Acta Neuropathologica Communications最新文献

{"title":"Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis.","authors":"Junya Yamaguchi, Fumiharu Ohka, Masafumi Seki, Kazuya Motomura, Shoichi Deguchi, Yoshiki Shiba, Yuka Okumura, Yuji Kibe, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Akihiro Nakamura, Kennosuke Karube, Ryuta Saito","doi":"10.1186/s40478-024-01879-9","DOIUrl":"10.1186/s40478-024-01879-9","url":null,"abstract":"<p><p>Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of \"Astrocytoma, IDH-mutant; High Grade\" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"169"},"PeriodicalIF":6.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492582","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: ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van Der Aa syndrome autopsy case.","authors":"Claudio D'Incal, Anke Van Dijck, Joe Ibrahim, Kevin De Man, Lina Bastini, Anthony Konings, Ellen Elinck, Claudia Theys, Illana Gozes, Zlatko Marusic, Mirna Anicic, Jurica Vukovic, Nathalie Van der Aa, Ligia Mateiu, Wim Vanden Berghe, R Frank Kooy","doi":"10.1186/s40478-024-01787-y","DOIUrl":"https://doi.org/10.1186/s40478-024-01787-y","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"168"},"PeriodicalIF":6.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492581","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 minimally invasive biomarker for sensitive and accurate diagnosis of Parkinson's disease.","authors":"Zerui Wang, Tricia Gilliland, Hyun Jo Kim, Maria Gerasimenko, Kailey Sajewski, Manuel V Camacho, Gurkan Bebek, Shu G Chen, Steven A Gunzler, Qingzhong Kong","doi":"10.1186/s40478-024-01873-1","DOIUrl":"10.1186/s40478-024-01873-1","url":null,"abstract":"<p><p>Seeding activities of disease-associated α-synuclein aggregates (αSyn^D), a hallmark of Parkinson's disease (PD), are detectable by seed amplification assay (αSyn-SAA) and being developed as a diagnostic biomarker for PD. Sensitive and accurate αSyn-SAA for blood or saliva would greatly facilitate PD diagnosis. This prospective diagnostic study conducted αSyn-SAA analyses on serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC). 124 subjects (82 PD, 42 HC) donated blood and had extensive clinical assessments, of whom 74 subjects (48 PD, 26 HC) also donated saliva at the same visits. An additional 57 subjects (35 PD, 22 HC) donated saliva and had more limited clinical assessments. The mean ages were 69.21, 66.55, 69.58, and 64.71 years for PD serum donors, HC serum donors, PD saliva donors, and HC saliva donors, respectively. αSyn^D seeding activities in either sample type alone or both sample types together were evaluated for PD diagnosis. Serum αSyn-SAA data from 124 subjects showed 80.49% sensitivity, 90.48% specificity, and 0.9006 accuracy (AUC of ROC); saliva αSyn-SAA data from 131 subjects attained 74.70% sensitivity, 97.92% specificity, and 0.8966 accuracy. Remarkably, the combined serum and saliva αSyn-SAA from 74 subjects with both sample types achieved better diagnostic performance: 95.83% sensitivity, 96.15% specificity, and 0.98 accuracy. In addition, serum αSyn^D seeding activities correlated inversely with Montreal Cognitive Assessment in males and positively with Hamilton Depression Rating Scale in females and in the < 70 age group, whereas saliva αSyn^D seeding activities correlated inversely with age at diagnosis in males and in the < 70 age group. Our data indicate that serum and saliva αSyn-SAA together can achieve high diagnostic accuracy for PD comparable to that of CSF αSyn-SAA, suggesting their potential utility for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice and clinical studies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"167"},"PeriodicalIF":6.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492580","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":"Mapping the glial transcriptome in Huntington's disease using snRNAseq: selective disruption of glial signatures across brain regions.","authors":"Sunniva M K Bøstrand, Luise A Seeker, Nadine Bestard-Cuche, Nina-Lydia Kazakou, Sarah Jäkel, Boyd Kenkhuis, Neil C Henderson, Susanne T de Bot, Willeke M C van Roon-Mom, Josef Priller, Anna Williams","doi":"10.1186/s40478-024-01871-3","DOIUrl":"10.1186/s40478-024-01871-3","url":null,"abstract":"<p><p>Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"165"},"PeriodicalIF":6.