Brain Pathology最新文献

{"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}

{"title":"Society News","authors":"","doi":"10.1111/bpa.13257","DOIUrl":"https://doi.org/10.1111/bpa.13257","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 3","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140544386","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 supratentorial mass in a young adult, with 25 years of follow-up","authors":"Francesca Baciorri,&nbsp;Samantha Sarcognato,&nbsp;Francesco Di Paola,&nbsp;Evelina Miele,&nbsp;Sabrina Rossi","doi":"10.1111/bpa.13260","DOIUrl":"10.1111/bpa.13260","url":null,"abstract":"&lt;p&gt;A 32-year-old male presented with a history of recent onset headaches. Imaging with magnetic resonance revealed a left parietal mass that showed heterogeneous gadolinium contrast enhancement, mild perilesional edema, and a small cystic component (Figure 1). The patient underwent surgical excision, with a complete resection of the mass. No adjuvant therapies were administered. Periodic follow-up magnetic resonance imaging did not show disease recurrence, and the patient is currently disease-free 25 years after the diagnosis (Box 1).&lt;/p&gt;&lt;p&gt;Histopathological examination showed a well-demarcated hypercellular neoplasm, with a multinodular growth, a rich vascular network, and perivascular paucicellular zones. The neoplastic cells displayed moderate nuclear atypia and diffuse lipomatous differentiation, which consisted of single large cytoplasmic vacuoles pushing the nuclei to the periphery of the cells, giving a signet ring appearance (Figure 2). The mitotic count reached 4 mitotic figures per 10 high-power fields, and necrosis and microvascular proliferation were absent.&lt;/p&gt;&lt;p&gt;By immunohistochemistry, the cells showed immunoreactivity for glial fibrillary acidic protein, S100, and focal dot-like cytoplasmic positivity for epithelial membrane antigen. Ki-67 labeling index was 10%. Electron microscopy was performed and revealed the presence of complex zipper-like intercellular junctions and microvilli, typical of ependymal differentiation (Figure 2). Twenty-five years later, the case was re-evaluated with additional immunostains and molecular analyses. The tumor proved positive for p65 and L1CAM, consistent with the diagnosis of supratentorial ependymoma, ZFTA fusion-positive (ST-EPN-ZFTA). While we failed to obtain good quality RNA for gene fusion investigation, we were able to perform DNA methylation analysis (Epic Illumina) on the original samples. In agreement with the pathological and immunohistochemical findings, the lesion classified as a ST-EPN-ZFTA (score 0.62), subtype A (score 0.58, DKFZ Classifier version v12.5). The copy number variation (CNV) profile obtained from DNA methylation analysis showed considerable background noise likely due to the age of the material; nevertheless, loss of chromosomes 9 and 22 was clearly observed (Figure 2).&lt;/p&gt;&lt;p&gt;Back in the days, a diagnosis of ependymoma with lipomatous differentiation, grade II, was made with the support of morphology, immunohistochemistry, and electron microscopy. After 25 years, the addition of new immunohistochemical markers and the DNA methylation profile confirmed the diagnosis and led to a more accurate definition of the lesion as a ST-EPN-ZFTA with diffuse lipomatous differentiation, grade 2.&lt;/p&gt;&lt;p&gt;We herein describe a case of ST-EPN-ZFTA with lipomatous differentiation arising in a young adult who did not show any recurrence over a follow-up period of 25 years. Lipomatous differentiation is described in a few central nervous system (CNS) tumors, such as medulloblastomas, centra","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570135","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 comprehensive histomolecular characterization of meningioangiomatosis: Further evidence for a precursor neoplastic lesion","authors":"Arnault Tauziède-Espariat,&nbsp;Julien Masliah-Planchon,&nbsp;Philipp Sievers,&nbsp;Felix Sahm,&nbsp;Volodia Dangouloff-Ros,&nbsp;Nathalie Boddaert,&nbsp;Lauren Hasty,&nbsp;Oumaima Aboubakr,&nbsp;Alice Métais,&nbsp;Fabrice Chrétien,&nbsp;Alexandre Roux,&nbsp;Johan Pallud,&nbsp;Thomas Blauwblomme,&nbsp;Kévin Beccaria,&nbsp;Franck Bourdeaut,&nbsp;Stéphanie Puget,&nbsp;Pascale Varlet","doi":"10.1111/bpa.13259","DOIUrl":"10.1111/bpa.13259","url":null,"abstract":"<p>Meningioangiomatosis (MAM) remains a poorly understood lesion responsible for epileptic disease. In the past, MAM was primarily described in the context of neurofibromatosis type 2 before being mainly reported sporadically. Moreover, the malformative or tumoral nature is still debated. Because a subset of MAM are associated with meningiomas, some authors