Rachel J Sharkey, Filomeno Cortese, Bradley G Goodyear, Lawrence W Korngut, Sarah M Jacob, Keith A Sharkey, Sanjay Kalra, Minh Dang Nguyen, Richard Frayne, Gerald Pfeffer
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.
肌萎缩性脊髓侧索硬化症(ALS)是大脑和脊髓运动神经元的一种神经退行性疾病。错误折叠蛋白的积累是肌萎缩侧索硬化症发病机制的核心,而淋巴系统正在成为减少蛋白病变的潜在治疗靶点。我们利用沿血管周围空间的弥散张量成像分析(DTI-ALPS)来评估糖膜功能,对 ALS 的糖膜功能进行纵向分析,并将其与运动神经元疾病谱中的一种疾病--原发性侧索硬化症(PLS)进行比较。我们对卡尔加里研究中心参加 CALSNIC 研究(加拿大 ALS 神经影像联合会)的 45 名参与者(包括 18 名 ALS 患者、5 名 PLS 患者和 22 名对照组患者)进行了 DTI-ALPS 分析,并将其与临床特征(年龄、性别、疾病表现、疾病严重程度和进展速度)以及白质高密度(WMH)负荷联系起来。这包括在三个时间点(间隔 4 个月)进行的纵向测量。在所有三个时间点上,ALS 患者的 DTI-ALPS 指数均低于 PLS 和对照组患者。该指数与临床因素无关,但随着年龄的增长呈下降趋势。我们的研究结果表明,运动神经元疾病的血流功能障碍具有异质性,这可能与潜在的发病机制有关。
{"title":"Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.","authors":"Rachel J Sharkey, Filomeno Cortese, Bradley G Goodyear, Lawrence W Korngut, Sarah M Jacob, Keith A Sharkey, Sanjay Kalra, Minh Dang Nguyen, Richard Frayne, Gerald Pfeffer","doi":"10.1093/brain/awae288","DOIUrl":"https://doi.org/10.1093/brain/awae288","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher J Record, Menelaos Pipis, Mariola Skorupinska, Julian Blake, Roy Poh, James M Polke, Kelly Eggleton, Tina Nanji, Stephan Zuchner, Andrea Cortese, Henry Houlden, Alexander M Rossor, Matilde Laura, Mary M Reilly
Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009 to 2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome sequencing and WGS and, latterly, WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. In summary, 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100 000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment, leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre and has benefitted from the use of WGS, particularly access to the raw data. However, almost one-quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.
{"title":"Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease.","authors":"Christopher J Record, Menelaos Pipis, Mariola Skorupinska, Julian Blake, Roy Poh, James M Polke, Kelly Eggleton, Tina Nanji, Stephan Zuchner, Andrea Cortese, Henry Houlden, Alexander M Rossor, Matilde Laura, Mary M Reilly","doi":"10.1093/brain/awae064","DOIUrl":"10.1093/brain/awae064","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009 to 2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome sequencing and WGS and, latterly, WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. In summary, 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100 000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment, leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre and has benefitted from the use of WGS, particularly access to the raw data. However, almost one-quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marianna Spatola, Nadège Nziza, Edward B Irvine, Deniz Cizmeci, Wonyeong Jung, Le Hong Van, Le Thanh Hoang Nhat, Vu Thi Ngoc Ha, Nguyen Hoan Phu, Dang Trung Nghia Ho, Guy E Thwaites, Douglas A Lauffenburger, Sarah Fortune, Nguyen Thuy Thuong Thuong, Galit Alter
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.
结核分枝杆菌(Mtb)是结核病(TB)的致病菌,一直是全球健康的负担。虽然结核分枝杆菌(Mtb)主要是呼吸道病原体,但它也可传播到其他器官,包括大脑和脑膜,引起结核性脑膜炎(TBM)。然而,人们对导致不同器官发生不同疾病的免疫机制知之甚少。人们关注的重点是 T 细胞反应在肺部控制 Mtb 的过程中的差异,但新出现的数据表明,抗体既是疾病控制的生物标志物,也是抗菌分子。鉴于人们越来越重视跨血脑屏障的分区抗体反应,我们在这里描述了TBM期间血液和大脑分区的抗体概况,并确定了Mtb特异性体液免疫反应在肺部Mtb感染(肺结核)和TBM之间是否存在差异。利用高通量系统血清学方法,我们深入分析了艾滋病毒阴性成人肺结核患者(10 人)与 TBM 患者(60 人)针对 10 种不同 Mtb 抗原的抗体反应,包括脂质抗原(LAM)和纯化蛋白衍生物(PPD)。抗体研究包括分析免疫球蛋白异型(IgG、IgM、IgA)和亚类水平(IgG1-4)、Mtb 特异性抗体与 Fc 受体或 C1q 结合的能力以及激活先天性免疫效应器功能(补体和 NK 细胞激活、单核细胞或中性粒细胞吞噬)的能力。我们采用机器学习方法来描述肺结核患者的血清和脑脊液反应,确定与疾病严重程度相关的预后因素,并定义区分肺结核与肺结核的关键抗体特征。在TBM患者中,我们发现了CSF特异性抗体谱,这种抗体谱标志着针对Mtb的独特、分区化的体液反应,其特点是Mtb特异性抗体的富集,能够强效激活补体并驱动单核细胞和中性粒细胞的吞噬作用,所有这些都与TBM发病时的严重程度较轻有关。此外,尽管肺结核患者的IgG滴度和Fcγ受体(FcγR)结合能力较低,但与肺结核患者相比,肺结核患者血清中的Mtb特异性抗体具有更强的激活单核细胞吞噬能力。总之,这些数据表明,体液反应的功能因感染部位(即肺部与脑部)而异,并证明了在TBM期间脑脊液中存在高度分区化的Mtb特异性抗体反应。此外,我们的研究结果表明,吞噬和补体介导的抗体可能会促进神经病理学的减弱和TBM病情的减轻。
{"title":"Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection.","authors":"Marianna Spatola, Nadège Nziza, Edward B Irvine, Deniz Cizmeci, Wonyeong Jung, Le Hong Van, Le Thanh Hoang Nhat, Vu Thi Ngoc Ha, Nguyen Hoan Phu, Dang Trung Nghia Ho, Guy E Thwaites, Douglas A Lauffenburger, Sarah Fortune, Nguyen Thuy Thuong Thuong, Galit Alter","doi":"10.1093/brain/awae066","DOIUrl":"10.1093/brain/awae066","url":null,"abstract":"<p><p>Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fatemeh Bahari, Volodymyr Dzhala, Trevor Balena, Kyle P Lillis, Kevin J Staley
Intraventricular haemorrhage is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability and/or hydrocephalus. Animal models suggest that brain tissue shrinkage, with subsequent vascular stretch and tear, is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for intraventricular haemorrhage are biomarkers of hypoxic-ischaemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction in these conditions. This is because immature neurons express the chloride, salt and water transporter NKCC1, which subserves regulatory volume increases in non-neural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic-ischaemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters are diminished. Consequentially, mature neurons swell (cytotoxic oedema), whereas immature neurons might shrink. After hypoxic-ischaemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, in addition to prevention of neuronal shrinkage and the ensuing intraventricular haemorrhage, in premature infants.
