Brain Pathology最新文献

{"title":"Nanoarchitecture of Ca_V2.1 channels and GABA_B receptors in the mouse hippocampus: Impact of APP/PS1 pathology.","authors":"Alejandro Martín-Belmonte, Carolina Aguado, Rocío Alfaro-Ruiz, Akos Kulik, Luis de la Ossa, Ana Esther Moreno-Martínez, Samuel Alberquilla, Lucía García-Carracedo, Miriam Fernández, Ana Fajardo-Serrano, Ester Aso, Ryuichi Shigemoto, Eduardo D Martín, Yugo Fukazawa, Francisco Ciruela, Rafael Luján","doi":"10.1111/bpa.13279","DOIUrl":"https://doi.org/10.1111/bpa.13279","url":null,"abstract":"<p><p>Voltage-gated Ca_V2.1 (P/Q-type) Ca²⁺ channels play a crucial role in regulating neurotransmitter release, thus contributing to synaptic plasticity and to processes such as learning and memory. Despite their recognized importance in neural function, there is limited information on their potential involvement in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we aimed to explore the impact of AD pathology on the density and nanoscale compartmentalization of Ca_V2.1 channels in the hippocampus in association with GABA_B receptors. Histoblotting experiments showed that the density of Ca_V2.1 channel was significantly reduced in the hippocampus of APP/PS1 mice in a laminar-dependent manner. Ca_V2.1 channel was enriched in the active zone of the axon terminals and was present at a very low density over the surface of dendritic tree of the CA1 pyramidal cells, as shown by quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL). In APP/PS1 mice, the density of Ca_V2.1 channel in the active zone was significantly reduced in the strata radiatum and lacunosum-moleculare, while it remained unaltered in the stratum oriens. The decline in Cav2.1 channel density was found to be associated with a corresponding impairment in the GABAergic synaptic function, as evidenced by electrophysiological experiments carried out in the hippocampus of APP/PS1 mice. Remarkably, double SDS-FRL showed a co-clustering of Ca_V2.1 channel and GABA_B1 receptor in nanodomains (~40-50 nm) in wild type mice, while in APP/PS1 mice this nanoarchitecture was absent. Together, these findings suggest that the AD pathology-induced reduction in Ca_V2.1 channel density and Ca_V2.1-GABA_B1 de-clustering may play a role in the synaptic transmission alterations shown in the AD hippocampus. Therefore, uncovering these layer-dependent changes in P/Q calcium currents associated with AD pathology can benefit the development of future strategies for AD management.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e13279"},"PeriodicalIF":6.4,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathologic TDP-43 downregulates myelin gene expression in the monkey brain","authors":"Longhong Zhu,&nbsp;Dazhang Bai,&nbsp;Xiang Wang,&nbsp;Kaili Ou,&nbsp;Bang Li,&nbsp;Qingqing Jia,&nbsp;Zhiqiang Tan,&nbsp;Jiahui Liang,&nbsp;Dajian He,&nbsp;Sen Yan,&nbsp;Lu Wang,&nbsp;Shihua Li,&nbsp;Xiao-Jiang Li,&nbsp;Peng Yin","doi":"10.1111/bpa.13277","DOIUrl":"10.1111/bpa.13277","url":null,"abstract":"<p>Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellar mass in a 31-year-old woman","authors":"Davide Mulone,&nbsp;Rita Polati,&nbsp;Evelina Miele,&nbsp;Sara Patrizi,&nbsp;Andrea Mafficini,&nbsp;Valeria Barresi","doi":"10.1111/bpa.13268","DOIUrl":"10.1111/bpa.13268","url":null,"abstract":"&lt;p&gt;A 31-year-old woman presented to the emergency department with a one-month history of headache, dizziness, and phosphenes.&lt;/p&gt;&lt;p&gt;Magnetic resonance imaging (MRI) revealed a 5 cm, well-circumscribed mass with small cystic areas, in the left cerebellar hemisphere. It was isointense, with focal hyperintensity and heterogeneous contrast enhancement, on T1-weigheted images, and hyperintense, with focal accentuation of hyperintensity, on T2-weigheted images (Figure 1).&lt;/p&gt;&lt;p&gt;Intra-operative cytological smear showed uniform neurocytic cells without mitoses or pleomorphism. Histological examination of formalin-fixed paraffin-embedded (FFPE) surgical specimens revealed a tumor composed of small monomorphic cells with round to oval nuclei (Figure 2A) and rare mitoses (two in 50 high-power fields) arranged in sheets or lobules. In some areas, the tumor cells exhibited a clear cytoplasm and an oligodendroglial-like appearance (Figure 2A, Box 1). In others, the presence of fibrillary matrix around the vessels was reminiscent of perivascular pseudorosettes (Figure 2B). Lipidized cells, scattered or in small foci, were focally identified (Figure 2A, circles). Necrosis and microvascular proliferation were absent.