Acta Neuropathologica最新文献

{"title":"A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression","authors":"Gema Muñoz González,&nbsp;Bert A. ´t Hart,&nbsp;Marianna Bugiani,&nbsp;Jason R. Plemel,&nbsp;Geert J. Schenk,&nbsp;Gijs Kooij,&nbsp;Antonio Luchicchi","doi":"10.1007/s00401-025-02923-1","DOIUrl":"10.1007/s00401-025-02923-1","url":null,"abstract":"<div><p>Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also ‘normal’ appearing tissue in both white and gray matter, referred to as ‘normal-appearing white matter’ and ‘normal-appearing gray matter’, respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these ‘normal-appearing’ CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02923-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805709","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":"Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U","authors":"Sara Alidadiani,&nbsp;Júlia Faura,&nbsp;Sarah Wynants,&nbsp;Nele Peeters,&nbsp;Marleen Van den Broeck,&nbsp;Linus De Witte,&nbsp;Rafaela Policarpo,&nbsp;Simon Cheung,&nbsp;Cyril Pottier,&nbsp;Nikhil B. Ghayal,&nbsp;Merel O. Mol,&nbsp;Marka van Blitterswijk,&nbsp;Evan Udine,&nbsp;Mariely DeJesus-Hernandez,&nbsp;Matthew Baker,&nbsp;NiCole A. Finch,&nbsp;Yan W. Asmann,&nbsp;Jeroen G. J. van Rooij,&nbsp;Aivi T. Nguyen,&nbsp;R. Ross Reichard,&nbsp;Alissa L. Nana,&nbsp;Oscar L. Lopez,&nbsp;Adam L. Boxer,&nbsp;Howard J. Rosen,&nbsp;Salvatore Spina,&nbsp;Jochen Herms,&nbsp;Keith A. Josephs,&nbsp;Ronald C. Petersen,&nbsp;Robert A. Rissman,&nbsp;Annie Hiniker,&nbsp;Lee-Cyn Ang,&nbsp;Lea T. Grinberg,&nbsp;Glenda M. Halliday,&nbsp;Bradley F. Boeve,&nbsp;Neill R. Graff-Radford,&nbsp;Harro Seelaar,&nbsp;Manuela Neumann,&nbsp;Julia Kofler,&nbsp;Charles L. White III,&nbsp;William W. Seeley,&nbsp;John C. van Swieten,&nbsp;Dennis W. Dickson,&nbsp;Ian R. A. Mackenzie,&nbsp;Wouter De Coster,&nbsp;Rosa Rademakers","doi":"10.1007/s00401-025-02919-x","DOIUrl":"10.1007/s00401-025-02919-x","url":null,"abstract":"<div><p>Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the <i>GLI1</i> transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (<i>MBP</i>), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02919-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805711","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":"Reply: PART and amyloid cascade hypotheses are alive and well (but are not so simple)","authors":"Heiko Braak,&nbsp;Kelly Del Tredici","doi":"10.1007/s00401-025-02921-3","DOIUrl":"10.1007/s00401-025-02921-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02921-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787020","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":"PART and amyloid cascade hypotheses are alive and well (but are not so simple). Scientific commentary on: \"Sequence and trajectory of early Alzheimer's disease-related tau inclusions in the hippocampal formation of cases without amyloid-beta deposits\"","authors":"Peter T. Nelson,&nbsp;John F. Crary","doi":"10.1007/s00401-025-02920-4","DOIUrl":"10.1007/s00401-025-02920-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787430","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":"Estradiol rescues male hydroxyl radical-mediated Charcot-Marie-Tooth 2Z by Morc2a stabilization through autophagy inhibition in a murine model","authors":"Ji Won Kim,&nbsp;Soo Hyun Nam,&nbsp;Geon Seong Lee,&nbsp;Hye Yoon Chung,&nbsp;Eun Young Kim,&nbsp;Jeong Pil Han,&nbsp;Jae-Hyung Jang,&nbsp;Byung-Ok Choi,&nbsp;Su Cheong Yeom","doi":"10.1007/s00401-025-02922-2","DOIUrl":"10.1007/s00401-025-02922-2","url":null,"abstract":"<div><p>Charcot–Marie–Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (<i>MORC2</i>), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (<i>Morc2a</i>) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the <i>Morc2a</i> variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical–induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved <i>Morc2a</i> protein stability in the <i>quadriceps femoris</i> and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic <i>Morc2a</i> p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol’s ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human <i>MORC2</i> p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02922-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778143","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":"PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration","authors":"Michaela-Kristina Keck,&nbsp;Maysa Al-Hussaini,&nbsp;Nisreen Amayiri,&nbsp;Akosua Adoma Boakye Yiadom,&nbsp;Gabriel Chamyan,&nbsp;Edmund Cheesman,&nbsp;Cécile Faure-Conter,&nbsp;Miguel Garcia-Ariza,&nbsp;Guillaume Gauchotte,&nbsp;Martin Hasselblatt,&nbsp;Mette Jorgensen,&nbsp;John-Paul Kilday,&nbsp;Gabriela Lamas,&nbsp;Cinzia Lavarino,&nbsp;Marilyn M. Li,&nbsp;Fabiana Lubieniecki,&nbsp;Ossama M. Maher,&nbsp;David Meyronet,&nbsp;Jan Mueller,&nbsp;Mariarita Santi,&nbsp;Ulrich Schüller,&nbsp;Ana Luiza Seidinger,&nbsp;Martin Sill,&nbsp;Sniya Sudhakar,&nbsp;María Tallón García,&nbsp;Arnault Tauziede-Espariat,&nbsp;Pascale Varlet,&nbsp;Alexandre Vasiljevic,&nbsp;Andrea Wittmann,&nbsp;Andreas von Deimling,&nbsp;David A. Solomon,&nbsp;Felix Sahm,&nbsp;Anna Tietze,&nbsp;Katja von Hoff,&nbsp;Philipp Sievers,&nbsp;David T. W. Jones","doi":"10.1007/s00401-025-02917-z","DOIUrl":"10.1007/s00401-025-02917-z","url":null,"abstract":"<div><p>CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, <i>PLAGL1</i> or <i>PLAGL2</i>. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely <i>PLAGL1</i> fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring <i>PLAG1</i> gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the <i>PLAGL1</i>- and <i>PLAGL2</i>-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative <i>PLAG1</i> fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5’ fusion partners (<i>ASAP1</i>, <i>ADGRG1</i>, <i>TMEM68</i>, <i>TCF4</i>, <i>CHD7</i>, <i>NCALD</i>, <i>HNRNPK</i>, <i>LOC105378102</i>) were identified that upregulate wild-type <i>PLAG1</i> through promoter hijacking. Expression analysis shows upregulation of <i>PLAG1</i> as well as <i>IGF2</i>, <i>DLK1</i>, <i>Desmin</i>, <i>CYP2W1</i>, and <i>RET,</i> which are also robustly expressed in <i>PLAGL1/2</i>-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to <i>PLAGL1/2</i>-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by <i>PLAG1</i> gene fusion, which leads to upregulation of <i>PLAG1</i> and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02917-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766003","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":"Myocardial sympathetic distal axon loss in subjects with Lewy pathology in three autopsy cohorts","authors":"Ville Kivistö,&nbsp;Benjamin Englert,&nbsp;Jarno Tuimala,&nbsp;Eloise Kok,&nbsp;Henri Puttonen,&nbsp;Anna Raunio,&nbsp;Pekka J. Karhunen,&nbsp;Maria K. Lehtinen,&nbsp;Per Borghammer,&nbsp;Ella Ahvenainen,&nbsp;Kia Colangelo,&nbsp;Sara Savola,&nbsp;Maarit Tanskanen,&nbsp;Karri Kaivola,&nbsp;Pentti J. Tienari,&nbsp;Darshan Kumar,&nbsp;Anders Paetau,&nbsp;Olli Tynninen,&nbsp;Mikko I. Mäyränpää,&nbsp;Tuomo Polvikoski,&nbsp;Liisa Myllykangas","doi":"10.1007/s00401-025-02918-y","DOIUrl":"10.1007/s00401-025-02918-y","url":null,"abstract":"<div><p>Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. This novel tool was applied to septal samples of the Vantaa 85 + study (<i>n</i> = 138), which is a population-based autopsy study representing all subjects aged 85 years or older living in the city of Vantaa (southern Finland) in 1991. In addition, the tool was applied to left ventricle samples of the Helsinki Biobank (<i>n</i> = 87) and the forensic Tampere Sudden Death Study (TSDS, <i>n</i> = 127). The level of myocardial TH reactivity was compared between subjects with and without Lewy pathology in the central nervous system in all datasets. In the Vantaa 85 + study, TH reactivity was also compared between subjects with caudo-rostral and amygdala-based subtypes, and potential confounding factors (age at death, sex, myocardial infarction, senile systemic amyloidosis, and diabetes medication) were controlled for using multiple linear regression models. Presence of Lewy pathology was strongly associated with loss of TH reactivity at the myocardial level in all three autopsy cohorts (Vantaa 85 + <i>p</i> = 0.001, Helsinki Biobank <i>p</i> &lt; 0.001, TSDS <i>p</i> &lt; 0.001)). In the Vantaa 85 + study, the caudo-rostral subtype (<i>p</i> &lt; 0.001), but not