译175 | 生活方式与金森病--张磊

与其他的神经变性病一样，帕金森病(PD)的特点是运动和非运动症状的持续进展和恶化。潜在的神经保护治疗集中于PD的神经变性方面，如伴随着氧化磷酸化异常的线粒体功能受损、氧化应激增加和神经免疫受抑。但这些神经保护治疗未能改变PD的临床病程。^1,2对PD病理生理过程的新认识确认了可能的分子靶标，包括含有错误折叠的α突触核蛋白聚集体的堆积和其可能的朊蛋白样扩散。³这些治疗目前仅用于临床检测，它们的真正治疗潜能尚不清楚。即使成功，它们距离临床应用也还有相当长时间。因此，目前我们仍没有任何经证实的药物能够修饰PD患者的持续性病情进展。

尽管黑质纹状体多巴胺神经元的选择性变性已被广泛接受是PD的重要特征，可能还有其他的病理学改变在PD的发病机制中起作用。血脑屏障的破坏和脑微血管的改变可能是PD进展的重要因素。⁴小血管损害可能是神经变性过程的一个直接后果，与之相关的炎症反应加重了α突触核蛋白聚集体沉积，进而导致的血管内皮损伤。传统的心血管危险因素，其中最重要的是高血压和糖尿病，也会影响PD患者脑微血管。此外而且，用MRI评估上的脑白质疏松评价这些变化的程度，可能有助于了解对PD的进展速度也有影响。5影响平衡和步态这些中线问题的频率与脑白质变化的程度负担更重有关，这表明对这些危险因素的积极管理提示这些危险因素的积极控制可能推迟PD致残性姿势改变的出现。^5,6

心血管危险因素是重要的，可能是的神经变性级联瀑布的修饰因子，其存在被认为他们的出现已被提示是PD的独立危险因素，其他的还有遗传易感性和环境暴露。⁷代谢综合征包括高血压、高血糖伴发胰岛素抵抗、高甘油三酯、伴低密度脂蛋白增高和高密度脂蛋白水平降低的血脂代谢异常和腰围增加的中心性肥胖。⁸代谢综合征患者患糖尿病、心脑血管疾病的风险增加。虽然代谢综合征确切地增加了糖尿病、卒中、心肌梗死风险，但它在其他疾病中的作用仍有争论。以往对PD的研究结果不一致，一些有几个研究报道了代谢综合征增加PD的患病风险；然而，当分析代谢综合征的多种成分时被分析，研究结果却没有证实这一发现。^7,9

虽然在代谢综合征可能促进PD的起病尚仍未被完全确定时，其对PD进展的影响一直没有被研究。本期Neurology®中Leehey等进行了相关的报道。但直到本期“Neurology®”期刊Leehey等人的研究报告才对其对PD进展的影响进行研究。¹⁰应用来自PD长期研究1中国家神经疾病和卒中探索试验(NET-PD LS 1)的1022个参与者的数据，他们报道了二次分析的结果，比较了伴有代谢综合征和不伴代谢综合征的PD进展速度。在3年的随访期内，疾病进展用一致性帕金森病评分量表的第I到第III部分进行测定，认知状态被用Symbol Digit Modalities Tests scores评价。这项本研究的主要发现是，那些伴并发代谢综合征的患者运动功能恶化更快，并且这些患者与无那些没有代谢综合征的患者比较，每年多恶化0.5分。尽管共存代谢综合征可能是认知损害的危险因素，但本研究在两组间未没有发现任何区别。

这是第二个关于注肌酸的可能的神经保护作用的研究分析，本分析有几个重要的缺陷需要被考虑。研究流程中未没有收集所有的必要的衡量代谢综合征的数据，其中最主要的是缺乏，详细的血脂水平、空腹血糖和腰围。因此，不可能进行另外的这些因素对PD进展影响的分析。而且，这两组研究对象不匹配不好，代谢综合征组年龄更大一些，男性比例更高。虽然这些缺陷在统计分析中被纠正，但研究结论需要被重复以进一步证实。最后，本研究仅包括了那些在整个研究过程中，一直保持同样的代谢综合征状态的患者，因此，我们无法评价代谢状态的改善是否改变了PD的病程，这需要前瞻性研究进一步阐明，该研究旨在设计时即考虑显示这种可能的差异区别。

尽管有上述诸多缺陷，这仍然是一个重要的研究，它进一步强化了代谢综合征和PD之间的联系。神经科医生在治疗PD时可能想知道他们是否有足够的证据支持来积极地控制PD患者的代谢综合征。治疗代谢综合征的第一步就是改变生活方式，即改变饮食习惯，规律运动。8有几项个研究表明已经显示PD患者进行规律运动有益，但这不是在合并共存代谢综合征的前提下进行的分析。^11,12因此，在常规基础水平上增加体育锻炼可能具有改善PD和代谢综合征的潜力，这应该让每一个PD患者知道。

神经科医生在PD治疗中的作用越来越大在逐渐增加，我们从单纯的运动障碍疾病治疗转移到了运动和多个的非运动症状的复杂治疗。越来越多的数据支持这样的事实，我们需要不断扩展我们的作用，以包括生活方式的改变和积极地处理合并存在的代谢综合征。

