucidating ANXA11’s mechanistic connection to TDP-43.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03043-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400794","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":"Mutation-specific neuropathologic signatures in MAPT-associated frontotemporal lobar degeneration","authors":"Marika Bogdani,&nbsp;Vaishnavi S. Jadhav,&nbsp;Brian C. Kraemer,&nbsp;Thomas J. Grabowski,&nbsp;Suman Jayadev,&nbsp;Kimiko Domoto-Reilly,&nbsp;Nicole F. Liachko,&nbsp;Thomas D. Bird,&nbsp;C. Dirk Keene,&nbsp;Caitlin S. Latimer","doi":"10.1007/s00401-026-03047-w","DOIUrl":"10.1007/s00401-026-03047-w","url":null,"abstract":"<div><p>Autosomal-dominant frontotemporal lobar degeneration with tau pathology (FTLD-tau) is caused by pathogenic variants in the <i>MAPT</i> gene. Although abnormal tau aggregation is a shared endpoint, <i>MAPT</i> mutations produce distinct cellular phenotypes and regional patterns of tau deposition, the mutation specificity and familial consistency of which remain poorly defined. We performed a systematic neuropathologic and transcriptomic analysis of brains from clinically characterized families carrying <i>MAPT</i> V337M, P301L, or L284L mutations. Multiple affected members per family were examined, with interfamily comparisons for P301L. Quantitative assessment of regional tau burden, cellular morphology, and co-pathologies revealed distinct, mutation-specific signatures. The V337M mutation was characterized by predominantly neuronal tau pathology with vesicular pretangles, scattered neurofibrillary tangles, and fine neurites, with minimal glial involvement. P301L exhibited prominent astrocytic tau pathology, including globular and proximal inclusions, accompanied by neuronal pretangles. L284L produced extensive oligodendroglial tau pathology with thick fibrillar coiled bodies in gray and white matter. Additional distinguishing features included hippocampal sclerosis and TDP-43 pathology in V337M; severe cortical neuronal loss and dentate fascia tau in P301L; and extensive white matter and brainstem tau, including ventral pontine neurons, in L284L. These morphologic profiles were conserved within families and, for P301L, across unrelated families. Transcriptomic analyses suggested mutation-linked expression changes concordant with cellular pathology. These findings define reproducible, mutation-specific neuropathologic and molecular signatures of <i>MAPT</i>-associated FTLD-tau, emphasizing the importance of genotype-driven stratification in studies of tauopathy pathogenesis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03047-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379957","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":"Molecular changes during AT/RT progression associated with epithelial–mesenchymal transition and extracellular matrix changes","authors":"Lea Altendorf,&nbsp;Anton Althammer,&nbsp;Rajanya Roy,&nbsp;Karoline Hack,&nbsp;Flavia W. de Faria,&nbsp;Arend Koch,&nbsp;Vanessa Thaden,&nbsp;Melanie Schoof,&nbsp;Martin U. Schuhmann,&nbsp;Peter Hauser,&nbsp;Pascal D. Johann,&nbsp;Martin Hasselblatt,&nbsp;Michael C. Frühwald,&nbsp;Kornelius Kerl,&nbsp;Ulrich Schüller","doi":"10.1007/s00401-026-03050-1","DOIUrl":"10.1007/s00401-026-03050-1","url":null,"abstract":"<div><p>Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors during infancy and associated with a dismal prognosis. The majority of patients suffer from tumor progression or recurrence, but underlying mechanisms remain unknown. To better understand such mechanisms, we performed single-nucleus RNA sequencing (snRNAseq) of eight paired primary tumors and recurrences. Tumor cells and cells of the tumor microenvironment (TME) were analyzed separately. Potentially therapy-resistant tumor cells were identified through the comparison of global gene expression profiles between primary and recurrent tumor cell populations using <i>CIBERSORT</i>. Histopathology, in vitro experiments, bulk RNA sequencing, and survival analysis were performed for validation. Paired primary and recurrent AT/RT showed significant differences in their gene expression profiles. Potentially therapy-resistant AT/RT-MYC tumor cells revealed changes in the extracellular matrix (ECM) as well as altered developmental processes and immune signaling pathways. Respective gene signatures were correlated with inferior survival in AT/RT-MYC patients. Tumor cells of relapsed AT/RT-MYC underwent partial epithelial–mesenchymal transition (pEMT), a feature that was confirmed by immunohistochemistry (IHC) and by analyzing AT/RT cells after standard therapy in vitro. Together, we identified potential mechanisms of tumor relapse and therapy resistance in AT/RT, which could be employed to improve therapy in future.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03050-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349652","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":"Prion-like transmission and propagation of human β-amyloid to the bank vole rodent model","authors":"Michele Angelo Di Bari,&nbsp;Rosalia Bruno,&nbsp;Geraldina Riccardi,&nbsp;Ilaria Vanni,&nbsp;Claudia D’Agostino,&nbsp;Romolo Nonno,&nbsp;Elena De Cecco,&nbsp;Anna Burato,&nbsp;Giuseppe Legname,&nbsp;Franco Cardone,&nbsp;Fabio Moda,&nbsp;Giorgio Giaccone,&nbsp;Marcella Catania,&nbsp;Giuseppe Di Fede,&nbsp;Fabrizio Tagliavini,&nbsp;Umberto Agrimi","doi":"10.1007/s00401-026-03041-2","DOIUrl":"10.1007/s00401-026-03041-2","url":null,"abstract":"<div><p>Over the past decades, growing experimental and observational evidence has suggested that Aβ and pTau, the hallmarks of Alzheimer’s