Acta Neuropathologica最新文献

{"title":"Correction to: Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification","authors":"Michaela-Kristina Keck, Martin Sill, Andrea Wittmann, Piyush Joshi, Damian Stichel, Pengbo Beck, Konstantin Okonechnikow, Philipp Sievers, Annika K. Wefers, Federico Roncaroli, Shivaram Avula, Martin G. McCabe, James T. Hayden, Pieter Wesseling, Ingrid Øra, Monica Nistér, Mariëtte E. G. Kranendonk, Bastiaan B. J. Tops, Michal Zapotocky, Josef Zamecnik, Alexandre Vasiljevic, Tanguy Fenouil, David Meyronet, Katja von Hoff, Ulrich Schüller, Hugues Loiseau, Dominique Figarella-Branger, Christof M. Kramm, Dominik Sturm, David Scheie, Tuomas Rauramaa, Jouni Pesola, Johannes Gojo, Christine Haberler, Sebastian Brandner, Tom Jacques, Alexandra Sexton Oates, Richard Saffery, Ewa Koscielniak, Suzanne J. Baker, Stephen Yip, Matija Snuderl, Nasir Ud Din, David Samuel, Kathrin Schramm, Mirjam Blattner-Johnson, Florian Selt, Jonas Ecker, Till Milde, Andreas von Deimling, Andrey Korshunov, Arie Perry, Stefan M. Pfister, Felix Sahm, David A. Solomon, David T. W. Jones","doi":"10.1007/s00401-023-02538-4","DOIUrl":"10.1007/s00401-023-02538-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"511 - 514"},"PeriodicalIF":12.7,"publicationDate":"2023-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02538-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9135942","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":"Retinal pathological features and proteome signatures of Alzheimer’s disease","authors":"Yosef Koronyo,&nbsp;Altan Rentsendorj,&nbsp;Nazanin Mirzaei,&nbsp;Giovanna C. Regis,&nbsp;Julia Sheyn,&nbsp;Haoshen Shi,&nbsp;Ernesto Barron,&nbsp;Galen Cook-Wiens,&nbsp;Anthony R. Rodriguez,&nbsp;Rodrigo Medeiros,&nbsp;Joao A. Paulo,&nbsp;Veer B. Gupta,&nbsp;Andrei A. Kramerov,&nbsp;Alexander V. Ljubimov,&nbsp;Jennifer E. Van Eyk,&nbsp;Stuart L. Graham,&nbsp;Vivek K. Gupta,&nbsp;John M. Ringman,&nbsp;David R. Hinton,&nbsp;Carol A. Miller,&nbsp;Keith L. Black,&nbsp;Antonino Cattaneo,&nbsp;Giovanni Meli,&nbsp;Mehdi Mirzaei,&nbsp;Dieu-Trang Fuchs,&nbsp;Maya Koronyo-Hamaoui","doi":"10.1007/s00401-023-02548-2","DOIUrl":"10.1007/s00401-023-02548-2","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ₄₂) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ₄₂, S100 calcium-binding protein B⁺ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ₄₂, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"409 - 438"},"PeriodicalIF":12.7,"publicationDate":"2023-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02548-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9260860","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":"Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts","authors":"Ann C. McKee,&nbsp;Thor D. Stein,&nbsp;Bertrand R. Huber,&nbsp;John F. Crary,&nbsp;Kevin Bieniek,&nbsp;Dennis Dickson,&nbsp;Victor E. Alvarez,&nbsp;Jonathan D. Cherry,&nbsp;Kurt Farrell,&nbsp;Morgane Butler,&nbsp;Madeline Uretsky,&nbsp;Bobak Abdolmohammadi,&nbsp;Michael L. Alosco,&nbsp;Yorghos Tripodis,&nbsp;Jesse Mez,&nbsp;Daniel H. Daneshvar","doi":"10.1007/s00401-023-02540-w","DOIUrl":"10.1007/s00401-023-02540-w","url":null,"abstract":"<div><p>Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"371 - 394"},"PeriodicalIF":12.7,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02540-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10269357","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":"Even heterozygous loss of CDKN2A/B greatly accelerates