Acta Neuropathologica最新文献

{"title":"Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration","authors":"Timothy E. Richardson,&nbsp;Jonathan Cherry,&nbsp;Shrishtee Kandoi,&nbsp;Susan K. Rohde,&nbsp;Madeline Uretsky,&nbsp;Fatima Tuz-Zahra,&nbsp;Kevin F. Bieniek,&nbsp;Kurt Farrell,&nbsp;Marco M. Hefti,&nbsp;Michael B. Miller,&nbsp;Yorghos Tripodis,&nbsp;Thor D. Stein,&nbsp;Carolina Maldonado-Díaz,&nbsp;Satomi Hiya,&nbsp;Thomas G. Beach,&nbsp;María M. Corrada,&nbsp;Brittany N. Dugger,&nbsp;Margaret E. Flanagan,&nbsp;Matthew P. Frosch,&nbsp;Marla Gearing,&nbsp;Lea T. Grinberg,&nbsp;Lawrence A. Hansen,&nbsp;Debra Hawes,&nbsp;Elizabeth Head,&nbsp;C. Dirk Keene,&nbsp;Julia Kofler,&nbsp;Edward B. Lee,&nbsp;Peter T. Nelson,&nbsp;Derek H. Oakley,&nbsp;Richard J. Perrin,&nbsp;Robert A. Rissman,&nbsp;Shahriar Salamat,&nbsp;Julie A. Schneider,&nbsp;Geidy E. Serrano,&nbsp;Andrew F. Teich,&nbsp;Juan C. Troncoso,&nbsp;Thomas Wisniewski,&nbsp;Randall L. Woltjer,&nbsp;John F. Crary,&nbsp;Dennis W. Dickson,&nbsp;Ann C. McKee,&nbsp;Jamie M. Walker","doi":"10.1007/s00401-026-03031-4","DOIUrl":"10.1007/s00401-026-03031-4","url":null,"abstract":"<div><p>Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of <i>β</i>-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03031-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148009744","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 phosphoproteomic landscape of the neurological manifestations in tuberous sclerosis complex","authors":"Marie Girodengo,&nbsp;Simeon R. Mihaylov,&nbsp;Katarzyna Klonowska,&nbsp;Laura Mantoan Ritter,&nbsp;Helen R. Flynn,&nbsp;J. Mark Skehel,&nbsp;Elias Bou Farhat,&nbsp;Eleonora Aronica,&nbsp;Matthew White,&nbsp;David J. Kwiatkowski,&nbsp;Sila K. Ultanir,&nbsp;Joseph M. Bateman","doi":"10.1007/s00401-026-03022-5","DOIUrl":"10.1007/s00401-026-03022-5","url":null,"abstract":"<div><p>Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in <i>TSC1</i> and <i>TSC2,</i> resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations in TSC patients include epilepsy, autism and intellectual disability. Two types of brain lesions, cortical tubers and subependymal giant cell astrocytomas (SEGAs), cause the majority of neurological manifestations in TSC. We have limited understanding of the molecular changes that occur in tubers and SEGAs and how these contribute to disease pathogenesis. To investigate this, we performed proteomic and phosphoproteomic analysis of TSC patient tuber and SEGA tissue. Tubers showed evidence of alterations in mitochondrial respiration, cytoskeleton organisation and neuronal function. However, we were unable to detect mTORC1 activation in tubers, likely due to the small number of cells with complete inactivation of <i>TSC1</i> or <i>TSC2</i>. By contrast, SEGAs showed evidence of strong mTORC1 activation and large-scale changes in the proteome and phosphoproteome. SEGAs exhibited increased expression of ribosomal proteins and activation of a neuroinflammatory response. Phosphoproteomics identified 6060 phosphosites within 2154 proteins increased in SEGAs. Phosphorylation of multiple proteins involved in RNA-metabolism, including mRNA splicing, was increased in SEGAs. Consistent with this, we found evidence of extensive alterations in mRNA transcript splicing in SEGA tissue that is shared with a wide range of cancers. These data greatly expand the repertoire of known mTORC1 target proteins in the human brain and reveal that large-scale mis-regulation of mRNA splicing may promote the formation of SEGAs in TSC.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13190377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979985","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 plasma protein signature for cerebral amyloid angiopathy","authors":"Alpana Singh,&nbsp;Marisa N. Denkinger,&nbsp;Antoine Leuzy,&nbsp;Kari Dieckhoff,&nbsp;Jame Liu,&nbsp;Taina M. Marques,&nbsp;Edwin Monuki,&nbsp;Craig Stark,&nbsp;Joshua D. Grill,&nbsp;Christy Hom,&nbsp;David Sultzer,&nbsp;Eric Doran,&nbsp;Ira Lott,&nbsp;Kevin Wood,&nbsp;Brianna Gawronski,&nbsp;Lourdes Gonzalez,&nbsp;Parichita Choudhury,&nbsp;Alireza Atri,&nbsp;Thomas G. Beach,&nbsp;Geidy E. Serrano,&nbsp;S. Ahmad Sajjadi,&nbsp;Kendall Van Keuren-Jensen,&nbsp;Eric M. Reiman,&nbsp;Elizabeth Head,&nbsp;Nicholas