Sanad M El-Khatib, Arya R Vagadia, Anh C D Le, Janet E Baulch, Ding Quan Ng, Mingyu Du, Kevin G Johnston, Zhiqun Tan, Xiangmin Xu, Alexandre Chan, Munjal M Acharya
{"title":"BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.","authors":"Sanad M El-Khatib, Arya R Vagadia, Anh C D Le, Janet E Baulch, Ding Quan Ng, Mingyu Du, Kevin G Johnston, Zhiqun Tan, Xiangmin Xu, Alexandre Chan, Munjal M Acharya","doi":"10.1186/s40478-024-01906-9","DOIUrl":"https://doi.org/10.1186/s40478-024-01906-9","url":null,"abstract":"<p><p>Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"190"},"PeriodicalIF":6.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851878","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":"The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function.","authors":"Wei Jiang, Jian Zhang, Molin Wang, Yongxin Zou, Qiao Liu, Yu Song, Gongping Sun, Yaoqin Gong, Fan Zhang, Baichun Jiang","doi":"10.1186/s40478-024-01903-y","DOIUrl":"10.1186/s40478-024-01903-y","url":null,"abstract":"<p><p>Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"188"},"PeriodicalIF":6.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778901","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}
John D Arena, Douglas H Smith, Ramon Diaz Arrastia, D Kacy Cullen, Rui Xiao, Jiaxin Fan, Danielle C Harris, Cillian E Lynch, Victoria E Johnson
{"title":"The neuropathological basis of elevated serum neurofilament light following experimental concussion.","authors":"John D Arena, Douglas H Smith, Ramon Diaz Arrastia, D Kacy Cullen, Rui Xiao, Jiaxin Fan, Danielle C Harris, Cillian E Lynch, Victoria E Johnson","doi":"10.1186/s40478-024-01883-z","DOIUrl":"10.1186/s40478-024-01883-z","url":null,"abstract":"<p><p>Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood-brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"189"},"PeriodicalIF":6.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778841","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}
Vivian I Ko, Kailee Ong, Deborah Y Kwon, Xueying Li, Alicia Pietrasiewicz, James S Harvey, Mukesh Lulla, Guruharsha Bhat, Don W Cleveland, John M Ravits
{"title":"CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.","authors":"Vivian I Ko, Kailee Ong, Deborah Y Kwon, Xueying Li, Alicia Pietrasiewicz, James S Harvey, Mukesh Lulla, Guruharsha Bhat, Don W Cleveland, John M Ravits","doi":"10.1186/s40478-024-01902-z","DOIUrl":"10.1186/s40478-024-01902-z","url":null,"abstract":"<p><p>Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"187"},"PeriodicalIF":6.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778836","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":"Spatial transcriptomics in focal cortical dysplasia type IIb.","authors":"Yujiao Wang, Yihe Wang, Linai Guo, Chunhao Shen, Yongjuan Fu, Penghu Wei, Yongzhi Shan, Qian Wu, Yue-Shan Piao, Guoguang Zhao","doi":"10.1186/s40478-024-01897-7","DOIUrl":"10.1186/s40478-024-01897-7","url":null,"abstract":"<p><p>Focal cortical dysplasia (FCD) type IIb (FCD IIb) is an epileptogenic malformation of the neocortex that is characterized by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). Approximately 30-60% of lesions are associated with brain somatic mutations in the mTOR pathway. Herein, we investigated the transcriptional changes around the DNs and BCs regions in freshly frozen brain samples from three patients with FCD IIb by using spatial transcriptomics. We demonstrated that the DNs region in a gene enrichment network enriched for the mTOR signalling pathway, autophagy and the ubiquitin‒proteasome system, additionally which are involved in regulating membrane potential, may contribute to epileptic discharge. Moreover, differential expression analysis further demonstrated stronger expression of components of the inflammatory response and complement activation in the BCs region. And the DNs and BCs regions exhibited common functional modules, including regulation of cell morphogenesis and developmental growth. Furthermore, the expression of representative proteins in the functional enrichment module mentioned above was increased in the lesions of FCD IIb, such as p62 in DNs and BCs, UCHL1 in DNs, and C3 and CLU in BCs, which was confirmed via immunohistochemistry. Collectively, we constructed a spatial map showing the potential effects and functions of the DNs and BCs regions at the transcriptomic level and generated publicly available data on human FCD IIb to facilitate future research on human epileptogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"185"},"PeriodicalIF":6.2,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754449","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}
