Psychiatry/Mental Health Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Department of Psychiatry and Human Behavior, School of Medicine, and Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, Irvine, CA, USA.
Alzheimers Res Ther. 2022 Feb 7;14(1):25. doi: 10.1186/s13195-021-00954-w.
Cholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer's disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood.
This study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer's disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4β2 nicotinic cholinergic receptor binding (V/fp) was measured using 2-[F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest.
SPM analysis showed the group V/f binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p < .05, FWE-corrected). Pairwise comparisons revealed lower binding in the AD group compared to the CU group in similar regions. Binding in the entorhinal cortex was lower in the MCI group than in the CU group; binding in the hippocampus was lower in the AD group than in the MCI group. AD participants taking cholinesterase inhibitor medication had lower 2FA binding in the bilateral hippocampus and thalamus compared to those not taking medication. In the CU group, age was negatively associated with 2FA binding in each region of interest (r = - .33 to - .59, p < .05 for each, uncorrected). Attention, immediate recall, and delayed recall scores were inversely associated with 2FA binding in most regions across the full sample. In the combined group of CU and MCI participants, attention was inversely associated with 2FA binding in most regions, beyond the effect of hippocampal volume.
Nicotinic cholinergic receptor binding in specific limbic and subcortical regions is lower in MCI and further reduced in AD dementia, compared to CU older adults, and is related to cognitive deficits. Cognitive decline with age may be a consequence of reduced cholinergic receptor density or binding affinity that may also promote vulnerability to other Alzheimer's processes. Contemporary modification of the "cholinergic deficit" of aging and AD may reveal opportunities to prevent or improve clinical symptoms.
胆碱能神经递质系统功能障碍导致阿尔茨海默病和其他综合征的认知障碍。然而，涉及的特定胆碱能机制和大脑结构、改变的时间进程以及与特定认知缺陷的关系尚不清楚。
本研究纳入了 102 名老年人：42 名认知正常（CU）、28 名轻度认知障碍（MCI）和 32 名阿尔茨海默病（AD）痴呆。每位参与者都接受了神经心理学评估。使用 2-[F]氟-3-(2(S)氮杂环丁烷甲氧基)吡啶（2FA）和 PET 成像测量区域脑α4β2 烟碱型乙酰胆碱受体结合（V/fp）。进行了组间差异的体素分析。使用六个预先指定的感兴趣区的结合值评估受体结合与认知、年龄和胆碱酯酶抑制剂药物使用之间的关系。
SPM 分析显示，双侧内嗅皮层、海马体、岛叶、前扣带回、丘脑和基底节的组 V/f 结合差异（p<.05，FWE 校正）。两两比较显示，与 CU 组相比，AD 组在相似区域的结合较低。与 CU 组相比，MCI 组的内嗅皮层结合较低；与 MCI 组相比，AD 组的海马体结合较低。服用胆碱酯酶抑制剂药物的 AD 参与者的双侧海马体和丘脑的 2FA 结合低于未服用药物的参与者。在 CU 组中，年龄与每个感兴趣区的 2FA 结合呈负相关（r=-.33 至-.59，p<.05，未校正）。注意力、即时回忆和延迟回忆评分与整个样本中大多数区域的 2FA 结合呈负相关。在 CU 和 MCI 参与者的联合组中，注意力与大多数区域的 2FA 结合呈负相关，超出了海马体体积的影响。
与认知正常的老年人相比，MCI 患者和 AD 痴呆患者的特定边缘和皮质下区域的烟碱型乙酰胆碱受体结合减少，进一步减少，与认知缺陷有关。随着年龄的增长认知能力下降可能是由于胆碱能受体密度或结合亲和力降低所致，这也可能导致对其他阿尔茨海默病过程的易感性增加。目前对衰老和 AD 的“胆碱能缺陷”的修饰可能会揭示预防或改善临床症状的机会。