J. Ashton","doi":"10.1007/s00401-026-03030-5","DOIUrl":"10.1007/s00401-026-03030-5","url":null,"abstract":"<div><p>Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer’s disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (<i>N</i> = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (<i>N</i> = 110). We evaluated the differential protein expression in antemortem plasma sample taken &lt; 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86–0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13190554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979997","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":"Future directions in the treatment of brain metastases: evaluating the role of cellular players in the tumour microenvironment","authors":"Chris W. Govaerts,&nbsp;J. Marc C. van Dijk,&nbsp;Anouk van der Hoorn,&nbsp;Frank A. E. Kruyt","doi":"10.1007/s00401-026-03011-8","DOIUrl":"10.1007/s00401-026-03011-8","url":null,"abstract":"<div><p>Recent clinical trials have demonstrated the efficacy of different modalities of systemic therapy in treating brain metastases, including immune checkpoint inhibitors and various types of targeted therapy. These findings expand treatment options for these intracranial tumours, which are linked to significant morbidity and poor outcomes. Despite these advances, important challenges remain. These include the difficulty of identifying predictors of intracranial response to such therapies. The intracranial activity of anti-tumour agents is dependent on the complex interplay between the cellular components of the tumour microenvironment, consisting of both brain-resident cell types and peripheral immune cells. A deeper understanding of these interactions is essential for identifying mechanisms that contribute to inter- and intratumoural heterogeneity in treatment sensitivity. This review provides a comprehensive overview of the mechanisms by which the constituent cell types of the tumour microenvironment of brain metastases contribute to tumour progression and therapy resistance. Herein, a conceptual model of the relevant biological pathways is outlined along with references to how specific vulnerabilities could be utilised to develop more effective therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969405","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":"APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis","authors":"Yuya Hatano,&nbsp;Asa Nakahara,&nbsp;Mari Tada,&nbsp;Akiyoshi Kakita,&nbsp;Osamu Onodera,&nbsp;Tomohiko Ishihara","doi":"10.1007/s00401-026-03029-y","DOIUrl":"10.1007/s00401-026-03029-y","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (<i>APOE</i>) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 – largely restricted to motor regions – and type 2 – characterized by widespread cortical involvement. <i>APOE</i> genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among <i>APOE</i> ε4, temporal clinical parameters, Alzheimer’s disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. <i>APOE</i> ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking <i>APOE</i> ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that <i>APOE</i> ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer’s disease pathology. Incorporation of <i>APOE</i> genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03029-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147938346","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 signatures and biomarker development for limbic-predominant age-related TDP-43 encephalopathy (LATE)","authors":"Ling Wu,&nbsp;Tobilola Akingbade,&nbsp;Peter T. Nelson,&nbsp;Shih-Hsiu J. Wang,&nbsp;Bin Xu","doi":"10.1007/s00401-026-03027-0","DOIUrl":"10.1007/s00401-026-03027-0","url":null,"abstract":"<div><p>Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease marked by TDP-43 proteinopathy, affecting approximately one-third of individuals aged 80 and above. LATE neuropathological change (LATE-NC) is characterized by the accumulation of phosphorylated TDP-43 preferentially in the limbic system, with potential extension to the neocortex and other brain regions. Notably, the anatomic pattern of LATE-NC differs from that seen in frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP).  LATE-NC can occur in a “pure” form but more commonly exists alongside other dementia-related comorbidities, including both degenerative and vascular pathologies. When those “mixed” pathologies are factored in, LATE contributes significantly to cognitive decline in human populations.  