{"title":"Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport.","authors":"Fatemeh Bahari, Volodymyr Dzhala, Trevor Balena, Kyle P Lillis, Kevin J Staley","doi":"10.1093/brain/awae161","DOIUrl":"10.1093/brain/awae161","url":null,"abstract":"<p><p>Intraventricular haemorrhage is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability and/or hydrocephalus. Animal models suggest that brain tissue shrinkage, with subsequent vascular stretch and tear, is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for intraventricular haemorrhage are biomarkers of hypoxic-ischaemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction in these conditions. This is because immature neurons express the chloride, salt and water transporter NKCC1, which subserves regulatory volume increases in non-neural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic-ischaemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters are diminished. Consequentially, mature neurons swell (cytotoxic oedema), whereas immature neurons might shrink. After hypoxic-ischaemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, in addition to prevention of neuronal shrinkage and the ensuing intraventricular haemorrhage, in premature infants.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Li, Megan L Uhelski, Robert Y North, Juliet M Mwirigi, Claudio E Tatsui, Kathleen E McDonough, Juan P Cata, German Corrales, Greg Dussor, Theodore J Price, Patrick M Dougherty
Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
{"title":"Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy.","authors":"Yan Li, Megan L Uhelski, Robert Y North, Juliet M Mwirigi, Claudio E Tatsui, Kathleen E McDonough, Juan P Cata, German Corrales, Greg Dussor, Theodore J Price, Patrick M Dougherty","doi":"10.1093/brain/awae178","DOIUrl":"10.1093/brain/awae178","url":null,"abstract":"<p><p>Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Great science does not communicate itself: but who should and how?","authors":"Cristina Kroon, Britta J Eickholt","doi":"10.1093/brain/awae217","DOIUrl":"10.1093/brain/awae217","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genetic diseases affecting the retina can result in partial or complete loss of visual function. Leber's congenital amaurosis (LCA) is a rare blinding disease, usually inherited in an autosomally recessive manner, with no cure. Retinal gene therapy has been shown to improve vision in LCA patients caused by mutations in the RPE65 gene (LCA2). However, little is known about how activity in central visual pathways is affected by the disease or by subsequent gene therapy. Functional MRI (fMRI) was used to assess retinal signal transmission in cortical and subcortical visual structures before and 1 year after retinal intervention. The fMRI paradigm consisted of 15-s blocks of flickering (8 Hz) black and white checkerboards interleaved with 15 s of blank (black) screen. Visual activation in the brain was assessed using the general linear model, with multiple comparisons corrected using the false discovery rate method. Response to visual stimulation through untreated eyes of LCA2 patients showed heightened fMRI responses in the superior colliculus and diminished activities in the lateral geniculate nucleus (LGN) compared to controls, indicating a shift in the patients' visual processing towards the retinotectal pathway. Following gene therapy, stimuli presented to the treated eye elicited significantly stronger fMRI responses in the LGN and primary visual cortex, indicating some re-engagement of the geniculostriate pathway (GS) pathway. Across patients, the post-treatment LGN fMRI responses correlated significantly with performance on a clinical test measuring light sensitivity. Our results demonstrate that the low vision observed in LCA2 patients involves a shift in visual processing toward the retinotectal pathway, and that gene therapy partially reinstates visual transmission through the GS pathway. This selective boosting of retinal output through the GS pathway and its correlation to improved visual performance, following several years of degenerative retinal disease, is striking. However, while retinal gene therapy and other ocular interventions have given hope to RPE65 patients, it may take years before development of therapies tailored to treat the diseases in other low vision patients are available. Our demonstration of a shift toward the retinotectal pathway in these patients may spur the development of new tools and rehabilitation strategies to help maximize the use of residual visual abilities and augment experience-dependent plasticity.