argue that MAM corresponds to an infiltration pattern of these tumors. For these reasons, MAM has not been added to the World Health Organization (WHO) Classification of Central Nervous System Tumors as a specific entity. In the present study, we characterized a series of pure MAM (<i>n</i> = 7) and MAM associated with meningiomas (<i>n</i> = 4) using histopathology, immunohistochemistry, genetic (fluorescent in situ and DNA sequencing analyses), and epigenetic (DNA-methylation profiling) data. We evidenced two distinct morphological patterns: MAM with a fibroblastic-like pattern having few lesional cells, and MAM with a more cellular pattern. A subset was associated with the genetic alterations previously reported in meningiomas (such as a <i>KMT2C</i> mutation and a hemizygous deletion of chromosome 22q including the <i>NF2</i> gene). The DNA-methylation profile, using a t-distributed stochastic neighbor embedding analysis, evidenced that MAM (pure or associated with meningiomas) clustered in a separate group from pediatric meningiomas. The present results seem to suggest that MAM represents a neoplastic lesion and encourage the further study of similar additional series so that it may be included in a future WHO classification.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13259","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569662","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 mass in the pineal region of a young woman","authors":"Lorraina J. Robinson,&nbsp;Eric Goold,&nbsp;David Anderson,&nbsp;Robert C. Rennert,&nbsp;William T. Couldwell,&nbsp;Changhong Xing","doi":"10.1111/bpa.13258","DOIUrl":"10.1111/bpa.13258","url":null,"abstract":"&lt;p&gt;This case involves an 18-year-old female with no significant past medical history who was found to have a large pineal and third ventricular tumor with obstructive hydrocephalus after experiencing subacute, progressive headaches, and an acute episode of sudden vision loss. She underwent a ventriculoperitoneal shunt at an outside facility with improvement in her vision before presenting as a transfer to our facility. Brain magnetic resonance imaging upon transfer demonstrated a large, heterogenous enhancing mass (6.6 × 6.1 × 5.7 cm) centered in the pineal region with extension into the third and right lateral ventricles (Figure 1). The tumor exerted mass effect by splaying the bilateral thalami with effacement of the basal cisterna, effacement of the cerebral aqueduct, and an 8 mm tonsillar herniation. Surgery was pursued for a definitive diagnosis and tumor debulking. Intraoperatively, the tumor demonstrated variable soft and firm consistency with moderate vascularity. Post-operative imaging did not demonstrate clear residual tumor. She was discharged with no new neurologic deficits.&lt;/p&gt;&lt;p&gt;Histology of H&amp;E-stained sections demonstrated a moderately hypercellular neoplasm consisting of an admixture of small to medium-sized spindle cells embedded in a heavily collagenized and myxoid matrix (Box 1, Figure 2A, B). Tumor cells were observed forming disorganized, haphazard architectural patterns while some tumor cells were seen floating in a loose basophilic myxoid matrix (Figure 2A). The mitotic index was &lt;1/10 high-power-fields. Necrosis was absent. By immunohistochemistry, the tumor cells were patchy positive for CD163 (Figure 2C) and CD99 (Figure 2D), focally positive for desmin (Figure 2D inset), and negative for GFAP, OLIG2, CD34, and SSTR2. MIB-1 proliferation index was overall low (1%–2%) (Figure 2E) but focally increased at approximately 10% (Figure 2E inset). Immunostaining for SMARCB1 showed loss of expression in many of the tumor cells (Figure 2F).&lt;/p&gt;&lt;p&gt;NeoTYPE brain tumor profile (DNA and RNA) from NeoGenomics was performed, and no pathogenic mutations or fusions were detected. However, a variant of unknown clinical significance involving the &lt;i&gt;SMARCB1&lt;/i&gt; gene c.91G&gt;A (p.Glu31Lys) E31K NM_003073.5:c.91G&gt;A was detected. Whole genome methylation profiling was performed at the National Institute of Health (NIH)/National Cancer Institute (NCI) for confirmation of the diagnosis. The composite NIH/NCI methylation profile classified the tumor with a high confidence score (0.99) as a desmoplastic myxoid tumor, &lt;i&gt;SMARCB1&lt;/i&gt;-altered.&lt;/p&gt;&lt;p&gt;Desmoplastic myxoid tumor (DMT) of the pineal region, &lt;i&gt;SMARCB1&lt;/i&gt;-mutant.