&lt;/p&gt;&lt;p&gt;By immunohistochemistry, the tumor was extensively positive for synaptophysin (Figure 2C) and NeuN (Figure 2D) and negative for OLIG2, EMA, and IDH1 p. R132H. GFAP immunostaining was restricted to reactive astrocytes. Ki-67 labelling index was 2% (Figure 2E).&lt;/p&gt;&lt;p&gt;Next-generation sequencing revealed the lack of mutations or copy number variations in &lt;i&gt;APC&lt;/i&gt;, &lt;i&gt;PTCH1&lt;/i&gt;, &lt;i&gt;CTNNB1&lt;/i&gt;, &lt;i&gt;IDH1/2&lt;/i&gt;, and &lt;i&gt;TP53&lt;/i&gt;. DNA methylation profiling indicated a match with cerebellar liponeurocytoma (calibrated score, 0.99; v. 12.5 Heidelberg Classifier). Copy number analysis using DNA methylation array revealed a flat profile. In t-distributed stochastic neighbor embedding (t-SNE) analysis, the tumor was positioned separately from medulloblastoma and central or extraventricular neurocytoma methylation classes (Figure 2F).&lt;/p&gt;&lt;p&gt;Cerebellar liponeurocytoma, CNS WHO grade 2 (2021 WHO CNS tumor classification).&lt;/p&gt;&lt;p&gt;Cerebellar liponeurocytoma is a rare, slow-growing tumor, with approximately 70 cases reported to date [&lt;span&gt;1&lt;/span&gt;]. By definition, it occurs in the cerebellum, mostly in the cerebellar hemispheres of adults between the third and fifth decades of life [&lt;span&gt;1&lt;/span&gt;], and displays neuronal or neurocytic differentiation and lipoma-like changes [&lt;span&gt;2&lt;/span&gt;], caused by lipid accumulation in neuroepithelial tumor cells.&lt;/p&gt;&lt;p&gt;The diagnosis of cerebellar liponeurocytoma is relatively straightforward when extensive lipomatous foci are present but it can be challenging if lipomatous foci are limited, as in the present case. On MRI, cerebellar liponeurocytoma is well-circumscribed, with fat deposits appearing as hyperintense in T1 and as accentuated hyperintensity in T2. In this case, the areas of hyperintensity in T1 and accentuation o","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased microvascular claudin-5 levels in cerebral amyloid angiopathy associated with intracerebral haemorrhage","authors":"Lieke Jäkel,&nbsp;Kiki K. W. J. Claassen,&nbsp;Anna M. De Kort,&nbsp;Wilmar M. T. Jolink,&nbsp;Yannick Vermeiren,&nbsp;Floris H. B. M. Schreuder,&nbsp;Benno Küsters,&nbsp;Catharina J. M. Klijn,&nbsp;H. Bea Kuiperij,&nbsp;Marcel M. Verbeek","doi":"10.1111/bpa.13270","DOIUrl":"10.1111/bpa.13270","url":null,"abstract":"<p>Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease","authors":"Caitlyn Fastenau,&nbsp;Madison Bunce,&nbsp;Mallory Keating,&nbsp;Jessica Wickline,&nbsp;Sarah C. Hopp,&nbsp;Kevin F. Bieniek","doi":"10.1111/bpa.13267","DOIUrl":"10.1111/bpa.13267","url":null,"abstract":"<p>Glycosylation is the most common form of post-translational modification in the brain. Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer's disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate-associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of <i>O</i>- and <i>N</i>-linked glycans in autopsy-confirmed AD post-mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell-to-cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both <i>N</i>- and <i>O</i>-linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater <i>N</i>-sialylation of the Aβ plaque microenvironment compared with <i>O</i>-sialylation. Plaque-associated microglia displayed the most intense <i>N</i>-sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of <i>N</i>- and <i>O</i>-sialylation between cored and diffuse Aβ plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in <i>N</i>-sialylation and no influence of <i>O</i>-sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal intradural pseudocyst formation in central nervous system superficial siderosis","authors":"Kiyoshi Ito,&nbsp;Mitsunori Yamada,&nbsp;Kai Uehara,&nbsp;Yusuke Takahashi,&nbsp;Minori Kodaira,&nbsp;Yoshiki Sekijima,&nbsp;Yasuko Toyoshima,&nbsp;Akiyoshi Kakita,&nbsp;Kunihiko Makino,&nbsp;Hiroki Ohashi,&nbsp;Kazuhiro Hongo,&nbsp;Tetsuyoshi Horiuchi","doi":"10.1111/bpa.13269","DOIUrl":"10.1111/bpa.13269","url":null,"abstract":"<p>The figure shows tissue samples taken from three previous cases, revealing the cause of hemosiderin deposition in the central nervous system because of superficial siderosis.