However, LATE currently lacks a molecular-specific diagnostic method for definitive diagnosis in living people. There are new consensus-based guidelines for predicting the presence of either pure LATE-NC or LATE-NC combined with Alzheimer’s disease neuropathologic change (ADNC). Aimed at developing more specific diagnostic methods, recent research efforts have been directed toward identifying unique features on neuroimaging and molecular signatures in biological fluids such as blood and cerebrospinal fluid to facilitate clinical diagnosis for LATE. This review discusses current progress in molecular understanding of LATE-NC, the search for biomarkers for LATE, and highlights key gaps that need to be addressed to advance early detection and improve patient management and clinical trial stratification.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03027-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147938347","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":"Frequency of mixed neuropathologies in individuals with down syndrome with and without Alzheimer's dementia","authors":"Lisi Flores-Aguilar,&nbsp;Thomas D. Zaikos,&nbsp;Isabel Rivera,&nbsp;Sierra T. Wright,&nbsp;Jerry Lou,&nbsp;Brianna Gawronski,&nbsp;Lourdes Gonzalez,&nbsp;Jillian V. Berry,&nbsp;Jeremy Rouanet,&nbsp;Natalie C. Edwards,&nbsp;Dan K. Hoang,&nbsp;Kevin Wood,&nbsp;Ann-Charlotte Granholm,&nbsp;Elliott J. Mufson,&nbsp;Edwin S. Monuki,&nbsp;Milos D. Ikonomovic,&nbsp;Julia Kofler,&nbsp;Eric W. Doran,&nbsp;Ira T. Lott,&nbsp;Minodora O. Totoiu,&nbsp;Christy L. Hom,&nbsp;Florence Lai,&nbsp;William H. Yong,&nbsp;Frederick A. Schmitt,&nbsp;Jordan Harp,&nbsp;Peter T. Nelson,&nbsp;Jose Gutierrez,&nbsp;Patrick J. Lao,&nbsp;Donna M. Wilcock,&nbsp;Adam M. Brickman,&nbsp;Elizabeth Head,&nbsp;for the Alzheimer’s Biomarker Consortium-Down syndrome (ABC-DS)","doi":"10.1007/s00401-026-03028-z","DOIUrl":"10.1007/s00401-026-03028-z","url":null,"abstract":"<div><p>Individuals with Down syndrome (DS) develop Alzheimer's disease neuropathological change (ADNC) by the age of 40 years, and most develop dementia by their early 50s. The frequency of co-pathologies in clinically and neuropathologically characterized adults with DS has not been systematically characterized. We characterized the frequency of ADNC and common co-pathologies, including cerebral amyloid angiopathy (CAA), Lewy pathology (LP), limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), hippocampal sclerosis (HS), and other cerebrovascular and macroscopic findings reported in standardized National Alzheimer’s Coordinating Center (NACC) neuropathology forms in 63 adults with DS over 40 years. A secondary exploratory objective was to compare the neuropathological profiles between individuals with (n = 55) and without (n = 8) dementia from the same autopsy cohort. In the full autopsy cohort, cortical and hippocampal atrophy, and moderate-to-severe locus coeruleus hypopigmentation was a common finding. Pure ADNC, was present in only 29% of individuals. CAA was the most frequent co-pathology, present in approximately 84% of individuals followed by LP (21%), HS (19%), and LATE-NC (17%). Atherosclerosis and arteriolosclerosis were infrequent. In exploratory comparisons between dementia groups, brain weight was significantly lower in individuals with dementia than in those without (900 ± 116 vs 1060 ± 108 g P = .0006), and severe hippocampal atrophy and locus coeruleus hypopigmentation were more frequent in those with dementia (P = .049, P = .009, respectively). Advanced Braak NFT stage, frequent neuritic plaques, and high ADNC were more frequent in individuals with dementia (P = .0001, P = .03, P = .0016, respectively). LATE-NC and HS occurred exclusively in individuals with dementia, while LP and CAA were found in both groups. Individuals without dementia showed a less complex co-pathology profile than those with dementia. Our findings demonstrate that co-pathologies are present in people with DS, and that despite their genetic predisposition to AD, some individuals with DS may exhibit resilience and resistance mechanisms to AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03028-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147938345","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 