the amygdala-based subtype (<i>p</i> = 0.60), was associated with myocardial denervation/dysfunction, and this association was independent of other known causes of sympathetic denervation/dysfunction. Caudo-rostral subtype and myocardial infarction were the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population (Vantaa 85 +). In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02918-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756204","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":"Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord","authors":"John F. Tuddenham,&nbsp;Masashi Fujita,&nbsp;Emily Lee,&nbsp;Nivedita Nimmagadda,&nbsp;Anthony Khairallah,&nbsp;Claire Harbison,&nbsp;Xena E. Flowers,&nbsp;Guillermo Coronas-Samano,&nbsp;Silas Maniatis,&nbsp;Aidan Daly,&nbsp;Julie A. Schneider,&nbsp;Andrew F. Teich,&nbsp;Jean Paul G. Vonsattel,&nbsp;Peter A. Sims,&nbsp;Wassim Elyaman,&nbsp;Elizabeth M. Bradshaw,&nbsp;Lyle W. Ostrow,&nbsp;Hemali Phatnani,&nbsp;Neil A. Shneider,&nbsp;David A. Bennett,&nbsp;Philip L. De Jager,&nbsp;Serge Przedborski,&nbsp;Vilas Menon,&nbsp;Marta Olah","doi":"10.1007/s00401-025-02913-3","DOIUrl":"10.1007/s00401-025-02913-3","url":null,"abstract":"<div><p>Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726429","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: Cerebral Braak stage and amygdala granular fuzzy astrocyte status have independent effects on neuronal 3R-tau and 4R-tau accumulations in the olfactory bulb, respectively, in cases with low to intermediate AD neuropathologic change","authors":"Osamu Yokota,&nbsp;Tomoko Miki,&nbsp;Hanae Nakashima-Yasuda,&nbsp;Hideki Ishizu,&nbsp;Takashi Haraguchi,&nbsp;Akinori Miyashita,&nbsp;Takeshi Ikeuchi,&nbsp;Masato Hasegawa,&nbsp;Naoto Nishikawa,&nbsp;Shintaro Takenoshita,&nbsp;Seishi Terada,&nbsp;Manabu Takaki","doi":"10.1007/s00401-025-02915-1","DOIUrl":"10.1007/s00401-025-02915-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717164","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":"Cognitive decline in community-dwelling older persons with primary age-related tauopathy: role of anatomical location of tangles and other co-existing brain pathologies","authors":"Sonal Agrawal,&nbsp;Lei Yu,&nbsp;Lisa L. Barnes,&nbsp;David A. Bennett,&nbsp;Patricia A. Boyle,&nbsp;Julie A. Schneider","doi":"10.1007/s00401-025-02916-0","DOIUrl":"10.1007/s00401-025-02916-0","url":null,"abstract":"<div><p>Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. At autopsy, PART was defined by a Braak NFT stage of I–IV in the absence or with limited amyloid-β (Thal ≤ 2). Tau tangle density from the hippocampus and inferior temporal cortex were evaluated by AT8-immunohistochemistry. Other brain pathologies (LATE-NC, Lewy bodies (LBs), and vascular pathologies) were also evaluated. Linear mixed effect models were employed to examine the associations between regional tau tangles and other brain pathologies with decline in global cognition and 5 cognitive domains. Among 1,859 participants, 527 (28%) had neuropathologically confirmed PART: 385 had possible PART and 142 had definite PART, with an average age at death of 88 ± 6.9 years and 63% being female. Nearly all PART participants (<i>N</i> = 524) had hippocampal tangles and 449 also exhibited tangles in the inferior temporal neocortex. After controlling demographics and other brain pathologies, hippocampal and inferior temporal neocortical tangle burden were each associated with decline in global cognition and episodic memory; however, the effect of inferior temporal neocortical tangles on decline was 3.2 times stronger than that of hippocampal tangles. In further analyses, when included together in the same model, only the association of inferior temporal neocortical tangle burden persisted. However, using Braak staging alone, we did not find a clinical–pathological relationship between tangles and cognitive decline. Additionally, LATE-NC, LBs, atherosclerosis, and cerebral infarcts were each independently associated with cognitive decline. Our data also indicated that LATE-NC may have stronger impact on cognitive decline in PART than tau tangles. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693455","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}