Azargoonjahromi Ali, Nasiri Hamide
Shiraz University of Medical Sciences, Shiraz, Iran.
Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
Mol Brain. 2025 Jul 1;18(1):55. doi: 10.1186/s13041-025-01229-3.
Amyloid-β42 (Aβ42) regulates synaptic plasticity and memory formation at physiological levels in the brain, but in Alzheimer's disease (AD), it can disrupt brain function and glucose metabolism. This disruption contributes to cognitive decline and neuropsychiatric symptoms, highlighting the need to better understand its complex effects. This study investigated the associations among cerebrospinal fluid (CSF) Aβ42 levels, cerebral glucose metabolism (assessed via FDG-PET), neuropsychiatric symptoms (evaluated using the NPI), and cognitive performance (measured by ADAS-Cog13 and MoCA) in individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) participants. After adjusting for age, gender, education, and ApoE ɛ4 status, a significant positive relationship between CSF Aβ42 levels and cerebral glucose metabolism was observed in the MCI and AD groups, but not in the CN group. In the MCI group, higher cerebral glucose metabolism was associated with reductions in both neuropsychiatric and depressive symptoms, suggesting that higher glucose metabolism reflect higher activation state of investigated brain regions. In contrast, in the CN group, elevated CSF Aβ42 levels were directly linked to increased depressive symptoms, indicating that higher CSF Aβ42 may contribute to depression even in the absence of cognitive decline. Further analysis revealed that CSF Aβ42 levels were indirectly associated with reduced neuropsychiatric and depressive symptoms through enhanced cerebral glucose metabolism as mediator solely in the MCI group. Regarding cognitive performance, cerebral glucose metabolism showed a strong relationship with cognition in both the MCI and AD groups. Furthermore, higher CSF Aβ42 levels were positively associated with better cognitive performance in the MCI and AD groups, with cerebral glucose metabolism potentially mediating this relationship, while no effect was seen in the CN group. In short, CSF Aβ42 positively influenced cerebral glucose metabolism, which was linked to reduced neuropsychiatric and depressive symptoms as well as improved cognitive performance in MCI and AD groups.
淀粉样β蛋白42（Aβ42）在大脑的生理水平上调节突触可塑性和记忆形成，但在阿尔茨海默病（AD）中，它会破坏脑功能和葡萄糖代谢。这种破坏会导致认知能力下降和神经精神症状，凸显了更好地了解其复杂影响的必要性。本研究调查了阿尔茨海默病患者、轻度认知障碍（MCI）患者和认知正常（CN）参与者的脑脊液（CSF）Aβ42水平、脑葡萄糖代谢（通过FDG-PET评估）、神经精神症状（使用NPI评估）和认知表现（通过ADAS-Cog13和MoCA测量）之间的关联。在调整年龄、性别、教育程度和ApoE ε4状态后，在MCI组和AD组中观察到CSF Aβ42水平与脑葡萄糖代谢之间存在显著的正相关关系，而在CN组中未观察到。在MCI组中，较高的脑葡萄糖代谢与神经精神症状和抑郁症状的减轻有关，这表明较高的葡萄糖代谢反映了所研究脑区的较高激活状态。相反，在CN组中，CSF Aβ42水平升高与抑郁症状增加直接相关，这表明即使在没有认知能力下降的情况下，较高的CSF Aβ42也可能导致抑郁。进一步分析表明，仅在MCI组中，CSF Aβ42水平通过增强脑葡萄糖代谢作为中介与神经精神症状和抑郁症状的减轻间接相关。关于认知表现，脑葡萄糖代谢在MCI组和AD组中均与认知有很强的关系。此外，在MCI组和AD组中，较高的CSF Aβ42水平与较好的认知表现呈正相关，脑葡萄糖代谢可能介导这种关系，而在CN组中未观察到这种影响。简而言之，CSF Aβ42对脑葡萄糖代谢有积极影响，这与MCI组和AD组中神经精神症状和抑郁症状的减轻以及认知表现的改善有关。