recurrence in aggressive meningioma","authors":"A. Basit Khan,&nbsp;Collin W. English,&nbsp;William C. Chen,&nbsp;Prazwal Athukuri,&nbsp;James C. Bayley V,&nbsp;Vicky L. Brandt,&nbsp;Arya Shetty,&nbsp;Caroline C. Hadley,&nbsp;Abrar Choudhury,&nbsp;Hsiang-Chih Lu,&nbsp;Arif O. Harmanci,&nbsp;Akdes S. Harmanci,&nbsp;Stephen T. Magill,&nbsp;David R. Raleigh,&nbsp;Tiemo J. Klisch,&nbsp;Akash J. Patel","doi":"10.1007/s00401-023-02543-7","DOIUrl":"10.1007/s00401-023-02543-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"501 - 503"},"PeriodicalIF":12.7,"publicationDate":"2023-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323927/pdf/nihms-1910664.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9756906","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":"Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex","authors":"Natalie Matosin,&nbsp;Janine Arloth,&nbsp;Darina Czamara,&nbsp;Katrina Z. Edmond,&nbsp;Malosree Maitra,&nbsp;Anna S. Fröhlich,&nbsp;Silvia Martinelli,&nbsp;Dominic Kaul,&nbsp;Rachael Bartlett,&nbsp;Amber R. Curry,&nbsp;Nils C. Gassen,&nbsp;Kathrin Hafner,&nbsp;Nikola S. Müller,&nbsp;Karolina Worf,&nbsp;Ghalia Rehawi,&nbsp;Corina Nagy,&nbsp;Thorhildur Halldorsdottir,&nbsp;Cristiana Cruceanu,&nbsp;Miriam Gagliardi,&nbsp;Nathalie Gerstner,&nbsp;Maik Ködel,&nbsp;Vanessa Murek,&nbsp;Michael J. Ziller,&nbsp;Elizabeth Scarr,&nbsp;Ran Tao,&nbsp;Andrew E. Jaffe,&nbsp;Thomas Arzberger,&nbsp;Peter Falkai,&nbsp;Joel E. Kleinmann,&nbsp;Daniel R. Weinberger,&nbsp;Naguib Mechawar,&nbsp;Andrea Schmitt,&nbsp;Brian Dean,&nbsp;Gustavo Turecki,&nbsp;Thomas M. Hyde,&nbsp;Elisabeth B. Binder","doi":"10.1007/s00401-023-02541-9","DOIUrl":"10.1007/s00401-023-02541-9","url":null,"abstract":"<div><p>Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. <i>FKBP5</i> is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that <i>FKBP5/</i>FKBP51 mRNA/protein (<i>FKBP5</i>/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel <i>FKBP5</i>/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (<i>n</i> = 1024) of <i>FKBP5/</i>1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical <i>FKBP5/</i>1 expression including in a cell type-specific manner. We identified consistently heightened <i>FKBP5/</i>1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on <i>FKBP5</i>/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in <i>FKBP5</i> levels may impact on synaptic plasticity, as <i>FKBP5</i> gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (<i>BDNF</i>) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"439 - 459"},"PeriodicalIF":12.7,"publicationDate":"2023-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02541-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9509181","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":"Loss of p16 expression is a sensitive marker of CDKN2A homozygous deletion in malignant meningiomas","authors":"Vivian Tang,&nbsp;Rufei Lu,&nbsp;Kanish Mirchia,&nbsp;Jessica Van Ziffle,&nbsp;Patrick Devine,&nbsp;Julieann Lee,&nbsp;Joanna J. Phillips,&nbsp;Arie Perry,&nbsp;David R. Raleigh,&nbsp;Calixto-Hope G. Lucas,&nbsp;David A. Solomon","doi":"10.1007/s00401-023-02544-6","DOIUrl":"10.1007/s00401-023-02544-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"497 - 500"},"PeriodicalIF":12.7,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02544-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9614992","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":"Archival wild-type poliovirus 1 infected central