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455413","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":"PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.","authors":"Florian Perrin, Lauren C Anderson, Shane P C Mitchell, Priyanka Sinha, Yuliia Turchyna, Masato Maesako, Mei C Q Houser, Can Zhang, Steven L Wagner, Rudolph E Tanzi, Oksana Berezovska","doi":"10.1186/s40478-024-01876-y","DOIUrl":"10.1186/s40478-024-01876-y","url":null,"abstract":"<p><p>The recently discovered interaction between presenilin 1 (PS1), a subunit of γ-secretase involved in amyloid-β (Aβ) peptide production, and GLT-1, the major brain glutamate transporter (EAAT2 in the human), may link two pathological aspects of Alzheimer's disease: abnormal Aβ occurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based fluorescence lifetime imaging microscopy (FLIM) to characterize the PS1/GLT-1 interaction in brain tissue from sporadic AD (sAD) patients. sAD brains showed significantly less PS1/GLT-1 interaction than those with frontotemporal lobar degeneration or non-demented controls. Familial AD (fAD) PS1 mutations, inducing a \"closed\" PS1 conformation similar to that in sAD brain, and gamma-secretase modulators (GSMs), inducing a \"relaxed\" conformation, respectively reduced and increased the interaction. Furthermore, PS1 influences GLT-1 cell surface expression and homomultimer formation, acting as a chaperone but not affecting GLT-1 stability. The diminished PS1/GLT-1 interaction suggests that these functions may not work properly in AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"166"},"PeriodicalIF":6.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455414","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":"Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction.","authors":"Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B VanderWall, Sailee S Lavekar, Clarisse M Fligor, Jade Harkin, Shelby M Hetzer, Shruti V Patil, Adriana Di Polo, Jason S Meyer","doi":"10.1186/s40478-024-01872-2","DOIUrl":"10.1186/s40478-024-01872-2","url":null,"abstract":"<p><p>The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants. Thus, to further advance this field of research, in the current study we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs, and have further validated some of these findings in a mouse model of ocular hypertension. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs. Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"164"},"PeriodicalIF":6.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455411","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":"Development and characterization of novel anti-acetylated tau monoclonal antibodies to probe pathogenic tau species in Alzheimer's disease.","authors":"Miles R Bryan Iii, Xu Tian, Jui-Heng Tseng, Baggio A Evangelista, Joey V Ragusa, Audra F Bryan, Winifred Trotman, David Irwin, Todd J Cohen","doi":"10.1186/s40478-024-01865-1","DOIUrl":"10.1186/s40478-024-01865-1","url":null,"abstract":"<p><p>Tauopathies, including Alzheimer's disease (AD), are a class of neurodegenerative diseases characterized by the presence of insoluble tau inclusions. Tau phosphorylation has traditionally been viewed as the dominant post-translational modification (PTM) controlling tau function and pathogenesis in tauopathies. However, we and others have identified tau acetylation as a primary PTM regulating both normal tau function as well as abnormal pathogenic features including aggregation. Prior work showed robust tau acetylation in aggregation hotspots located within the 2nd and 3rd repeat regions of tau (residues K280 and K311) in tauopathy brains, including AD, compared to non-tauopathy controls. By screening thousands of hybridoma clones, we generated site-specific and modification-specific monoclonal antibodies targeting acetylated tau at residues K280 or K311. To validate these antibodies in a bona fide neuronal system, we targeted the acetyltransferase CBP to the cytoplasm of neurons to promote tau acetylation. Several antibody clones specifically detected CBP-acetylated tau and co-localized with ac-tau in neurons. Additionally, our lead optimal anti-acetylated-tau monoclonal antibodies detected robust tau pathology in tangles and neuritic plaques of human AD brains. Given the now emerging interest in acetylated tau as critical regulator of tau functions, these sensitive and highly specific tools will allow us to further unravel the tau PTM code and, importantly, could be deployed as diagnostic or disease-modifying agents.