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Abstract：
The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown that MBI is associated with alterations in structural and functional neuroimaging studies, higher genetic predisposition to clinical diagnosis of Alzheimer\'s disease (AD), as well as amyloid and tau pathology assessed in the blood, cerebrospinal fluid, positron-emission tomography (PET) imaging and neuropathological examination. These findings shed more light on the MBI-related potential neurobiological mechanisms, paving the way for the development of targeted pharmacological approaches. In this review, we aim to discuss the available clinical evidence on the role of amyloid and tau pathology in MBI and the potential underlying pathophysiological mechanisms. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, disruption of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), abnormal neuroinflammatory responses including the kynurenine pathway, dysregulation of transforming growth factor beta (TGF-β1), epigenetic alterations including micro-RNA (miR)-451a and miR-455-3p, synaptic dysfunction, imbalance in neurotransmitters including acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and norepinephrine, as well as altered locus coeruleus (LC) integrity are some of the potential mechanisms connecting MBI with amyloid and tau pathology. The elucidation of the underlying neurobiology of MBI would facilitate the design and efficacy of relative clinical trials, especially towards amyloid- or tau-related pathways. In addition, we provide insights for future research into our deeper understanding of its underlying pathophysiology of MBI, and discuss relative therapeutic implications.
摘要：
在以后的生活中，非痴呆个体中持续神经精神症状（NPS）的出现，定义为轻度行为障碍(MBI)，与认知能力下降的风险更高有关。然而,潜在的病理生理机制在很大程度上仍未被探索。越来越多的证据表明，MBI与结构和功能神经影像学研究的改变有关，阿尔茨海默病(AD)临床诊断的遗传易感性较高，以及在血液中评估的淀粉样蛋白和tau病理学，脑脊液,正电子发射断层扫描（PET）成像和神经病理学检查。这些发现进一步阐明了MBI相关的潜在神经生物学机制。为靶向药理学方法的发展铺平了道路。在这次审查中,我们的目的是讨论关于淀粉样蛋白和tau蛋白病理在MBI中的作用以及潜在的潜在病理生理机制的现有临床证据。下丘脑-垂体-肾上腺（HPA）轴失调，神经营养因子的破坏，例如脑源性神经营养因子（BDNF），异常的神经炎症反应，包括犬尿氨酸途径，转化生长因子β（TGF-β1）的失调，表观遗传改变，包括微小RNA（miR）-451a和miR-455-3p，突触功能障碍,包括乙酰胆碱在内的神经递质失衡，多巴胺,血清素,γ-氨基丁酸（GABA）和去甲肾上腺素，以及改变的蓝斑（LC）完整性是将MBI与淀粉样蛋白和tau病理联系起来的一些潜在机制。对MBI潜在神经生物学的阐明将促进相关临床试验的设计和功效，尤其是与淀粉样蛋白或tau蛋白相关的途径。此外,我们为未来的研究提供见解，深入了解MBI的潜在病理生理学，并讨论相关的治疗意义。
