Comprehensive multimodal analysis of patients with neuroimmunological diseases

神经免疫疾病患者的综合多模态分析

• 批准号: 10692205
• 负责人: Bibiana Bielekova
• 金额: $ 219.93万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692205
• 关键词: Acute; Affect; Age; Algorithms; Animal Model; Area; Astrocytes; Axon; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Bypass; Categories; Cellular Phone; Central Nervous System; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Clinical Trials; Collection; Computer Models; Dantrolene; Data; Development; Diagnosis; Digit structure; Disease; Dose; Elderly; Enhancing Lesion; Etiology; Evaluation; FRAP1 gene; Functional disorder; Future; Generations; Genes; Goals; Gold; Growth; Hand; Healthcare Systems; Human; Human Pathology; Immune; Immune system; Impaired cognition; Inflammatory; Injury; Knowledge; Learning; Light; Linear Models; Link; Liquid substance; Literature; Magnetic Resonance Imaging; Maps; Mathematics; Measures; Mediating; Medical Imaging; Meta-Analysis; Modality; Modeling; Modification; Motor; Multiple Sclerosis; Nervous System Physiology; Nervous System Trauma; Neurodegenerative Disorders; Neurologic Examination; Neurons; Outcome; PI3K/AKT; Pathology; Patient Monitoring; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Physiological; Predictive Value; Process; Prognostic Marker; Proteins; Protocols documentation; Publications; Publishing; Randomized; Rare Diseases; Reaction Time; Relapsing-Remitting Multiple Sclerosis; Reporting; Reproducibility; Research; Research Design; Research Personnel; Role; Ryanodine Receptor Calcium Release Channel; Sample Size; Sampling; Self Administration; Sensitivity and Specificity; Serum; Severities; Signal Pathway; Signal Transduction; Spinal Cord; Spinal cord damage; Stimulus; Study models; Support System; Test Result; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transcript; United States Food and Drug Administration; Validation; Vision; base; central nervous system injury; clinical practice; cognitive disability; cognitive function; cognitive testing; cohort; data exploration; design; digital; disability; disease phenotype; effective therapy; endoplasmic reticulum stress; eye hand coordination; field study; human subject; immunomodulatory therapies; immunoregulation; improved; in vivo; inhibitor; molecular marker; multimodality; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; nervous system imaging; neurofilament; neuroimmunologic disease; neuroprotection; neurotoxic; novel; phase II trial; predictive marker; prevent; response; screening; time use; tissue repair; tool; web site

Neuroimmunological diseases of the central nervous system (CNS) represent a growing spectrum of diagnoses, most of which are considered rare disorders. The pathophysiology of these diseases is poorly understood, and effective therapies are sporadic. The most common immune-mediated CNS disease is multiple sclerosis (MS). The initial stage of MS, relapsing-remitting MS (RRMS) can be effectively treated by immunomodulatory treatments, if these are initiated at young age, before the substantial CNS damage occurred. Although there are currently more than 20 Food and Drug Administration (FDA)-approved treatments of MS, their efficacy on disability progression strongly declines with advancing age of patients, so that after age of 54 years, no efficacy on disability progression is seen on a group level. This protocol is advancing knowledge about disease mechanisms that are not targeted by current FDA-approved treatments and is also developing and validating tools of clinical utility. This review period (October 2021-August 2022) we have generated following results: 1. Neurological examination takes 30-60 minutes to perform, but clinicians have much less time they can spend with patients. To facilitate reliable quantification of neurological functions in current healthcare system we have been developing smartphone-based collection of simple tests of neurological functions called Neurological Functions Test Suite (NeuFun-TS) that can be self-administered by patients. The goal of NeuFun-TS is to reproduce most aspects of clinician-performed neurological examination. To optimize NeuFun-TS tests and prove their clinical utility, we are mapping the different outcomes of the digitalized tests to the gold standard of full neurological examination and quantitative central nervous system (CNS) imaging. One of these tests measures cognitive functions such as reaction time using digital modification for the smartphone use of the traditional cognitive test, the Symbol Digit Modalities Test (SDMT). We made the SDMT randomized, which prevents the memorization of the test, and mapped all contributing neurological functions that affect the randomized SDMT (rSDMT) test results: these include motoric disability of the dominant hand, but also vision and eye-hand coordination. Because these functions are measured by other simple tests in NeuFun-TS, we can use the outcomes from these alternative tests as covariates in rSDMT outcome to isolate measured function, in this case cognitive disability. Resulting novel smartphone-computed outcome from this simple cognitive test explains 75% of CNS tissue damage measured by qMRI in the independent validation cohort, with extremely low p-value. We also used longitudinal data to derive algorithmic identification of the learning effect and to demonstrate that averaging repeated tests (e.g., 2-4 weekly tests) lowers the threshold for identifying true progression in cognitive decline, e.g. during clinical trials or in routine clinical practice. 