profiling of alpha-synuclein pathology and seeding activity in Parkinson’s disease","authors":"Zeynep Bengisu Kaya,&nbsp;Danilyn Amerna,&nbsp;Ananya Susarla,&nbsp;Melina J. Lim,&nbsp;Maria Bregendahl,&nbsp;Hiroaki Sekiya,&nbsp;Michael DeTure,&nbsp;Owen A. Ross,&nbsp;Dennis W. Dickson,&nbsp;Suelen L. Boschen,&nbsp;Pamela J. McLean","doi":"10.1007/s00401-026-03026-1","DOIUrl":"10.1007/s00401-026-03026-1","url":null,"abstract":"<div><p>Parkinson’s disease (PD) is neuropathologically characterized by the abnormal accumulation of fibrillar alpha-synuclein (aSyn) within selectively vulnerable neuronal populations. Although this pathological hallmark is shared across individuals with PD, the disease presents with marked clinical heterogeneity in age of onset, progression rate, and clinical symptoms, the molecular basis of which remains incompletely understood. In this study, we examined whether biochemical and seeding-related properties of aSyn vary across clinically defined PD subgroups. Using well-characterized, autopsy-confirmed PD cases and matched controls we applied complementary biochemical, cell-based aggregation, and cell-free seed amplification assays (SAA) to investigate aSyn molecular heterogeneity and its potential contribution to disease diversity. Autopsy-confirmed PD cases were classified as early-onset (&lt; 60 years) or late-onset (&gt; 60 years), with the late-onset group further subdivided into fast-progressing (&lt; 5 years duration) and slow-progressing (&gt; 10 years duration). Analysis of detergent-insoluble fractions from PD brains revealed significantly elevated pSer129-aSyn levels compared to controls, while total aSyn was highest in late-onset PD. Seeding bioactivity measured via FRET-based biosensor cells was significantly increased in PD, albeit with substantial inter-individual variability; late-onset and slow-progressing groups exhibited the strongest activity. Seeding activity correlated positively with pSer129-aSyn levels. These findings were supported by high-content imaging, which demonstrated increased intracellular aggregate burden in PD samples. SAA confirmed robust seeding activity in PD, with shorter lag times relative to controls. Finally, proteinase K digestion of amplified products revealed differences in proteolytic resistance between PD and control samples, consistent with biochemical heterogeneity of seeding-competent species. Collectively, these findings suggest that aSyn pathology in PD is associated with marked inter-individual variability in biochemical and seeding properties. Our results highlight the importance of considering molecular heterogeneity at the individual patient level when investigating PD pathobiology and supports the need for precision medicine approaches for PD patients.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03026-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872744","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":"CnQuant: high-resolution chromosomal copy number profiling for precision oncology in the clinics","authors":"Benjamin Maciej Freyter,&nbsp;Claus Hultschig,&nbsp;Jon Brugger,&nbsp;Ivana Bratic Hench,&nbsp;Stephan Frank,&nbsp;Juergen Hench","doi":"10.1007/s00401-026-03025-2","DOIUrl":"10.1007/s00401-026-03025-2","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03025-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829879","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":"Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lyso-mitochondrial dysfunction, and lipid dyshomeostasis","authors":"Sofia Massaro Tieze,&nbsp;Alexander Esqueda,&nbsp;Rachel McAllister,&nbsp;Matija Lagator,&nbsp;Betül Yücel,&nbsp;Eric Sun,&nbsp;Katherine B. Henke,&nbsp;TuKiet T. Lam,&nbsp;Nicholas Lockyer,&nbsp;Kallol Gupta,&nbsp;Sreeganga S. Chandra","doi":"10.1007/s00401-026-03012-7","DOIUrl":"10.1007/s00401-026-03012-7","url":null,"abstract":"<div><p>Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; <i>CLN1</i>) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of lipofuscin in the aged and <i>CLN1</i> brain to be remarkably similar. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and <i>CLN1</i>. Notably, &gt; 95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that <i>CLN1</i> lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809312","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}