Diagnostic Utility of mtDNA Content and Exercise Challenge in Veterans with GWI

描述(由申请人提供)： 在1990-1991年海湾战争中服役的70万退伍军人中，每四人中就有一人患有慢性多系统疾病，称为海湾战争疾病(GWI)。GWI的症状从疲劳和疼痛到认知功能障碍和睡眠障碍，但很难量化和治疗，有时会导致他们被解雇。这一困难一直存在于描述 所谓的GWI并不否认它的存在。为此，科学界和医学界面临着开发新的诊断指标的挑战，这些指标可能会导致对GWI潜在的病理生理学的更深入的了解，并有能力区分那些有GWI和没有GWI的人。GWI的特点通常是多变性；然而，有一些一致性值得注意。例如，不同的症状涉及多个高能器官系统(如肌肉、中枢/自主神经、呼吸系统和胃肠道)。这些系统的正常运作需要部分线粒体的效率。根据NIH的说法，患有线粒体功能障碍或疾病的人也表现出不同的症状组合，包括运动不耐受、疲劳、头痛和全身虚弱-这些症状与GWI相同。此外，线粒体DNA(MtDNA)损伤与人类接触颗粒物、苯和多环芳烃呈正相关。因此，线粒体DNA[和呼吸链酶活性]的分析可能是GWI内源性和外源性暴露的一个很好的候选生物标志物。鉴于高能量需求，线粒体DNA的损伤也可能影响运动能力，导致深度疲劳和异常恢复。然而，GWI中的文献喜忧参半。在慢性疲劳综合征(CFS)患者中也观察到了类似的相互矛盾的结果--然而最近的数据表明，这些混合的结果是由于单一运动测试的局限性，该测试没有考虑到GWI和CFS患者所特有的运动后不适期。然而，在第一次(即重复比赛)后24小时进行第二次运动测试，在有和没有CFS的人之间产生了显著和显著的差异。我们怀疑这种重复的运动测试范式在这项初步研究中将具有类似的实用价值，并能够区分那些有GWI的人和没有GWI的人。[我们建议研究线粒体损伤和功能障碍的独立和互补标记物(即线粒体DNA含量、呼吸链酶活性)以及对重复运动试验的反应(即逐次呼吸代谢数据、乳酸等)。)作为GWI诊断测试的一种手段。]这项初步研究得出的数据可能不仅作为潜在的客观指标很重要，而且还可能显著提高我们对GWI病理生理学的理解。此外，潜在的翻译优势可能是快速的，因为目前有有效的治疗线粒体功能障碍的方法。

DESCRIPTION (provided by applicant): One in four of the ~700,000 Veterans who served in the 1990 - 1991 Gulf War suffer from chronic multisystem illnesses, referred to as Gulf War Illness (GWI). GWI symptoms vary from fatigue and pain to cognitive dysfunction and sleep disturbances, but have been difficult to quantify and treat sometimes leading to their dismissal. That difficulty persists in characterizing what is known as GWI does not negate its existence. To this end, the scientific and medical communities are challenged to develop new diagnostic indicators that may lead to an enhanced understanding of the underlying pathophysiology of GWI and an ability to differentiate those with and without GWI. GWI is often characterized by its variability; however, there is some uniformity that warrants attention. For example, the diverse symptomatology involves multiple high-energy organ systems (e.g. muscular, central/autonomic nervous, respiratory, and gastrointestinal). Proper functioning of these systems requires efficiency on part of the mitochondria. According to the NIH, individuals with mitochondrial dysfunction or disease also present with a heterogeneous mix of symptoms that include exercise intolerance, fatigue, headache, and general weakness - symptoms shared with GWI. Additionally, mitochondrial DNA (mtDNA) damage is positively associated with exposure to particulate matter, benzene, and polycyclic aromatic hydrocarbons in humans. Therefore, analysis of mtDNA [and respiratory chain enzyme activity] may be an excellent candidate biomarker for endogenous and exogenous exposures of GWI. Damage to mtDNA would also likely affect exercise performance given the high-energy demands, resulting in profound fatigue and abnormal recovery. However, the literature in GWI has been mixed. Similar contradictory results have also been observed in individuals with chronic fatigue syndrome (CFS) - yet recent data suggests that these mixed results are accounted for by the limitation of a single exercise test which fails to consider the post-exertional malaise period characteristic to those with GWI and CFS. However, performing a second exercise test 24 hours after the first (i.e. repeated-bout) results in sizeable and significant differences between those with and without CFS. We suspect this repeated-bout exercise test paradigm will be of similar utility in this pilot study and be capable of differentiting those with and without GWI. [We propose to study independent and complementary markers of mitochondrial damage and dysfunction (i.e. mtDNA content, respiratory chain enzyme activity) and the response to a repeated-bout exercise test (i.e. breath-by-breath metabolic data, lactate, etc.) as a means of diagnostic testing for GWI.] Data derived from this pilot study may not only be important as potential objective indicators, but may also significantly improve our understanding of the GWI pathophysiology. Additionally, the potential translational merits could be rapid as efficacious treatment is currently available for mitochondrial dysfunction.