Investigating the neuroprotective effect of exercise; the role of redox homeostasis

精准医疗：本项目的目的是探索氧化应激作为一种机制，通过运动为大脑提供保护。氧化应激是大脑健康的核心，当氧化剂（由代谢过程产生）压倒抗氧化剂（由身体产生作为防御）时就会出现。氧化剂和抗氧化剂之间的平衡被称为氧化还原平衡，氧化还原平衡是细胞功能的关键。氧化还原紊乱，更具体地说，氧化应激与精神障碍（如精神分裂症和抑郁症）、认知能力下降和神经退行性病变（包括痴呆症）直接相关。运动可以扰乱氧化应激，并可能重新平衡在精神健康障碍中观察到的氧化还原紊乱。此外，运动被认为是神经保护。我们认为这种神经保护能力是由于运动调节氧化还原平衡的能力。我们已经证明，可以使用非侵入性MR光谱法测量大脑中的谷胱甘肽（GSH）（Wood，Yucel等人，2009）。在最近的一项试点研究中，我们已经表明，我们可以检测到运动后GSH的变化，这些变化似乎是运动强度dependent.Study 1 -什么是最佳的运动扰动大脑GSH？在交叉研究设计中，我们将评估中等（MOD，60%VO2 max）;高（HIGH，80%VO2 max）;极高强度间歇运动（HIIT;在100%VO2 max下间隔4 x 1分钟，每个间隔之间恢复2分钟）对健康久坐（65-75岁的老年人和18-35岁的年轻人）参与者组大脑GSH的影响。比赛将按顺序随机化，并将间隔至少7天，以确保前一场比赛的任何适应性效果已经丧失。研究2 -运动可以干扰疾病中的大脑GSH吗？研究2的参与者将从两个临床组招募：1）诊断为md-aMCI的老年人（65-75岁）将通过Barberry医院（伯明翰和索利赫尔精神健康信托基金）的记忆诊所招募。2)将通过伯明翰和索利赫尔的早期干预服务招募首次发作精神病的年轻人（18-35岁）。研究2将采用为期12周的运动干预，其持续时间和强度由研究1确定为最有可能干扰脑GSH。将使用MEGA-PRESS和频谱编辑通过谷胱甘肽特异性MR波谱评估脑GSH（Terpstra，亨利et al. 2003）。我们的初步研究数据表明，我们可以使用这种技术测量运动引起的脑GSH变化。为了提供脑氧化应激的背景，将评估红细胞GSH和白色细胞硫氧还蛋白和过氧氧还蛋白。还将评估神经保护的血液标志物（IGF-1和BDNF）。一组神经心理学测试将探索临床实践中常规使用的认知功能测量。在MCI中，我们将评估注意力、工作记忆、情景记忆和执行功能（Haller，Missonnier et al. 2013）。在首发精神病中，我们将评估精神病理学和认知功能，特别关注阳性症状（Firth，Cotter et al. 2015）和言语记忆。我们假设，高运动回合将被研究1确定为最佳的运动，以增加大脑GSH后，一段时间的运动training.This研究将使我们更好地了解如何运动可以用于管理的条件，如抑郁症和精神分裂症，并在预防或延缓神经退行性疾病的进展。

Precision Medicine: Pathology to Population HealthThe aim of this project is to explore oxidative stress as a mechanism by which exercise offers protection for the brain. Oxidative stress is central to brain health, and arises when oxidants (produced by metabolic processes) overwhelm antioxidants (produced by the body as a defence). The balance between oxidants and antioxidants is referred to as redox balance and redox balance is key for cell function. Redox disturbance and more specifically, oxidative stress has been directly linked to mental disorders such as schizophrenia and depression, cognitive decline, and neurodegenerative pathology including dementia.Exercise can perturb oxidative stress and may rebalance the redox disturbances that are seen in disorders of mental health. Furthermore, exercise is known to be neuroprotective. We propose that this neuroprotective capacity is due to the ability of exercise to regulate redox balance. We have shown that glutathione (GSH) in the brain can be measured using non-invasive MR spectroscopy (Wood, Yucel et al. 2009). In a recent pilot study we have shown that we can detect changes in GSH following exercise, and that these changes appear to be exercise intensity dependent.Study 1 - What is the optimal exercise to perturb brain GSH? In a cross-over study design, we will assess the effect of moderate (MOD, 60%VO2 max); high (HIGH, 80%VO2 max); very high intensity interval exercise (HIIT; 4 x 1min intervals at 100% VO2 max with 2-min recovery between each interval) on brain GSH in healthy sedentary (older age 65-75 yrs and young 18-35 yrs) participant groups. Bouts will randomized in order and will be separated by at least 7 days to ensure any adaptive effect of a previous bout has been lost. Study 2 - Can exercise perturb brain GSH in disease?Participants for study 2 will be recruited from two clinical groups: 1) Older age adults (65-75 years) with a diagnosis of md-aMCI will be recruited via the memory clinics at the Barberry Hospital (Birmingham and Solihull Mental Health Trust). 2) Young adults with first episode psychosis (18-35 years) will be recruited via Early Intervention Services in Birmingham and Solihull. All will be currently treated and not acutely unwell.Study 2 will employ a 12-week exercise intervention, with duration and intensity identified by study 1 as having most potential for perturbing brain GSH. Brain GSH will be assessed by glutathione-specific MR spectroscopy using MEGA-PRESS and spectral editing (Terpstra, Henry et al. 2003). Data from our pilot study shows that we can measure exercise-induced change in brain GSH using this technique. To provide context to brain oxidative stress, red blood cell GSH, and white cell thioredoxin and peroxyredoxin, will be assessed. Blood markers of neuroprotection (IGF-1 and BDNF) will also be assessed. A battery of neuropsychological tests will explore measures of cognitive function that are routinely used in clinical practice. In MCI we will assess attention, working memory, episodic memory, and executive function (Haller, Missonnier et al. 2013). In first episode psychosis we will assess psychopathology and cognitive function, with a particular focus on positive symptoms (Firth, Cotter et al. 2015) and on verbal memory. We hypothesize that the HIGH exercise bout will be identified by study 1 as the optimal exercise to increase brain GSH following a period of exercise training.This research will allow us to better understand how exercise could be used in the management of conditions such as depression and schizophrenia, and in prevention or retardation of the progression of neurodegeneration.