Karami Azadeh, Darreh-Shori Taher, Schultzberg Marianne, Eriksdotter Maria
Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden.
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Campus Solna, Stockholm, Sweden.
Front Aging Neurosci. 2021 Aug 26;13:704583. doi: 10.3389/fnagi.2021.704583. eCollection 2021.
Alzheimer's disease (AD) is the most prevalent form of dementia with symptoms of deteriorating cognitive functions and memory loss, partially as a result of a decrease in cholinergic neurotransmission. The disease is incurable and treatment with cholinesterase inhibitors (ChEIs) is symptomatic. Choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), has been proven recently to be present in both cerebrospinal fluid (CSF) and plasma. As ChAT plays a role in regulating the extracellular ACh levels, it may have an impact on prognosis and cognitive performance in AD patients.
To measure ChAT activity and its protein concentration in CSF and plasma from patients with AD, mild cognitive impairment (MCI), or Subjective cognitive impairment (SCI).
Plasma and CSF samples were obtained from 21 AD, 32 MCI, and 30 SCI patients. The activity and protein levels of ChAT and acetylcholinesterase (AChE), the enzyme catalyzing the hydrolysis of ACh, were analyzed using an integrated activity and protein concentration ELISA-like assay. A Cholinergic Index was calculated as the ratio of ChAT to AChE activities in CSF. The data were analyzed in relation to dementia biomarkers and cognitive performance of the patients.
The CSF ChAT activity was significantly higher (55-67%) in MCI patients compared to AD and SCI cases. The CSF Cholinergic Index was 41 and 22% lower in AD patients than in MCI and SCI subjects, respectively. This index correlated positively with the Aβ/p-tau ratio in CSF in SCI but negatively with that in AD and MCI. The ChAT activity and protein levels in plasma exhibited significant differences with the pattern of AD>> >SCI.
This is the first study investigating soluble levels of the key cholinergic enzyme, ChAT, in both plasma and CSF of individuals at different clinical stages of dementia. Although further validation is needed, the overall pattern of the results suggests that in the continuum of AD, the cholinergic signaling exhibits an inverse U-shape dynamic of changes in the brain that greatly differs from the changes observed in the plasma compartment.
阿尔茨海默病（AD）是最常见的痴呆形式，具有认知功能恶化和记忆丧失的症状，部分原因是胆碱能神经传递减少。该疾病无法治愈，使用胆碱酯酶抑制剂（ChEIs）进行治疗只是对症治疗。胆碱乙酰转移酶（ChAT）是合成乙酰胆碱（ACh）的酶，最近已被证实在脑脊液（CSF）和血浆中均有存在。由于ChAT在调节细胞外ACh水平中起作用，它可能会影响AD患者的预后和认知表现。
测量AD、轻度认知障碍（MCI）或主观认知障碍（SCI）患者脑脊液和血浆中的ChAT活性及其蛋白浓度。
从21例AD、32例MCI和30例SCI患者中获取血浆和脑脊液样本。使用一种综合活性和蛋白浓度的类似ELISA的检测方法分析ChAT和乙酰胆碱酯酶（AChE，催化ACh水解的酶）的活性和蛋白水平。计算胆碱能指数，即脑脊液中ChAT与AChE活性的比值。对数据进行分析，并与患者的痴呆生物标志物和认知表现相关联。
与AD和SCI病例相比，MCI患者的脑脊液ChAT活性显著更高（55 - 67%）。AD患者的脑脊液胆碱能指数分别比MCI和SCI受试者低41%和22%。该指数在SCI中与脑脊液中的Aβ/p - tau比值呈正相关，但在AD和MCI中呈负相关。血浆中的ChAT活性和蛋白水平在AD＞＞SCI的模式下表现出显著差异。
这是第一项研究痴呆不同临床阶段个体血浆和脑脊液中关键胆碱能酶ChAT可溶性水平的研究。尽管需要进一步验证，但结果的总体模式表明，在AD的连续过程中，胆碱能信号在大脑中呈现出倒U形的动态变化，这与血浆部分观察到的变化有很大不同。
