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      The causal relationship between human brain morphometry and knee osteoarthritis: a two-sample Mendelian randomization study

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          Abstract

          Background

          Knee Osteoarthritis (KOA) is a prevalent and debilitating condition affecting millions worldwide, yet its underlying etiology remains poorly understood. Recent advances in neuroimaging and genetic methodologies offer new avenues to explore the potential neuropsychological contributions to KOA. This study aims to investigate the causal relationships between brain-wide morphometric variations and KOA using a genetic epidemiology approach.

          Method

          Leveraging data from 36,778 UK Biobank participants for human brain morphometry and 487,411 UK Biobank participants for KOA, this research employed a two-sample Mendelian Randomization (TSMR) approach to explore the causal effects of 83 brain-wide volumes on KOA. The primary method of analysis was the Inverse Variance Weighted (IVW) and Wald Ratio (WR) method, complemented by MR Egger and IVW methods for heterogeneity and pleiotropy assessments. A significance threshold of p < 0.05 was set to determine causality. The analysis results were assessed for heterogeneity using the MR Egger and IVW methods. Brain-wide volumes with Q_pval < 0.05 were considered indicative of heterogeneity. The MR Egger method was employed to evaluate the pleiotropy of the analysis results, with brain-wide volumes having a p-value < 0.05 considered suggestive of pleiotropy.

          Results

          Our findings revealed significant causal associations between KOA and eight brain-wide volumes: Left parahippocampal volume, Right posterior cingulate volume, Left transverse temporal volume, Left caudal anterior cingulate volume, Right paracentral volume, Left paracentral volume, Right lateral orbitofrontal volume, and Left superior temporal volume. These associations remained robust after tests for heterogeneity and pleiotropy, underscoring their potential role in the pathogenesis of KOA.

          Conclusion

          This study provides novel evidence of the causal relationships between specific brain morphometries and KOA, suggesting that neuroanatomical variations might contribute to the risk and development of KOA. These findings pave the way for further research into the neurobiological mechanisms underlying KOA and may eventually lead to the development of new intervention strategies targeting these neuropsychological pathways.

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          Most cited references69

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          Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study

          Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson’s disease into this case-control PET study. Patients with Parkinson’s disease were divided into 24 RBD-negative (PDRBD−) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD− and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10−13, ANOVA). When compared to the PDRBD− patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10−5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD− (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD− data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson’s disease.
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            Autism spectrum disorder: neuropathology and animal models.

            Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.
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              The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

              Aims This study aimed to make a comparison between the clinical laboratory-related factors, complete blood count (CBC) indices, cytokines, and lymphocyte subsets in order to distinguish severe coronavirus disease 2019 (COVID-19) cases from the non-severe ones. Materials and methods Relevant studies were searched in PubMed, Embase, Scopus, and Web of Science databases until March 31, 2020. Cochrane's Q test and the I2 statistic were used to determine heterogeneity. We used the random-effect models to pool the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Key findings Out of a total of 8557 initial records, 44 articles (50 studies) with 7865 patients (ranging from 13 to 1582), were included. Our meta-analyses with random-effect models showed a significant decrease in lymphocytes, monocyte, CD4+ T cells, CD8+ T cells, CD3 cells, CD19 cells, and natural killer (NK) cells and an increase in the white blood cell (WBC), neutrophils, neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP)/hs-CRP, erythrocyte sedimentation rate (ESR), ferritin, procalcitonin (PCT), and serum amyloid A (SAA), interleukin-2 (IL-2), IL-2R, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) in the severe group compared to the non-severe group. However, no significant differences were found in IL-1β, IL-17, and CD4/CD8 T cell ratio between the two groups. Significance Decrease in total lymphocytes and lymphocyte subsets as well as the elevation of CRP, ESR, SAA, PCT, ferritin, and cytokines, but not IL-1β and IL-17, were closely associated with COVID-19 severity, implying reliable indicators of severe COVID-19.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2065216/overviewRole: Role: Role: Role: Role:
                Role: Role: Role: Role: Role:
                Role: Role: Role: Role: Role:
                Role: Role: Role: Role:
                Role: Role: Role: Role:
                Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1855358/overviewRole: Role: Role: Role:
                Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2316818/overviewRole: Role: Role: Role: Role: Role:
                Role: Role: Role: Role:
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                08 July 2024
                2024
                : 15
                : 1420134
                Affiliations
                [1] 1 Shi’s Center of Orthopedics and Traumatology , Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, China
                [2] 2 Institute of Traumatology and Orthopedics , Shanghai Academy of Traditional Chinese Medicine , Shanghai, China
                [3] 3 Yunyang County People’s Hospital Rehabilitation Medicine Department , Chongqing, China
                [4] 4 Department of Traditional Chinese Medicine , Shanghai Yangzhi Rehabilitation Hospital (Yangzhi Affiliated Rehabilitation Hospital) , School of Medicine , Tongji University , Shanghai, China
                Author notes

                Edited by: Han Feng, Tulane University, United States

                Reviewed by: Chenguang Zhang, University of Texas Health Science Center at Houston, United States

                Mayana Bsoul, Tulane University, United States

                *Correspondence: Guoqing Du, 530427540@ 123456qq.com ; Hongsheng Zhan, zhanhongsheng2010@ 123456163.com
                [ † ]

                These authors have contributed equally to this work and share first authorship

                Article
                1420134
                10.3389/fgene.2024.1420134
                11260717
                39040992
                b9e79859-f856-4097-a004-7f35905f5bb1
                Copyright © 2024 Liu, Huang, Xiong, Wang, Shen, Zhang, Gao, Wang, Du and Zhan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 April 2024
                : 20 June 2024
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82174403 82374467 82374488 82074466
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Natural Science Foundation of China (82174403, 82374467, 82374488, 82074466); the Summit Plateau Team Project in Traumatology of Shanghai University of TCM, Shanghai Chronic Musculoskeletal Disease Clinical Medical Research Center (20mc1920600); Shanghai clinical specialty “Traditional Chinese Medicine Orthopaedic Traumatology” (shslczdzk03901); the second-round construction project of the National Traditional Chinese Medicine Academic School Inheritance Studio “Shi’s Traumatology Department”; the innovation team of “Research and Transformation of Chronic Musculoskeletal Diseases” in Shanghai’s high-level local universities [Shanghai Education Commission (2022) No. 3]; “Shanghai School of Traditional Chinese Medicine Inheritance” Extension Plan [ZY (2021-2023)-0209-02], ZH National Famous Veteran Traditional Chinese Medicine Expert Inheritance Studio Construction Project (2022-75).
                Categories
                Genetics
                Original Research
                Custom metadata
                Applied Genetic Epidemiology

                Genetics
                knee osteoarthritis,mendelian randomization,brain-wide morphometric variations,brain-wide volumes,brain morphometries,two-sample mendelian randomization

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