2. Several animal models of neurodegenerative diseases and pathology studies of several human neurodegenerative diseases identified abnormal phenotype of astrocytes that instead of supporting neuronal functions, become neurotoxic. Previous year we showed that some of the cerebrospinal fluid (CSF) biomarkers that are most strongly associated with MS severity (i.e., that are strongly elevated in MS patients who accumulate irreversible disability faster), such as SERPINA3, are released by such neurotoxic astrocytes. This year we mapped the signaling pathways involved in the transformation of primary human astrocytes to neurotoxic phenotype by pro-inflammatory stimuli. We identified primary role of endoplasmic reticulum stress and linked mTOR/PI3K/AKT signaling. We also identified several drugs and drug categories that reproducibly inhibit transformation of astrocytes to neurotoxic phenotype in concentrations achievable with FDA-approved dosing, if they cross the blood brain barrier. Among these, dantrolene, an inhibitor of ryanodine receptor channels (RYR1 and RYR3) was selected for in-vivo validation of predicted intrathecal pharmacodynamic effects in our ongoing platform clinical trial. 3. Serum neurofilament light chain (sNFL) is emerging as the most useful noninvasive biomarker of the acute injury to neurons and axons, with potential clinical value in diagnosing and monitoring patients with neurological diseases. However, simultanously measured NFL concentrations in the CSF and serum show that, while these are correlated, linear models explain only 40-60% of variance and CSF NFL levels have stronger predictive value for measuring acute CNS damage than sNFL. Thus, to increase clinical value of sNFL, we used 1,138 matched CSF-serum samples to comprehensively map processes that influence NFL concentrations in the CSF and blood to derive (and validate) mathematical adjustment of sNFL to better approximate CSF NFL. This adjustment caused 36% improvement in the ability of sNFL to predict MS activity (measured by contrast enhancing lesions on brain and spinal cord MRI) in the independent validation cohort with very low p-value. However, only sNFL, but not CSF NFL weakly but significantly correlated with MS severity. We show that this sNFL advantage originates in its ability to reflect spinal cord damage resulting in NFL release from peripheral axons eventually to blood, bypassing the CSF. While careful evaluation of published literature on CSF/serum NFL levels in diseases of peripheral versus central nervous system support our conclusions, this aspect of axonal pathology has not been appreciated in MS. Our results also show that more research is required before sNFL can be used for making therapeutic decisions in MS on a patients level. 4. Development of effective treatments requires understanding of disease mechanisms. For CNS diseases like MS, human pathology studies and animal models tend to identify candidate disease mechanisms. However, these studies cannot easily link identified processes to clinical outcomes, such as MS severity, required for causality assessment of candidate mechanisms. Technological advances now allow generation of thousands of biomarkers in living human subjects, derived from genes, transcripts, medical images and proteins or metabolites in biological fluids. These biomarkers can be assembled into computational models of clinical value, provided such models are generalizable. Reproducibility of models increases with technical rigor of study design, such as blinding, implementing controls, using large cohorts that encompass entire spectrum of disease phenotypes and, most importantly, validating models in independent cohort(s). To facilitate growth of this important research area, we performed a meta-analysis of publications that model MS clinical outcomes (n=302), extracting effect sizes, while also scoring technical quality of study design using pre-defined criteria. Finally, we generated a Shiny-App-based website that allows dynamic exploration of data using selective filtering. On average, published studies fulfilled only one out of seven criteria of study design rigor. Only 15.2% of studies used any validation strategy, and only 8% used the gold standard of independent cohort validation. Many studies also used small cohorts, e.g., for MRI and blood biomarker predictors, the median sample size was below 100 subjects. We observed inverse relationships between reported effect sizes and the numbers of study design criteria fulfilled, expanding analogous reports from non-MS fields, that studies that fail to limit bias over-estimate effect sizes. This meta-analysis represents a useful tool for researchers, reviewers, and funders to improve design of future modeling studies in MS and to easily compare new studies with published literature.