Darren Chan, Jenny Wanyu Zhang, Gah-Jone Won, Jeremy M Sivak
{"title":"Retinal cytoarchitecture is preserved in an organotypic perfused human and porcine eye model.","authors":"Darren Chan, Jenny Wanyu Zhang, Gah-Jone Won, Jeremy M Sivak","doi":"10.1186/s40478-024-01892-y","DOIUrl":"https://doi.org/10.1186/s40478-024-01892-y","url":null,"abstract":"<p><p>Pathobiology of the intact human retina has been challenging to study due to its relative inaccessibility and limited sample availability. Thus, there is a great need for new translational models that can maintain human retinal integrity and cytoarchitecture. The role of physiologic intraocular pressure (IOP) and fluid flow on retinal tissue has not been well studied. Here, we present an ex vivo organotypic model to assess the impact of physiological intraocular perfusion on retinal cytoarchitecture and cell survival. We demonstrate that retinal cytoarchitecture is remarkably well preserved following re-establishment of physiological IOP and aqueous humor dynamics for up to 24 h in ex vivo whole globe porcine and human eyes, comparable to freshly preserved control eyes. Accordingly, cell death was minimized in the perfused retinas, which also displayed normal markers of cellular metabolism and astrogliosis. These results are in marked contrast to contralateral control eyes without active perfusion, which displayed excessive cell death and disrupted cytoarchitecture at the same time point. These experiments demonstrate the critical impact that physiological pressure and fluid flow have on retinal tissue, and introduce a new pre-clinical model to study human and porcine retinal health and degeneration in a relevant biomechanical setting.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"186"},"PeriodicalIF":6.2,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765333","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}
Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka
{"title":"ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.","authors":"Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka","doi":"10.1186/s40478-024-01893-x","DOIUrl":"10.1186/s40478-024-01893-x","url":null,"abstract":"<p><p>Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43<sup>M337V</sup> in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43<sup>M337V</sup> and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43<sup>M337V</sup> with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43<sup>M337V</sup>. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43<sup>M337V</sup> overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"184"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737920","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}
Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg
{"title":"Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals.","authors":"Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg","doi":"10.1186/s40478-024-01891-z","DOIUrl":"10.1186/s40478-024-01891-z","url":null,"abstract":"<p><p>Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"182"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737929","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}
Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart
{"title":"Towards integrating imaging and immunology in glioblastoma: mapping blood immune system metrics to tumor magnetic resonance image data.","authors":"Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart","doi":"10.1186/s40478-024-01888-8","DOIUrl":"10.1186/s40478-024-01888-8","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is the most frequent and aggressive brain cancer. It is a highly immunology-driven disease as up to a third of its mass is composed of immune cells. Apart from immunology, imaging is a major research frontier. The VASARI (Visually AcceSAble Rembrandt Images) MRI feature set is a system designed to enable consistent description of gliomas using a set of defined visual features and controlled vocabulary. Even though imaging and immunology are both indispensable for glioblastoma phenotyping, a comprehensive integration of these two disciplines has not been performed so far.</p><p><strong>Material and methods: </strong>76 patients from a previous glioblastoma immunotherapy clinical trial were retrospectively screened for the availability of peripheral blood immunology and tumor imaging data at baseline, i.e. at the start of the study. For 41 patients both were available. MRI were then analyzed via volumetry and VASARI morphometry. The resulting 27 imaging variables were linked with 67 peripheral blood immunology variables from flow cytometry and PCR and all potential relations were mapped.