中英文对照部分

Parkinson disease (PD), similar to other neurodegenerative conditions, is characterized by relentless clinical progression with gradual worsening of both motor and nonmotor features. Potential neuroprotective therapies focusing on aspects of neurodegeneration in PD such as impaired mitochondrial function with abnormalities of oxidative phosphorylation, increased oxidative stress, and suppressed neuroinflammation, have failed to alter the clinical course of PD.^1,2 New insights into PD pathophysiology have identified potential molecular targets, including accumulation and potential prion-like spreading of aggregates containing misfolded α-synuclein protein.³ These therapies are only approaching clinical testing, and their true therapeutic potential remains unknown. Even if successful, they are many years away from clinical availability. Thus, at present, we do not have any proven pharmacologic options to modify the progressive decline of patients with PD.

Although selective neurodegeneration of nigrostriatal dopaminergic neurons is widely accepted as a key feature of PD, additional pathologic changes may play a role in PD pathogenesis. Damage to the blood-brain barrier and cerebral microvascular changes have been implicated as potentially important factors in PD progression.⁴ Microvascular damage may be a direct consequence of neurodegenerative processes, with endothelial damage from a-synuclein deposits aggravated by associated inflammatory reaction. Traditional cardiovascular risk factors, most not ably hypertension and diabetes mellitus, also affect the cerebral microvasculature in PD. Moreover, the degree of these changes, assessed as leukoaraiosis on MRI, may contribute to the rate of progression in PD.5 The frequency of midline problems affecting balance and gait was associated with a higher burden of white matter changes, suggesting that aggressive management of these risk factors may delay the onset of disabling postural changes in PD.^5,6

Cardiovascular risk factors are important as possible modifiers of a neurodegenerative cascade, and their presence has been suggested as an independent risk factor of PD, together with genetic predispositions and environmental exposures.⁷ Metabolic syndrome includes hypertension, insulin resistance with hyperglycemia, dyslipidemia with hypertriglyceridemia, elevated low-density lipoprotein and reduced high-density lipoprotein levels, and central obesity with increased waist circumference.⁸ Patients with metabolic syndrome have an elevated risk of developing diabetes mellitus and having cardiovascular and cerebrovascular disease. While metabolic syndrome is firmly linked to an increased incidence of diabetes mellitus, stroke, and myocardial infarction, its role in other conditions is still debated. Previous studies in PD have yielded inconsistent results. Several investigations have reported an increased risk of PD in patients with metabolic syndrome. However, other studies did not confirm this finding when various components of metabolic syndrome were analyzed.^7,9

While the possible contribution of metabolic syndrome to the onset of PD remains to be fully determined, its influence on the progression of PD has not been studied until the report in this issue of Neurology® by Leehey et al.¹⁰ Using data from 1,022 participants in the National Institute of Neurological Disorders and Stroke Exploratory Trials in PD Long-Term Study 1 (NET-PD LS 1), they report a secondary analysis comparing the rate of progression of PD in patients with and without metabolic syndrome. The disease progression was measured by annual assessment of Unified Parkinson’s Disease Rating Scale parts I through III, and cognitive status was assessed by the Symbol Digit Modalities Tests scores during 3 years of follow-up. The main finding of this study is a faster deterioration of motor function in patients who were classified as having metabolic syndrome and that these patients accrued an additional 0.5 point annually compared to patients without metabolic syndrome. Although the coexistence of metabolic syndrome may be a risk factor for cognitive decline, this study did not detect any difference in cognitive performance between the 2 groups.

The analysis has several important limitations that need to be considered. This was a secondary analysis of a study focused on possible neuroprotective role of creatine. The study protocol did not collect all data necessary for the assessment of metabolic syndrome, most notably a detailed lipid profile, fasting glucose, and waist circumference, and additional analysis of these factors for PD progression is not possible. Furthermore, the groups were not matched, with the metabolic syndrome cohort being older and having a greater proportion of men. This was corrected in the statistical analysis, but this finding needs to be replicated. Lastly, only those patients who maintained the same metabolic syndrome status during the whole study were included. Thus, we cannot assess whether the improvement of metabolic status altered the course of PD, and again, this needs to be addressed by a prospective study designed to show this possible difference.

Despite these limitations, this is an important study further strengthening the connection between metabolic syndrome and PD. The neurologists treating patients with PD may wonder whether they have enough evidence to support the active and aggressive control of metabolic syndrome in patients with PD. The first step in management of metabolic syndrome is lifestyle modification with dietary changes and regular exercise.8 Several studies have shown the benefits of regular physical activity in patients with PD, even though this was not analyzed in the context of coexisting metabolic syndrome.^11,12 Thus, increased physical activity on a regular basis has a potential to improve PD and metabolic syndrome, and this should be reviewed with every patient with PD.

The role of neurologists in PD treatment is ever increasing, and we moved from the treatment of movement disorder only to a complex management of both motor and multiple nonmotor symptoms. The emerging data support the fact that we need to expand our roles consistently to include coaching of lifestyle changes and active management of various features of metabolic syndrome if present.

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