中枢神经系统（CNS）的神经免疫性疾病代表了越来越多的诊断范围，其中大多数被认为是罕见疾病。这些疾病的病理生理学知之甚少，有效的疗法是零星的。最常见的免疫介导的中枢神经系统疾病是多发性硬化症（MS）。如果在发生实质性的中枢神经系统损伤之前，可以通过免疫调节治疗的初始阶段（RRMS）有效地治疗免疫调节治疗。尽管目前有20多个食品药物管理局（FDA）对MS的批准治疗方法，但随着患者的年龄增长，它们对残疾进展的功效大大下降，因此在54岁以后，在小组水平上没有看到残疾进展的疗效。该方案正在促进有关疾病机制的知识，而这些机制不是由当前FDA批准的治疗方法瞄准的，并且正在开发和验证临床实用程序的工具。 这个审查期（2021年10月至2022年8月）我们产生了以下结果： 1。神经检查需要30-60分钟的时间，但是临床医生可以花的时间少得多。为了促进当前医疗保健系统中神经功能的可靠量化，我们一直在开发基于智能手机的神经功能的简单测试，称为神经功能测试套件（NEUFUN-TS），这些测试套件（NEUFUN-TS）可以由患者自我管理。 Neufun-TS的目的是重现临床医生表现的神经系统检查的大多数方面。为了优化Neufun-TS测试并证明其临床实用性，我们将数字化测试的不同结果映射到了全神经检查和定量中枢神经系统（CNS）成像的黄金标准。这些测试之一测量了认知功能，例如使用数字修改来使用智能手机使用传统认知测试的反应时间，即符号数字模式测试（SDMT）。我们使SDMT随机进行了随机，从而阻止了测试的记忆，并绘制了所有影响随机SDMT（RSDMT）测试结果的神经功能：这些函数包括主导手的摩擦残疾，以及视觉和眼手配位。由于这些函数是通过Neufun-Ts中的其他简单测试来衡量的，因此我们可以将这些替代测试的结果用作RSDMT结果中的协变量来隔离测量的功能，在这种情况下为认知障碍。由此简单的认知测试产生的新型智能手机计算结果解释了QMRI在独立验证队列中测量的中枢神经系统组织损伤的75％，P值极低。我们还使用纵向数据来得出对学习效果的算法识别，并证明平均重复测试（例如2-4个每周测试）降低了确定认知能力下降中真正进步的阈值，例如。在临床试验或常规临床实践中。 2。几种人类神经退行性疾病的神经退行性疾病和病理研究的几种动物模型确定了星形胶质细胞的异常表型，而不是支持神经元功能，而是神经毒性。上一年，我们表明，一些与MS严重程度最密切相关的脑脊液（CSF）生物标志物（即，在更快地积累不可逆性残疾的MS患者中，诸如SERPINA3的MS患者（例如SERPINA3）（例如，这种神经毒性星形胶质细胞）释放。今年，我们通过促炎性刺激绘制了与原代人星形胶质细胞转化为神经毒性表型的信号通路。我们确定了内质网应激的主要作用，并连接了MTOR/PI3K/AKT信号。我们还确定了几种药物和药物类别，可以可重复地抑制星形胶质细胞转化为神经毒性表型，如果通过FDA批准的给药来实现的浓度，如果它们越过了血脑屏障。其中，在我们正在进行的平台临床试验中，选择了丹托烯，ryanodine受体通道的抑制剂（RYR1和RYR3）以在体内验证预测的鞘内药效学效应。 3。血清神经丝轻链（SNFL）是对神经元和轴突急性损伤的最有用的无创生物标志物，在诊断和监测神经系统疾病的患者方面具有潜在的临床价值。然而，同时测量的CSF和血清中NFL浓度表明，尽管它们是相关的，但线性模型仅解释了40-60％的方差和CSF NFL水平比SNFL的急性中枢神经系统损伤具有更强的预测价值。因此，为了增加SNFL的临床价值，我们使用了1,138个匹配的CSF-Serum样品来全面绘制影响CSF和血液中NFL浓度的过程，以得出（并验证）SNFL的数学调整以更好地近似CSF NFL。这种调整导致SNFL预测MS活性的能力提高了36％（通过具有非常低的P值的独立验证队列中的大脑和脊髓MRI的对比度增强病变来衡量）。但是，只有SNFL，但不明显不弱，但与MS严重程度显着相关。我们表明，这种SNFL优势源于它反映脊髓损伤的能力，导致NFL从外周轴突释放到血液，并绕过CSF。虽然对周围性和中枢神经系统疾病中CSF/血清NFL水平的已发表文献的仔细评估支持了我们的结论，但在MS中尚未对轴突病理学的这一方面得到认识。我们的结果还表明，在使用SNFL用于在患者水平上在MS中做出治疗决策之前，需要进行更多的研究。 4。开发有效治疗需要了解疾病机制。对于MS等中枢神经系统疾病，人类病理学研究和动物模型倾向于鉴定候选疾病机制。但是，这些研究无法轻易将确定的过程与因果关系评估候选机制所需的临床结果（例如MS严重性）联系起来。技术进步现在允许在生物液中产生数千种生物标志物，这些生物标志物是源自生物液中的基因，转录本，医学图像和蛋白质或代谢产物的。如果这些模型可推广，则可以将这些生物标志物组装成临床价值的计算模型。模型的可重复性随着研究设计的技术严格而增加，例如盲目，实施控制，使用涵盖整个疾病表型的大量同类，最重要的是，在独立队列中验证了模型。为了促进这一重要研究领域的增长，我们对MS临床结果进行建模的出版物进行了荟萃分析（n = 302），提取效果大小，同时还使用预定的标准为技术质量进行了研究质量。最后，我们生成了一个基于闪亮的应用程序的网站，该网站允许使用选择性过滤动态探索数据。平均而言，已发表的研究仅满足了严格的研究设计标准中的一个。只有15.2％的研究使用了任何验证策略，只有8％的研究使用了独立队列验证的黄金标准。许多研究还使用了小型队列，例如，对于MRI和血液生物标志物预测指标，中位样本量低于100名受试者。我们观察到报告的效应大小与研究标准的数量之间的反比关系，从而扩大了非MS领域的类似报告，即无法限制偏见过高效应大小的研究。 这项荟萃分析是研究人员，审阅者和资助者改善MS中未来建模研究的设计，并轻松将新研究与已发表的文献进行比较的有用工具。