{"title":"Central visual pathways affected by degenerative retinal disease before and after gene therapy.","authors":"Manzar Ashtari, Jean Bennett, David A Leopold","doi":"10.1093/brain/awae096","DOIUrl":"10.1093/brain/awae096","url":null,"abstract":"<p><p>Genetic diseases affecting the retina can result in partial or complete loss of visual function. Leber's congenital amaurosis (LCA) is a rare blinding disease, usually inherited in an autosomally recessive manner, with no cure. Retinal gene therapy has been shown to improve vision in LCA patients caused by mutations in the RPE65 gene (LCA2). However, little is known about how activity in central visual pathways is affected by the disease or by subsequent gene therapy. Functional MRI (fMRI) was used to assess retinal signal transmission in cortical and subcortical visual structures before and 1 year after retinal intervention. The fMRI paradigm consisted of 15-s blocks of flickering (8 Hz) black and white checkerboards interleaved with 15 s of blank (black) screen. Visual activation in the brain was assessed using the general linear model, with multiple comparisons corrected using the false discovery rate method. Response to visual stimulation through untreated eyes of LCA2 patients showed heightened fMRI responses in the superior colliculus and diminished activities in the lateral geniculate nucleus (LGN) compared to controls, indicating a shift in the patients' visual processing towards the retinotectal pathway. Following gene therapy, stimuli presented to the treated eye elicited significantly stronger fMRI responses in the LGN and primary visual cortex, indicating some re-engagement of the geniculostriate pathway (GS) pathway. Across patients, the post-treatment LGN fMRI responses correlated significantly with performance on a clinical test measuring light sensitivity. Our results demonstrate that the low vision observed in LCA2 patients involves a shift in visual processing toward the retinotectal pathway, and that gene therapy partially reinstates visual transmission through the GS pathway. This selective boosting of retinal output through the GS pathway and its correlation to improved visual performance, following several years of degenerative retinal disease, is striking. However, while retinal gene therapy and other ocular interventions have given hope to RPE65 patients, it may take years before development of therapies tailored to treat the diseases in other low vision patients are available. Our demonstration of a shift toward the retinotectal pathway in these patients may spur the development of new tools and rehabilitation strategies to help maximize the use of residual visual abilities and augment experience-dependent plasticity.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Del Vecchio, Pietro Avanzini, Marzio Gerbella, Sara Costa, Flavia Maria Zauli, Piergiorgio d'Orio, Elena Focacci, Ivana Sartori, Fausto Caruana
Simulation theories predict that the observation of other's expressions modulates neural activity in the same centres controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity. First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (Rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (i) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the 'emotional resonance model'; (ii) in the Rolandic operculum it evoked face/mouth sensorimotor responses, in line with the 'motor resonance' model; and (iii) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the Rolandic operculum is part of the parieto-frontal circuits and poorly connected with the former. These results support the hypothesis that the pathways hypothesized by the 'emotional resonance' and the 'motor resonance' models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.
{"title":"Anatomo-functional basis of emotional and motor resonance elicited by facial expressions.","authors":"Maria Del Vecchio, Pietro Avanzini, Marzio Gerbella, Sara Costa, Flavia Maria Zauli, Piergiorgio d'Orio, Elena Focacci, Ivana Sartori, Fausto Caruana","doi":"10.1093/brain/awae050","DOIUrl":"10.1093/brain/awae050","url":null,"abstract":"<p><p>Simulation theories predict that the observation of other's expressions modulates neural activity in the same centres controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity. First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (Rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (i) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the 'emotional resonance model'; (ii) in the Rolandic operculum it evoked face/mouth sensorimotor responses, in line with the 'motor resonance' model; and (iii) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the Rolandic operculum is part of the parieto-frontal circuits and poorly connected with the former. These results support the hypothesis that the pathways hypothesized by the 'emotional resonance' and the 'motor resonance' models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139746056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolutionary perspectives on mRNA signatures of neurodegeneration-related brain remodelling.","authors":"Ting Shen, Corey T McMillan","doi":"10.1093/brain/awae267","DOIUrl":"10.1093/brain/awae267","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}