Brain Pathology最新文献

{"title":"Endothelial Netrin-4 regulates oligodendrocyte precursor cell proliferation and differentiation via ET-1 signaling in preterm white matter injury","authors":"Fuxing Dong,&nbsp;Weixing Yan,&nbsp;Qiqi Meng,&nbsp;Xueli Song,&nbsp;Bing Cheng,&nbsp;Yaping Liu,&nbsp;Yanan Liu,&nbsp;Chao Ren,&nbsp;Ruiqin Yao","doi":"10.1111/bpa.70067","DOIUrl":"10.1111/bpa.70067","url":null,"abstract":"<p>Perinatal hypoxia–ischemia is a leading cause of preterm white matter injury (PWMI), yet mechanisms underlying oligodendrocyte precursor cells (OPCs) dysfunction remain poorly understood. Here, we identify endothelial-derived Netrin-4 (<i>Ntn4</i>) as a critical regulator of OPCs proliferation and differentiation in PWMI. Developmental analysis revealed that Netrin-4, predominantly expressed in cerebrovascular endothelial cells (ECs), peaks during postnatal myelination and correlates with OPCs marker PDGFR-<i>α</i>. Conditional endothelial deletion of <i>Ntn4</i> in mice impaired spatial memory, induced anxiety-like behavior, and reduced mature oligodendrocytes, accompanied by disrupted myelin ultrastructure. In a PWMI model, endothelial <i>Ntn4</i> knockout exacerbated myelination deficits and suppressed OPCs proliferation, while inducible deletion at later stages enhanced OPCs differentiation. Mechanistically, Netrin-4-overexpressing ECs elevated ET-1 secretion, which promoted OPCs proliferation but inhibited differentiation via ET-1 receptor EDNRB. Our findings reveal that endothelial Netrin-4 is a dual regulator of OPCs dynamics in PWMI, driving proliferation via ET-1 while impairing differentiation. Targeting the Netrin-4/ET-1 axis restores OPCs maturation, offering a potential strategy to mitigate myelination deficits in PWMI.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970713","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 6-year-old boy with left temporal lobe mass","authors":"Kaiyu Liu,&nbsp;Shilei Zhang,&nbsp;Mengqiu Cao,&nbsp;Renhua Huang,&nbsp;Jiong Hu,&nbsp;Hongda Shao,&nbsp;Yichao Jin,&nbsp;Bingqian Shen,&nbsp;Hongyu Zhou,&nbsp;Lihua Sun,&nbsp;Xiaohua Zhang","doi":"10.1111/bpa.70080","DOIUrl":"10.1111/bpa.70080","url":null,"abstract":"&lt;p&gt;A 6-year-old boy presented to the neurosurgical department with recurrent episodes of vomiting over the past week. CT imaging revealed an isodense mass measuring approximately 32 × 27 mm with a calcified rim, 7 mm in maximum thickness. The adjacent bony structures were intact and unaffected by the tumor. MRI revealed a well-defined, circular tumor in the parasellar region of the middle cranial fossa, isointense on T1WI, mildly hyperintense on T2WI, with homogeneous, significant enhancement on post-contrast T1WI. The calcified rim at the tumor margins, apposed to the dural surface, showed low signal intensity on T2WI. A non-enhancing, T2WI hyperintense area suggested a possible colloid-like cystic component. No dural tail sign was observed (Figure 1).&lt;/p&gt;&lt;p&gt;The patient was subjected to a surgical procedure for the excision of the brain tumor. The tumor appeared grayish-white and firm. Its boundary with the temporal lobe parenchyma was indistinct. Focal calcified components of the tumor had breached the leptomeninges, with adhesions to the dura mater. The tumor was excised along its visible boundaries. Additionally, tissue from the surrounding area, including the sandy-textured peripheral zone and regions with gliotic proliferation, was carefully removed. After the patient's discharge, no further treatment was arranged and follow-up evaluations were scheduled as needed.&lt;/p&gt;&lt;p&gt;The intra-operative frozen section revealed a spindle cell tumor with no obvious cellular atypia, hemorrhage, or necrosis. Combined with radiological findings of a solid mass apposed to the dura mater, meningioma was initially considered as a possible diagnosis.