Foster Philip P, Rosenblatt Kevin P, Kuljiš Rodrigo O
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Medical Branch Galveston, TX, USA.
Front Neurol. 2011 May 6;2:28. doi: 10.3389/fneur.2011.00028. eCollection 2011.
Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer's disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The "inward" continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal "outward" continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.
诸如智力刺激、认知和社交参与、营养以及各类运动等生活方式因素，似乎能够降低患常见的与年龄相关疾病的风险，如阿尔茨海默病（AD）和血管性痴呆。事实上，许多研究表明，促进身体活动对预防晚年认知功能衰退具有保护作用。步行速度减慢或衰退与老年人在评估心理运动速度和语言流畅性测试中的表现不佳相关。健身训练会影响广泛的认知过程，观察到的最大积极影响在于执行（即额叶）功能。研究表明，运动可改善诸如由海马体介导的任务等其他认知功能，并导致海马体可塑性发生重大变化。有趣的是，这种运动诱导的可塑性在携带APOE ε4的个体中也很明显，APOE ε4是晚发性AD的一个风险因素，可能会调节治疗效果。基于Braak和Braak（1991年）以及Braak等人（1993年）的AD分期，我们提出运动的影响发生在两个时间 - 空间连续事件中。一个是从等皮质（新皮质）到内嗅皮质/海马体的“向内”连续过程，涉及淀粉样变性，另一个是神经纤维改变的相互“向外”连续过程。在这些连续过程核心部位的运动诱导的海马体肥大，根据预防神经元变性的潜力进行评估。运动诱导产生的生长因子，如脑源性神经营养因子（BDNF），已被证明可增强神经发生，并在积极的认知效应中起关键作用。胰岛素样生长因子（IGF - 1）可能介导运动对BDNF、神经发生和认知表现的诱导反应。还推测它通过脉络丛增加清除率来调节脑淀粉样β（Aβ）水平。生长因子，特别是成纤维细胞生长因子和IGF - 1受体及其下游信号通路，可能与作为衰老抑制基因起作用的Klotho基因相互作用。神经元可能不是唯一受运动影响的细胞。神经胶质细胞（星形胶质细胞和小胶质细胞）、神经血管单元和第四元素也可能以不同方式受到AD进程的影响。正如多维矩阵方法所建议的，需要对这些因素进行分析，以增进我们对这个复杂的多因素过程的理解，这对于战胜日益严重且相互交织的全球痴呆症、糖尿病和肌肉减少症流行至关重要，这些流行病正威胁着全球医疗保健系统。身体活动以及旨在增强和/或模拟运动效果的干预措施，连同为神经退行性疾病开发认知康复的初步努力，可能在缓解这些流行病方面发挥重要作用。
