1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias Street 72-74, 11528 Athens, Greece.
1st Department of Psychiatry, Aiginition University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias Street 72-74, 11528 Athens, Greece.
Cells. 2024 Jul 8;13(13):1164. doi: 10.3390/cells13131164.
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.
在晚年非痴呆个体中出现持续性神经精神症状（NPS），定义为轻度行为障碍（MBI），与认知能力下降的风险增加有关。然而，潜在的病理生理机制在很大程度上仍未得到探索。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、对阿尔茨海默病（AD）临床诊断的更高遗传易感性以及血液、脑脊液、正电子发射断层扫描（PET）成像和神经病理学检查中评估的淀粉样蛋白和 tau 病理学有关。这些发现更深入地了解了与 MBI 相关的潜在神经生物学机制，为开发靶向药物治疗方法铺平了道路。在这篇综述中，我们旨在讨论淀粉样蛋白和 tau 病理学在 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）轴的失调、神经营养因子（如脑源性神经营养因子（BDNF））的破坏、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 micro-RNA (miR)-451a 和 miR-455-3p、突触功能障碍、神经递质包括乙酰胆碱、多巴胺、血清素、γ-氨基丁酸（GABA）和去甲肾上腺素的失衡，以及改变蓝斑（LC）完整性是一些将 MBI 与淀粉样蛋白和 tau 病理学联系起来的潜在机制。阐明 MBI 的潜在神经生物学将有助于设计和评估相关临床试验，特别是针对淀粉样蛋白或 tau 相关途径。此外，我们为未来的研究提供了见解，以加深我们对 MBI 潜在病理生理学的理解，并讨论了相关的治疗意义。