&lt;/p&gt;&lt;p&gt;Hematoxylin and eosin (H&amp;E) staining showed a prominent fibrous stroma composed of abundant collagen and spindle cells resembling fibroblasts, arranged in a storiform or fascicular pattern, with many areas of calcification (Box 1).Immunohistochemical analysis demonstrated that the spindle cells were negative for EMA, PR, SSTR2, and STAT6, ruling out meningioma and solitary fibrous tumor. In contrast, SOX10, GFAP, and OLIG2 were strongly positive in a subset of cells, confirming the presence of glial components. These glial components showed strong positivity for BRAF V600E immunohistochemical staining, while IDH1 p.R132H was negative and ATRX was positive.&lt;/p&gt;&lt;p&gt;The Ki-67 proliferation index was 3%. Only a few synaptophysin-positive neurons were identified after thorough examination of all sections. Next-generation sequencing identified only the &lt;i&gt;BRAF V600E&lt;/i&gt; mutation, with no other pathogenic mutations or fusions detected (Figure 2).&lt;/p&gt;&lt;p&gt;Desmoplastic infantile ganglioglioma, CNS WHO grade 1.&lt;/p&gt;&lt;p&gt;According to the 2021 WHO classification of CNS tumors, desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG) is categorized as a type of glioneuronal tumor with low invasiveness. This tumor predominantly occurs in early childhood, typically under 2 years old, though non-infantile cases have also been","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163973","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":"Amyloid-β aggregates induce vasculopathy via ferroptosis in brain endothelial cells","authors":"Suhyeon Son,&nbsp;Suji Kim,&nbsp;Min-Tae Jeon,&nbsp;Moonseok Choi,&nbsp;Kyu-Sung Kim,&nbsp;Suji Lee,&nbsp;Seung-Yeol Nah,&nbsp;Do-Geun Kim","doi":"10.1111/bpa.70074","DOIUrl":"10.1111/bpa.70074","url":null,"abstract":"<p>Amyloid-β (Aβ) plaque is the defining pathological feature of Alzheimer's disease (AD) and a target of various therapeutic agents for affected patients. Recent studies have demonstrated the dysfunction of the blood–brain barrier (BBB) in AD; however, how Aβ plaque induces BBB dysfunction, particularly in brain endothelial cells (ECs), remains elusive. This study investigates the lipid peroxidation-mediated ferroptosis pathway induced by Aβ via conducting RNA sequencing, phosphorylation analysis, metabolite analysis, western blotting, and immunofluorescent staining both in vitro and in vivo. Here, we demonstrate that Aβ is associated with lipid metabolic pathways following Aβ exposure in brain ECs. Additionally, Aβ aggregates induce the formation and accumulation of peroxidized lipid droplets. Lastly, Aβ is significantly reduced in brain ECs and 5xFAD mice by the inhibition of the lipid metabolic pathway associated with lipid peroxidation and ROS formation. Our findings from in vitro and in vivo both suggest that Aβ plays a causative role in the process of lipid peroxidation and might provide a potential target for the development of therapeutic interventions for AD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324496","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 50-year-old man with a 12-year history of extensive pachymeningeal thickening","authors":"Alyssa M. Lee,&nbsp;Siddhartha Gaddamanugu,&nbsp;Kathyrn L. Eschbacher,&nbsp;Aishwarya Ravindran","doi":"10.1111/bpa.70075","DOIUrl":"10.1111/bpa.70075","url":null,"abstract":"&lt;p&gt;The patient is a 50-year-old male who initially presented 12 years ago with persistent sinus problems, headache, and occasional onset of dizziness and diplopia. Magnetic resonance imaging (MRI) of the brain revealed a homogeneously enhancing extra-axial 4.2 cm retroclival mass involving the prepontine cistern, perimesencephalic cisterns, extending along the tentorium and medial middle fossa, and anteriorly along the posterior fossa into the internal auditory canal, radiologically compatible with meningioma. He underwent external beam radiation