disease (AD), may spread through the nervous system via a prion-like mechanism. Here, we investigated the transmissibility of Aβ and <i>p</i>Tau by inoculating bank voles, a wild-type rodent highly susceptible to prion diseases, with brain homogenates from four sporadic and five familial AD-affected patients. We observed that (i) neo-formed Aβ deposits and pTau inclusions were induced in recipient vole brains; (ii) Aβ pathology appeared to follow a specific neurotropic distribution; (iii) Aβ proteinopathy propagated through vole-to-vole inoculation. Our findings provide the first experimental evidence that human Aβ seeds are transmissible to a wild-type rodent model, further supporting the prion-like nature of Aβ. These results strongly support recent studies suggesting iatrogenic Aβ transmission, underscoring the need to evaluate the impact of Aβ seed exposure on human health.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03041-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348910","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":"Inhibition of tRNA fragments dysregulated in human mTLE exacerbates pathology and seizure activity","authors":"Noora Puhakka,&nbsp;Vamshidhar R. Vangoor,&nbsp;Andreia Gomes-Duarte,&nbsp;Marina de Wit,&nbsp;Mark Broekhoven,&nbsp;Laura Wieg,&nbsp;Nicky C. H. van Kronenburg,&nbsp;Bente Mossink,&nbsp;Neville Magielse,&nbsp;R. Jeroen Pasterkamp","doi":"10.1007/s00401-026-03046-x","DOIUrl":"10.1007/s00401-026-03046-x","url":null,"abstract":"<div><p>Mesial temporal lobe epilepsy (mTLE) is a subtype of focal epilepsy in which approximately one-third of patients develop pharmaco-resistance, likely driven by multiple mechanisms including structural changes and dysregulated non-coding RNAs (ncRNAs). However, our understanding of the contribution of ncRNAs to mTLE pathogenesis remains incomplete, and many classes remain uncharacterized. Notably, transfer RNAs (tRNAs) and their stress-induced fragments are emerging as important regulators of gene expression and candidate fluid-based biomarkers. However, their tissue-level expression and role in disease pathogenesis remain poorly understood. Therefore, in this study we performed profiling of tRNA and tRNA-derived fragments (tRFs), in human hippocampal and cortical samples from hippocampal sclerosis mTLE (mTLE-HS) and non-hippocampal sclerosis mTLE (mTLE non-HS) patients and postmortem controls by total RNA sequencing (RNA-seq) and small non-coding RNA sequencing (sncRNA-seq). Our data reveal widespread changes in the neural expression of pre-tRNA, tRNA and tRF expression in human mTLE brain tissue. One of the most prominent changes observed was a downregulation of 5’ fragments derived from <i>tRNA-His-GTG</i>. Knockdown of this tRNA and its 5’ fragments combined with total RNA-seq in neuronal cells identified <i>5’tRNA-His-GTG</i> fragments as strong regulators of gene expression, including of epilepsy-associated genes. For example, Cannabinoid Receptor 1 (<i>CNR1</i>) was identified as a possible downstream target of <i>5’tRF-His-GTG</i>. To investigate the contribution of <i>5’tRF-His-GTG</i> to TLE pathogenesis and seizure activity, the increased expression of this tRF that was observed at 24 h after <i>status epilepticus</i> (SE) in mice was targeted using inhibitors. This induced increased seizures and altered network activity, with reduced theta and alpha power bands, and enhanced glial fibrillary acidic protein (GFAP) expression. Together, our study confirms and extends previous findings by identifying widespread changes in human brain tRF expression in mTLE and demonstrates for the first time that tRF manipulation affects seizure activity and mTLE pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03046-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336170","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":"VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy","authors":"Christian A. Suarez,&nbsp;Sara K. Pittman,&nbsp;Michio Inoue,&nbsp;Eileen M. Lynch,&nbsp;Andrew Moran,&nbsp;Angèle N. Merlet,&nbsp;Emmanuelle Lacenne,&nbsp;Teresinha Evangelista,&nbsp;Conrad C. Weihl","doi":"10.1007/s00401-026-03044-z","DOIUrl":"10.1007/s00401-026-03044-z","url":null,"abstract":"<div><p>X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in <i>Vma21,</i> an assembly chaperone required for vacuolar H⁺–ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional <i>Vma21</i> knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of <i>Vma21</i> in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of <i>Vma21</i> produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03044-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148323731","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":"Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis","authors":"Lukas Lütje,&nbsp;J. Q. Alida Chen,&nbsp;Jörg Hamann,&nbsp;Joost Smolders,&nbsp;Inge Huitinga,&nbsp;Aletta M. R. van den Bosch","doi":"10.1007/s00401-026-03040-3","DOIUrl":"10.1007/s00401-026-03040-3","url":null,"abstract":"<div><p>Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.</p><p>Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele <i>HLA-DRB1*15:01</i> (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the <i>DYSF–ZNF638</i> locus (rs10191329). Perivascular cuffs associated with increased microglia/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active/inactive and inactive lesions, and a shorter disease duration.</p><p>Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03040-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322752","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}