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrillar extracellular matrix produced by pericyte-like cells facilitates glioma cell dissemination","authors":"Petr Vymola,&nbsp;Elena Garcia-Borja,&nbsp;Jakub Cervenka,&nbsp;Eva Balaziova,&nbsp;Barbora Vymolova,&nbsp;Jana Veprkova,&nbsp;Petr Vodicka,&nbsp;Helena Skalnikova,&nbsp;Robert Tomas,&nbsp;David Netuka,&nbsp;Petr Busek,&nbsp;Aleksi Sedo","doi":"10.1111/bpa.13265","DOIUrl":"10.1111/bpa.13265","url":null,"abstract":"<p>Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13265","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A role for vessel-associated extracellular matrix proteins in multiple sclerosis pathology","authors":"Marco Pisa,&nbsp;Joseph L. Watson,&nbsp;Jonathan I. Spencer,&nbsp;Guy Niblett,&nbsp;Yasamin Mahjoub,&nbsp;Andrew Lockhart,&nbsp;Richard L. Yates,&nbsp;Sydney A. Yee,&nbsp;Gina Hadley,&nbsp;Jennifer Ruiz,&nbsp;Margaret M. Esiri,&nbsp;Benedict Kessler,&nbsp;Roman Fischer,&nbsp;Gabriele C. DeLuca","doi":"10.1111/bpa.13263","DOIUrl":"10.1111/bpa.13263","url":null,"abstract":"<p>Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. <i>HLA-DRB1*15</i>, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to <i>HLA-DRB1*15</i> status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by <i>HLA-DRB*15</i> status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in <i>HLA-DRB*15</i>-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 <i>HLA-DRB1*15</i>-positive and <i>23 HLA-DRB1*15</i>-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (−36.5%, <i>p</i> = 0.036 and − 24.7%, <i>p</i> = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (<i>p</i> = 0.015 and <i>p</i> = 0.001, respectively), particularly in <i>HLA-DRB1*15</i>-positive cases (<i>p</i> = 0.007 and <i>p</i> = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, <i>p</i> = 0.001; cervical cord +49.1%, <i>p</i> = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “A 4-year-old boy with a ventricular mass”","authors":"","doi":"10.1111/bpa.13266","DOIUrl":"10.1111/bpa.13266","url":null,"abstract":"<p>\u0000 <span>Zhou, J</span>, <span>Qu, K</span>, <span>Lv, M</span>, <span>Gao, Y</span>, <span>Zhang, L</span>, <span>Duan, L</span>, et al. <span>A 4-year-old boy with a ventricular mass</span>. <i>Brain Pathology.</i> <span>2022</span>; <span>32</span>(<span>5</span>):e13081. https://doi.org/10.1111/bpa.13081\u0000 </p><p>Figure 1 of this article has been published in another article shortly before by a different group of authors from the same institute elsewhere [<span>1</span>]. The authors have confirmed that they had access to the MR images and the histology results of their study from the hospitals public database and were not aware of the other group's publication. Although both articles describe the same patient, and partially overlapping results, yet the content is sufficiently different not to be considered redundant.</p><p>The authors have obtained retrospective permission for the reproduction of this image from the Chinese Journal of Contemporary Neurology &amp; Neurosurgery. The updated caption of Figure 1 with the copyright statement is as follows:</p><p><b>FIGURE 1</b> Axial T1-weighted contrast enhanced magnetic resonance imaging shows the low intensity mass was located on the front edge of the right brain ventricle, with a few darker strands and no enhancement (arrowhead). Reprinted with permission, Copyright 2022, Chinese Journal of Contemporary Neurology &amp; Neurosurgery [<span>1</span>].</p><p>The authors also wished to make a correction to the affiliation of the co-authors, Kexuan Qu and Mengxing Lv.</p><p>The correct affiliation is: Department of Pathology, Kunming Children's Hospital, Kunming, P.R. China and Department of Blood Transfusion, Kunming Children's Hospital, Kunming, P. R. China</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140675656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis","authors":"Qi-Jie Zhang,&nbsp;Jie Lin,&nbsp;You-Liang Wang,&nbsp;Long Chen,&nbsp;Ying Ding,&nbsp;Fu-Ze Zheng,&nbsp;Huan-Huan Song,&nbsp;Ao-Wei Lv,&nbsp;Yu-Ying Li,&nbsp;Qi-Fu Guo,&nbsp;Min-Ting Lin,&nbsp;Wei Hu,&nbsp;Liu-Qing Xu,&nbsp;Wen-Long Zhao,&nbsp;Ling Fang,&nbsp;Meng-Chao Cui,&nbsp;Zhi-Fei Fu,&nbsp;Wan-Jin Chen,&nbsp;Jing Zhang,&nbsp;Zhi-Qiang Wang,&nbsp;Ning Wang,&nbsp;Ying Fu","doi":"10.1111/bpa.13261","DOIUrl":"10.1111/bpa.13261","url":null,"abstract":"<p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; <i>p</i> &lt; 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}