therapy (50.4 gray in 28 fractions) for the presumed radiologic diagnosis of meningioma. His symptoms resolved; however, MRI-brain continued to demonstrate a persistent lesion with a slight interval decrease from 4.2 to 4.0 cm. Concurrent computed tomography (CT) angiogram showed a lack of hyperostosis of the clivus, arguing against meningioma diagnosis, subsequently prompting the differential diagnosis of neurosarcoidosis versus idiopathic hypertrophic cranial pachymeningitis. He continued to follow up every 6 months since then; however, his clinical symptoms continued to worsen with the development of generalized arthralgia, fatigue, progressive bilateral hearing loss, imbalance, and papilledema resulting in a presumed clinical diagnosis of neurosarcoidosis. He underwent right ventriculoperitoneal shunting and right cochlear implantation with transient resolution of symptoms. After 12 years since the initial presentation, he presented to the emergency department with altered mental status, seizures, and left hemiparesis. MRI-brain showed persistence of the meningeal lesion (Figure 1) with brain parenchymal involvement. Infectious disease evaluation was negative. Given the clinical impression of neurosarcoidosis, a rheumatology evaluation was pursued which demonstrated left perinephric soft tissue thickening on CT-abdomen/pelvis, raising the differential diagnosis of sarcoidosis, lymphoma, Erdheim–Chester disease (ECD), and inflammatory pseudotumor. No other organs were involved by radiology evaluation. Biopsies of both the dural-based mass and the perinephric soft tissue mass were performed. The patient was initiated on empiric treatment with dexamethasone, rituximab, and subsequently cobimetinib, with worsening of neurologic symptoms. He passed away within a week from diagnosis due to massive pulmonary embolism and cardiac arrest (Box 1).&lt;/p&gt;&lt;p&gt;Biopsy of dural mass showed extensive involvement by abundant lymphoplasmacytic and histiocytic infiltrates. These histiocytes were characterized by enlarged round to oval nuclei, inconspicuous nucleoli, and abundant pale eosinophilic to foamy cytoplasm; foci of emperipolesis were present (Figure 2). By immunohistochemistry, these histiocytes were positive for CD163, S100, cyclinD1, and were negative for CD1a, SSTR2, BRAF V600E, and ALK. SSTR2 immunostaining highlighted the leptomeninges, which demonstrated reactive changes and showed no evidence of a mass-form","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099792","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":"Malignant craniopharyngiomas: Institutional experience and literature review","authors":"Thomas J. Auen,&nbsp;Isabella W. Zhang,&nbsp;Weiwei Zhang,&nbsp;Jordan M. Burr,&nbsp;Matthew L. Carda,&nbsp;James L. Wisecarver,&nbsp;Nicole Shonka,&nbsp;Jesse L. Cox,&nbsp;Sahara J. Cathcart,&nbsp;Allison Cushman-Vokoun,&nbsp;Jie Chen","doi":"10.1111/bpa.70068","DOIUrl":"10.1111/bpa.70068","url":null,"abstract":"<p>Malignant craniopharyngiomas, de novo or via malignant transformation, are exceedingly rare with a dismal prognosis and unclear treatment standards. Little is known about the factors involved in their pathogenesis. A natural language search, performed in our institutional CoPath system, identified 65 adamantinomatous craniopharyngiomas from 56 patients (25 males, 31 females; median age at initial diagnosis = 22 years). Among those, a unique case of malignant craniopharyngioma was identified in a 36-year-old male initially diagnosed with a benign adamantinomatous craniopharyngioma 16 years prior. A literature review identified 44 cases of malignant craniopharyngiomas (current case included) with a median age of 28 years and a median overall survival of 6 months, independent of sex, age, histologic variant, tumor size, or radiation therapy. Eighteen (41%) malignant craniopharyngiomas occurred in patients without a history of radiation, suggesting