</p><p><strong>Results: </strong>In an initial broad screening, 94 imaging-immunology associations were discovered. Notably, features of the contrast-enhancing margin like its thickness and its shape were positively correlated with various T cell species including activated cytotoxic CD8+ T cells and central memory CD8+ T cells. The T2-volume was correlated with CD56+CD16- natural killer cells, and the necrosis volume was correlated with immunopolarizing mRNAs in the blood (IFN-γ, GATA3, ROR-gt). After multiple testing correction, two imaging-immunology associations were confirmed as significant: a thick contrast-enhancing margin was correlated with lower regulatory T cell markers in the blood and invasion of deep white matter was correlated with less T helper 17 factors.</p><p><strong>Conclusion: </strong>We here provide first evidence that imaging and peripheral blood immunology features can go hand in hand and that imaging variables can correlate with systemic immunophenotypes. Especially a thick contrast-enhancing margin seems to indicate a pro-inflammatory immune state. Via pioneering the integration of imaging and immunology, we not only advance basic glioblastoma science but we also open up novel avenues for research. In the future, e.g. patient stratification for therapy development could be based on imaging-guided immunophenotyping.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"183"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737932","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}
Gang Xiao, Guilong Tanzhu, Xuan Gao, Lifeng Li, Zhiyuan Liu, Xuefeng Xia, Rongrong Zhou
{"title":"An immune scoring system predicts prognosis and immune characteristics in lung adenocarcinoma brain metastases by RNA sequencing.","authors":"Gang Xiao, Guilong Tanzhu, Xuan Gao, Lifeng Li, Zhiyuan Liu, Xuefeng Xia, Rongrong Zhou","doi":"10.1186/s40478-024-01895-9","DOIUrl":"10.1186/s40478-024-01895-9","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have reported that the tumor immune microenvironment (TIME) was associated with the prognosis of lung cancer patients and the efficacy of immunotherapy. However, given the significant challenges in obtaining specimens of brain metastases (BrMs), few studies explored the correlation between the TIME and the prognosis in patients with BrMs from lung adenocarcinoma (LUAD).</p><p><strong>Methods: </strong>Transcript profiling of archival formalin-fixed and paraffin-embedded specimens of BrMs from 70 LUAD patients with surgically resected BrMs was carried out using RNA sequencing. An immune scoring system, the green-yellow module score (GYMS), was developed to predict prognosis and immune characteristics in both BrMs and primary LUAD using Weighted Correlation Network analysis (WGCNA) and GSVA analysis. We comprehensively evaluated the immunological role of GYMS based on gene expression profile of LUAD BrMs by systematically correlating GYMS with immunological characteristics and immunotherapy responsiveness in the BrMs. Immunohistochemistry was applied for validation.</p><p><strong>Results: </strong>We found that the high-GYMS group had better clinical prognosis and inflamed immune landscape including high infiltrations of various immune cells, increased immunomodulatory expression, and enriched immune-related pathways by using RNA-seq and immunohistochemical analysis. Low-GYMS group presented a lacked immune infiltration characteristic. Besides, the high-GYMS group had lower TIDE score and higher T-cell inflamed score than low-GYMS group. The GYMS has been validated in independent BrMs cohorts and primary NSCLC cohort treated with anti-PD-1/PD-L1, showing strong reproducibility and stability in both primary LUAD and BrMs. In addition, we construct a GYMS-related risk signature for patients with LUAD BrMs to predict prognosis.</p><p><strong>Conclusions: </strong>We identified two immune-related subtypes which used to estimate prognosis and immune characteristics and developed a reliable GYMS-related risk signature in LUAD BrMs. These results will enhance the understanding of the immune microenvironment in LUAD BrMs and lay the theoretical foundation for the development of personalized therapies for LUAD patients with BrMs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"181"},"PeriodicalIF":6.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724369","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}