&lt;/p&gt;&lt;p&gt;As defined by the most recent 2021 World Health Organization (WHO) Central Nervous System tumor classification, DMT of the pineal region, &lt;i&gt;SMARCB1&lt;/i&gt;-mutant, maintains a unique &lt;i&gt;SMARCB1&lt;/i&gt;-mutation while histologically displaying desmoplasia and myxoid changes but lacking histopathological signs of maligna","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 3","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288275","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":"NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors","authors":"Kathryn L. Eschbacher,&nbsp;Quynh T. Tran,&nbsp;Evgeny A. Moskalev,&nbsp;Sarah Jenkins,&nbsp;Karen Fritchie,&nbsp;Robert Stoehr,&nbsp;Alissa Caron,&nbsp;Michael J. Link,&nbsp;Paul D. Brown,&nbsp;Andrew Guajardo,&nbsp;Daniel J. Brat,&nbsp;Ashley Wu,&nbsp;Sandro Santagata,&nbsp;David N. Louis,&nbsp;Priscilla K. Brastianos,&nbsp;Alexander B. Kaplan,&nbsp;Brian Alexander,&nbsp;Sabrina Rossi,&nbsp;Fabio Ferrarese,&nbsp;David R. Raleigh,&nbsp;Minh P. Nguyen,&nbsp;John Gross,&nbsp;Jose Velazquez Vega,&nbsp;Fausto Rodriguez,&nbsp;Arie Perry,&nbsp;Maria Martinez-Lage,&nbsp;Brent A. Orr,&nbsp;Florian Haller,&nbsp;Caterina Giannini","doi":"10.1111/bpa.13256","DOIUrl":"10.1111/bpa.13256","url":null,"abstract":"<p>Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (<i>n</i> = 80) and targeted <i>TERT</i> promoter mutation testing (<i>n</i> = 98). Associations were examined with <i>NAB2::STAT6</i> fusion status (<i>n</i> = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. <i>NAB2::STAT6</i> fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (<i>p</i> = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (<i>p</i> = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (<i>n</i> = 38), Cluster 2 (<i>n</i> = 22), and Cluster 3 (<i>n</i> = 20). Methylation clusters were significantly associated with fusion type (<i>p</i> &lt; 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all <i>TERT</i> promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (<i>p</i> = 0.027), but not overall survival (OS). In summary, <i>NAB2::STAT6</i> fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, <i>TERT</i> promoter mutation status, histologic phenotype, and MFS.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140206382","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":"Oligodendrocyte progenitor cells' fate after neonatal asphyxia—Puzzling implications for the development of hypoxic–ischemic encephalopathy","authors":"Justyna Janowska,&nbsp;Justyna Gargas,&nbsp;Karolina Zajdel,&nbsp;Michal Wieteska,&nbsp;Kamil Lipinski,&nbsp;Malgorzata Ziemka-Nalecz,&nbsp;Malgorzata Frontczak-Baniewicz,&nbsp;Joanna Sypecka","doi":"10.1111/bpa.13255","DOIUrl":"10.1111/bpa.13255","url":null,"abstract":"<p>Premature birth or complications during labor can cause temporary disruption of cerebral blood flow, often followed by long-term disturbances in brain development called hypoxic–ischemic (HI) encephalopathy. Diffuse damage to the white matter is the most frequently detected pathology in this condition. We hypothesized that oligodendrocyte progenitor cell (OPC) differentiation disturbed by mild neonatal asphyxia may affect the viability, maturation, and physiological functioning of oligodendrocytes. To address this issue, we studied the effect of temporal HI in the in vivo model in P7 rats with magnetic resonance imaging (MRI), microscopy techniques and biochemical analyses. Moreover, we recreated the injury in vitro performing the procedure of oxygen–glucose deprivation on rat neonatal OPCs to determine its effect on cell viability, proliferation, and differentiation. In the in vivo model, MRI evaluation revealed changes in the volume of different brain regions, as well as changes in the directional diffusivity of water in brain tissue that may suggest pathological changes to myelinated neuronal fibers. Hypomyelination was observed in the cortex, striatum, and CA3 region of the hippocampus. Severe changes to myelin ultrastructure were observed, including delamination of myelin sheets. Interestingly, shortly after the injury, an increase in oligodendrocyte proliferation was observed, followed by an overproduction of myelin proteins 4 weeks after HI. Results verified with the in vitro model indicate, that in the first days after damage, OPCs do not show reduced viability, intensively proliferate, and overexpress myelin proteins and oligodendrocyte-specific transcription factors. In conclusion, despite the increase in oligodendrocyte proliferation and myelin protein expression after HI, the production of functional myelin sheaths in brain tissue is impaired. Presented study provides a detailed description of oligodendrocyte pathophysiology developed in an effect of HI injury, resulting in an altered CNS myelination. The described models may serve as useful tools for searching and testing effective of effective myelination-supporting therapies for HI injuries.