mechanisms other than radiation contribute to their pathogenesis. Since BRCA1-Associated Protein 1 (BAP1) and TP53 mutations have recently been reported in a case of malignant craniopharyngioma, we assessed these genes in the current case. Next-generation sequencing identified variants in BAP1 (c.1850delGinsCA;p.R617fs), TP53 (c.428delT;p.V143fs), and CTNNB1 (c.110C&gt;T;p.S37F). In conclusion, our results demonstrate that malignant craniopharyngioma tends to occur in young adults with a median overall survival of only 6 months. The current case is the second reported to harbor BAP1 and TP53 mutations by sequencing. BAP1 and TP53 mutations may play an important role in the pathogenesis of malignant craniopharyngioma and may offer potential targets for therapeutic intervention.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905647","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":"Optic nerve sheath meningioma exhibits neural niche-associated transcriptomic features and rare copy number variation-linked evolution","authors":"Daisuke Sato,&nbsp;Satoru Miyawaki,&nbsp;Yu Sakai,&nbsp;Kenta Ohara,&nbsp;Yu Teranishi,&nbsp;Yudai Hirano,&nbsp;Motoyuki Umekawa,&nbsp;Takahiro Tsuchiya,&nbsp;Shotaro Ogawa,&nbsp;So Hirata,&nbsp;Hiroki Hongo,&nbsp;Hideaki Ono,&nbsp;Daisuke Komura,&nbsp;Tetsuo Ushiku,&nbsp;Shumpei Ishikawa,&nbsp;Nobuhito Saito","doi":"10.1111/bpa.70078","DOIUrl":"10.1111/bpa.70078","url":null,"abstract":"<p>Optic nerve sheath meningioma (ONSM) is a rare tumor that arises from the meninges enveloping the optic nerve. Although the genetic landscape of meningiomas has been extensively studied, the molecular alterations underlying ONSM remain poorly understood. We retrospectively analyzed consecutive patients surgically treated for ONSM between 2000 and 2025 at our institution, with available histological specimens. Intracranial meningiomas secondarily extending into the optic canal were excluded. Fresh-frozen tumor samples were subjected to whole-exome sequencing, and transcriptomic analyses were conducted and compared with those of intracranial meningiomas from four public datasets. Six cases were included, five of whom were female, with a median age of 63.5 years. While most cases remained stable after surgery, one patient experienced multiple recurrences and ultimately succumbed. Primary tumors were characterized by the absence of <i>NF2</i> alterations, occasional <i>POLR2A</i> mutations, and few copy number variations (CNVs). Transcriptomic profiling in primary tumors revealed a neurotrophic microenvironment reflective of the close association with the optic nerve. The recurrent case exhibited high-risk CNVs at diagnosis and developed into an aggressive disease as additional CNV burdens accumulated, including the homozygous deletion of <i>CDKN2A/B</i>. Its expression profile was in line with that of hypermitotic, proliferative intracranial meningiomas. ONSM represents a predominantly <i>NF2</i>-intact meningioma subtype defined by neural niche-associated transcriptional signatures. Although typically indolent, ONSM can, in rare instances, evolve into an aggressive disease through further accumulation of CNVs.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099720","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":"TrkA abundance is increased in cutaneous nerves in bortezomib-induced neuropathy","authors":"Yuying Jin,&nbsp;Nadine Cebulla,&nbsp;Daniel Schirmer,&nbsp;Eva Runau,&nbsp;Leon Flamm,&nbsp;Calvin Terhorst,&nbsp;Laura Jähnel,&nbsp;Johanna Güse,&nbsp;Nicola Giordani,&nbsp;Annett Wieser,&nbsp;Julian Brennecke,&nbsp;Annemarie Sodmann,&nbsp;Martin Kortüm,&nbsp;Robert Blum,&nbsp;Claudia Sommer","doi":"10.1111/bpa.70079","DOIUrl":"10.1111/bpa.70079","url":null,"abstract":"<p>Tropomyosin receptor kinase A (TrkA), a high-affinity receptor for nerve growth factor (NGF), is implicated in nociception and local angiogenesis. We