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"163"},"PeriodicalIF":6.2,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455412","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":"Metabolic remodeling in glioblastoma: a longitudinal multi-omics study.","authors":"Maxime Fontanilles, Jean-David Heisbourg, Arthur Daban, Frederic Di Fiore, Louis-Ferdinand Pépin, Florent Marguet, Olivier Langlois, Cristina Alexandru, Isabelle Tennevet, Franklin Ducatez, Carine Pilon, Thomas Plichet, Déborah Mokbel, Céline Lesueur, Soumeya Bekri, Abdellah Tebani","doi":"10.1186/s40478-024-01861-5","DOIUrl":"10.1186/s40478-024-01861-5","url":null,"abstract":"<p><p>Monitoring tumor evolution and predicting survival using non-invasive liquid biopsy is an unmet need for glioblastoma patients. The era of proteomics and metabolomics blood analyzes, may help in this context. A case-control study was conducted. Patients were included in the GLIOPLAK trial (ClinicalTrials.gov Identifier: NCT02617745), a prospective bicentric study conducted between November 2015 and December 2022. Patients underwent biopsy alone and received radiotherapy and temozolomide. Blood samples were collected at three different time points: before and after concomitant radiochemotherapy, and at the time of tumor progression. Plasma samples from patients and controls were analyzed using metabolomics and proteomics, generating 371 omics features. Descriptive, differential, and predictive analyses were performed to assess the relationship between plasma omics feature levels and patient outcome. Diagnostic performance and longitudinal variations were also analyzed. The study included 67 subjects (34 patients and 33 controls). A significant differential expression of metabolites and proteins between patients and controls was observed. Predictive models using omics features showed high accuracy in distinguishing patients from controls. Longitudinal analysis revealed temporal variations in a few omics features including CD22, CXCL13, EGF, IL6, GZMH, KLK4, and TNFRSP6B. Survival analysis identified 77 omics features significantly associated with OS, with ERBB2 and ITGAV consistently linked to OS at all timepoints. Pathway analysis revealed dynamic oncogenic pathways involved in glioblastoma progression. This study provides insights into the potential of plasma omics features as biomarkers for glioblastoma diagnosis, progression and overall survival. Clinical implication should now be explored in dedicated prospective trials.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"162"},"PeriodicalIF":6.2,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405885","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 pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.","authors":"Silke Vanderhaeghe, Jovan Prerad, Arun Kumar Tharkeshwar, Elien Goethals, Katlijn Vints, Jimmy Beckers, Wendy Scheveneels, Eveline Debroux, Katrien Princen, Philip Van Damme, Marc Fivaz, Gerard Griffioen, Ludo Van Den Bosch","doi":"10.1186/s40478-024-01866-0","DOIUrl":"10.1186/s40478-024-01866-0","url":null,"abstract":"<p><p>Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA⁺ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP^R191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"161"},"PeriodicalIF":6.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399044","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":"Comparative targeted lipidomics between serum and cerebrospinal fluid of multiple sclerosis patients shows sex and age-specific differences of endocannabinoids and glucocorticoids.","authors":"Philip Meier, Sandra Glasmacher, Anke Salmen, Andrew Chan, Jürg Gertsch","doi":"10.1186/s40478-024-01864-2","DOIUrl":"10.1186/s40478-024-01864-2","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation (r = 0.3, p < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"160"},"PeriodicalIF":6.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387203","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}