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140166088","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":"Dysregulation of the renin-angiotensin system in vascular dementia","authors":"H. M. Tayler,&nbsp;O. A. Skrobot,&nbsp;D. H. Baron,&nbsp;P. G. Kehoe,&nbsp;J. S. Miners","doi":"10.1111/bpa.13251","DOIUrl":"10.1111/bpa.13251","url":null,"abstract":"<p>The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (<i>n</i> = 42), Alzheimer's disease (<i>n</i> = 50), mixed AD/VaD (<i>n</i> = 50) and age-matched controls (<i>n</i> = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE-1 and ACE-2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang-II, Ang-III and Ang-(1–7)) levels were measured by ELISA. ACE-1 protein level and enzyme activity, and Ang-II and Ang-III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE-1 and Ang-II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE-2 level was elevated in frontal white matter in vascular dementia. Ang-(1–7) level was elevated across all dementia groups compared to age-matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE-1 protein was reduced and ACE-2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058728","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":"Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory-related omics signatures to computational repurposing of drug candidates","authors":"Paz Cartas-Cejudo,&nbsp;Adriana Cortés,&nbsp;Mercedes Lachén-Montes,&nbsp;Elena Anaya-Cubero,&nbsp;Elena Puerta,&nbsp;Maite Solas,&nbsp;Joaquín Fernández-Irigoyen,&nbsp;Enrique Santamaría","doi":"10.1111/bpa.13252","DOIUrl":"10.1111/bpa.13252","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD-associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (<i>n</i> = 17/group) showed a Braak stage-dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD-related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass-spectrometry or RNA-sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map-based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin-like growth factor 1 (IGF-1), microtubules, and Polo-like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD-associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron-like SH-SY5Y cells with the EGFR inhibitor AG-1478 showed a neuroprotective effect against hydrogen peroxide-induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid-beta (Aβ)-induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058729","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":"Astrocytic phagocytosis in the medial prefrontal cortex jeopardises postoperative memory consolidation in mice","authors":"Xin Ma,&nbsp;Yuan Le,&nbsp;Lin Hu,&nbsp;Wen Ouyang,&nbsp;Cheng Li,&nbsp;Daqing Ma,&nbsp;Jianbin Tong","doi":"10.1111/bpa.13253","DOIUrl":"10.1111/bpa.13253","url":null,"abstract":"<p>Memory impairment is one of the main characteristics of postoperative cognitive dysfunction. It remains elusive how postoperative pathological changes of the brain link to the memory impairment. The clinical setting of perioperation was mimicked via partial hepatectomy under sevoflurane anaesthesia together with preoperative restraint stress (Hep-Sev-stress) in mice. Memory changes were assessed with fear conditioning. The medial prefrontal cortex (mPFC)-dorsal hippocampus connectivity was evaluated with injecting neurotracer 28 days before surgery. Astrocytic activation was limited via injecting AAV-GFAP-hM4Di-eGFP into the mPFC. Astrocytic and microglial phagocytosis of synapses were visualised with co-labelling hippocampal neuronal axon terminals with PSD-95 and S100β or Iba1. Neuroinflammation and oxidative stress status were also detected. Hep-Sev-stress impaired the memory consolidation (mean [standard error], 49.91 [2.55]% vs. 35.40 [3.97]% in the contextual memory, <i>p</i> = 0.007; 40.72 [2.78]% vs. 27.77 [2.22]% in cued memory, <i>p</i> = 0.002) and the cued memory retrieval (39.00 [3.08]% vs. 24.11 [2.06]%, <i>p</i> = 0.001) in mice when compared with these in the naïve controls. Hep-Sev-stress damaged the connectivity from the dorsal hippocampus to mPFC but not from the mPFC to the dorsal hippocampus and increased the astrocytic but not microglial phagocytosis of hippocampal neuronal axon terminals in the mPFC. The intervention also induced neuroinflammation and oxidative stress in the dorsal hippocampus and the mPFC in a regional-dependent manner. Limiting astrocyte activation in the mPFC alleviated memory consolidation impairment induced by Hep-Sev-stress. Postoperative memory consolidation was impaired due to astrocytic phagocytosis-induced connectivity injury from the dorsal hippocampus to the medial prefrontal cortex.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058727","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}