investigated TrkA localization and abundance in skin biopsies from multiple myeloma patients who developed peripheral neuropathy during bortezomib treatment. We recruited 50 multiple myeloma patients with bortezomib-induced peripheral neuropathy (BIPN), including 31 without pain and 19 with pain, and 27 matched healthy controls at University Hospital Würzburg (2021–2024). Skin biopsies from the distal leg were analyzed to determine intraepidermal nerve fiber density (IENFD) and area, TrkA mean fluorescence intensity (MFI) and gene expression levels. Additionally, the area of blood vessels and proximity to nerves was measured. BIPN patients exhibited significant sensory abnormalities, decreased IENFD, and increased TrkA protein abundance in surviving epidermal nerve fibers, correlating with cycles of bortezomib treatment. No substantial difference in TrkA gene expression was observed between groups. All BIPN patients demonstrated increased dermal vascularization compared with control, and only those without pain showed increased nerve-vessel interactions. These results suggest a strong association between dysregulated TrkA signaling and altered neurovascular interactions with small fiber pathology in BIPN.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123883","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":"The L108I polymorphism in mouse prion protein drives spontaneous disease and enhances transmission of atypical and classical prion strains","authors":"Hasier Eraña,&nbsp;Enric Vidal,&nbsp;Natalia Fernández-Borges,&nbsp;Jorge M. Charco,&nbsp;Carlos M. Díaz-Domínguez,&nbsp;Cristina Sampedro-Torres-Quevedo,&nbsp;Josu Galarza-Ahumada,&nbsp;Eva Fernández-Muñoz,&nbsp;Maitena San-Juan-Ansoleaga,&nbsp;Miguel Ángel Pérez-Castro,&nbsp;Nuno Gonçalves-Anjo,&nbsp;Patricia Piñeiro,&nbsp;Samanta Giler,&nbsp;Nora González-Martín,&nbsp;Nuria L. Lorenzo,&nbsp;Africa Manero-Azua,&nbsp;Guiomar Perez de Nanclares,&nbsp;Mariví Geijo,&nbsp;Manuel A. Sánchez-Martín,&nbsp;Jesús R. Requena,&nbsp;Joaquín Castilla","doi":"10.1111/bpa.70083","DOIUrl":"10.1111/bpa.70083","url":null,"abstract":"<p>Prion diseases are fatal neurodegenerative disorders that can be idiopathic, associated with genetic mutations, or acquired by infection with misfolded prion protein. We developed two complementary transgenic mouse models to investigate how the L108I substitution in mouse prion protein (PrP) influences spontaneous prion formation and transmission characteristics. The transgenic mouse model overexpressing the variant at approximately three times wild-type (WT) PrP levels (TgMo(L108I)3x) consistently developed a spontaneous neurodegenerative disorder between 219 and 536 days of age with 100% penetrance. This spontaneous disease exhibited biochemical and neuropathological characteristics of atypical prion disorders, featuring a distinctive 7–10 kDa protease-resistant PrP fragment and pathology comparable to small ruminants' atypical scrapie and certain forms of Gerstmann–Sträussler–Scheinker syndrome (GSS). In contrast, the knock-in model expressing the same variant at physiological levels (TgMo(L108I)1x) showed no spontaneous disease beyond 600 days, demonstrating that both the specific amino acid substitution and elevated expression levels are necessary for spontaneous prion formation. The spontaneously generated prions transmitted efficiently to models expressing the I108 variant and to Tga20 mice overexpressing WT PrP but encountered a robust transmission barrier toward WT mice, indicating strain-specific replication requirements. The TgMo(L108I)3x model demonstrated exceptional versatility as a universal acceptor for heterogeneous prion isolates, demonstrating superior efficiency in propagating atypical variants like GSS A117V (57 ± 0.6 days) and rapid propagation of classical scrapie-derived mouse prion strains, including Rocky Mountains Laboratory mouse prion strain (RML) (85 ± 3.8 days) and 22L (95 ± 1 days). Comparative analysis revealed that the L108I substitution differentially impacts strain propagation, with greater acceleration of RML (~33% shorter incubation) than 22L (~0.5% shorter) compared to WT mice. These complementary systems offer powerful experimental platforms for investigating the molecular determinants of spontaneous prion formation, strain selection and transmission barriers, providing insights into idiopathic prion pathogenesis and developing therapeutic interventions.