nervous system tissues of the pre-vaccination era in Switzerland reveal a distinct virus genotype","authors":"Nicole Wildi,&nbsp;Stefano Bagatella,&nbsp;Michel C. Koch,&nbsp;Anna Oevermann,&nbsp;Torsten Seuberlich","doi":"10.1007/s00401-023-02545-5","DOIUrl":"10.1007/s00401-023-02545-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 3","pages":"357 - 359"},"PeriodicalIF":12.7,"publicationDate":"2023-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02545-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9971421","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":"Variant allelic frequency of driver mutations predicts success of genomic DNA methylation classification in central nervous system tumors","authors":"Pouya Jamshidi,&nbsp;Matthew McCord,&nbsp;Kristyn Galbraith,&nbsp;Lucas Santana-Santos,&nbsp;Lawrence J. Jennings,&nbsp;Matija Snuderl,&nbsp;Craig Horbinski","doi":"10.1007/s00401-023-02542-8","DOIUrl":"10.1007/s00401-023-02542-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 3","pages":"365 - 367"},"PeriodicalIF":12.7,"publicationDate":"2023-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10321064","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":"Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS","authors":"Andreas Agrafiotis,&nbsp;Raphael Dizerens,&nbsp;Ilena Vincenti,&nbsp;Ingrid Wagner,&nbsp;Raphael Kuhn,&nbsp;Danielle Shlesinger,&nbsp;Marcos Manero-Carranza,&nbsp;Tudor-Stefan Cotet,&nbsp;Kai-Lin Hong,&nbsp;Nicolas Page,&nbsp;Nicolas Fonta,&nbsp;Ghazal Shammas,&nbsp;Alexandre Mariotte,&nbsp;Margot Piccinno,&nbsp;Mario Kreutzfeldt,&nbsp;Benedikt Gruntz,&nbsp;Roy Ehling,&nbsp;Alessandro Genovese,&nbsp;Alessandro Pedrioli,&nbsp;Andreas Dounas,&nbsp;Sören Franzenburg,&nbsp;Hayrettin Tumani,&nbsp;Tania Kümpfel,&nbsp;Vladyslav Kavaka,&nbsp;Lisa Ann Gerdes,&nbsp;Klaus Dornmair,&nbsp;Eduardo Beltrán,&nbsp;Annette Oxenius,&nbsp;Sai T. Reddy,&nbsp;Doron Merkler,&nbsp;Alexander Yermanos","doi":"10.1007/s00401-023-02537-5","DOIUrl":"10.1007/s00401-023-02537-5","url":null,"abstract":"<div><p>B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 3","pages":"335 - 355"},"PeriodicalIF":12.7,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02537-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9273007","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":"Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis","authors":"Raymond Nicks,&nbsp;Nathan F. Clement,&nbsp;Victor E. Alvarez,&nbsp;Yorghos Tripodis,&nbsp;Zachery H. Baucom,&nbsp;Bertrand R. Huber,&nbsp;Jesse Mez,&nbsp;Michael L. Alosco,&nbsp;Nurgul Aytan,&nbsp;Jonathan D. Cherry,&nbsp;Kerry A. Cormier,&nbsp;Carol Kubilius,&nbsp;Rebecca Mathias,&nbsp;Sarah E. Svirsky,&nbsp;Morgan J. Pothast,&nbsp;Audrey M. Hildebrandt,&nbsp;Jaeyoon Chung,&nbsp;Xudong Han,&nbsp;John F. Crary,&nbsp;Ann C. McKee,&nbsp;Matthew P. Frosch,&nbsp;Thor D. Stein","doi":"10.1007/s00401-023-02539-3","DOIUrl":"10.1007/s00401-023-02539-3","url":null,"abstract":"<div><p>Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (<i>n</i> = 401) as well as a group with HS-aging without CTE (<i>n</i> = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (<i>p</i> = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (<i>p</i> &lt; 0.001) through increased CTE stage (<i>p</i> &lt; 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"395 - 408"},"PeriodicalIF":12.7,"publicationDate":"2023-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9260355","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}