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149223","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 regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease","authors":"Maud M. A. Bouwman,&nbsp;Irene Frigerio,&nbsp;Yvon Galis-de Graaf,&nbsp;Wilma D. J. van de Berg,&nbsp;Laura E. Jonkman","doi":"10.1111/bpa.70081","DOIUrl":"10.1111/bpa.70081","url":null,"abstract":"<p>Synaptic loss in the (para)hippocampus is a major contributor to cognitive decline in Alzheimer's disease (AD), yet its regional specificity and pathological correlates remain poorly understood. Here, we quantified synaptophysin-positive puncta across hippocampal subregions (CA4, CA2, CA1, and subiculum) and parahippocampal cortex (entorhinal cortex, parahippocampal and fusiform gyrus) in postmortem tissue from 28 AD and 17 controls, and assessed relationships to neuropathological severity and cognitive decline. Amyloid-β, phosphorylated tau (p-tau) load and neurofilament light (NfL) immunoreactivity were quantified, and Clinical Dementia Rating scores were collected as a cognitive measure. Group differences were analyzed with linear mixed models; correlations between synaptic puncta, pathology and cognitive scores with linear regressions, corrected for age, sex and multiple comparisons. We found selective synaptic loss in the entorhinal cortex (−14%, <i>p</i> = 0.017) and parahippocampal gyrus (−14%, <i>p =</i> 0.021) in AD versus controls. Hippocampal synaptic density negatively correlated with amyloid-β in controls (<i>r</i> = −0.52, <i>p</i> &lt; 0.001) and positively in AD (<i>r</i> = 0.25, <i>p</i> = 0.007), suggesting a disease-dependent shift. In AD, hippocampal, but not parahippocampal, subregions with higher p-tau burden showed greater synaptic density (<i>r</i> = 0.21, <i>p</i> = 0.003), raising questions about the role of p-tau in synaptic loss at late stages. Axonal damage (i.e., higher NfL load) in the parahippocampal cortex associated with synaptic loss locally and in interconnected subregions. Worse cognitive performance was strongly associated with synaptic loss in the CA1 (<i>r</i> = −0.64, <i>p</i> = 0.003), subiculum (<i>r</i> = −0.62, <i>p</i> = 0.012), entorhinal cortex (<i>r</i> = −0.60, <i>p</i> = 0.008), parahippocampal (<i>r</i> = −0.48, <i>p</i> = 0.041) and fusiform gyrus (<i>r</i> = −0.67, <i>p</i> = 0.002). These findings highlight the vulnerability of the entorhinal cortex and parahippocampal gyrus to synaptic loss in AD. Our results suggest that amyloid-β and p-tau pathology may play a limited role in synaptic loss at end-stage disease, and the strong link between synaptic loss in (para)hippocampal subregions and cognitive decline underscores the need for monitoring synaptic change in light of disease progression and evaluating therapeutic interventions.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 4","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149207","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 40-year-old woman with a spinal mass.","authors":"Melissa Mejia-Bautista, Margarita Loxas, Pouya Jamshidi, Drew Duckett, Jean-Paul Wolinsky, Jared T Ahrendsen","doi":"10.1111/bpa.70111","DOIUrl":"https://doi.org/10.1111/bpa.70111","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70111"},"PeriodicalIF":6.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142744","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}