School of Public Health, University of Haifa, 199 Aba Khoushy Ave., Haifa, 3498838, Israel.
Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, 02118, USA.
Alzheimers Res Ther. 2023 Sep 12;15(1):154. doi: 10.1186/s13195-023-01301-x.
Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex.
This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined.
Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (β ± SE = - 0.12 ± 0.06, p = 0.034 and β ± SE = 0.08 ± 0.04, p = 0.026, respectively).
Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.
临床前研究强调了内源性大麻素（内源性大麻素；eCBs）在神经退行性变中的重要性。然而，先前的观察性研究仅关注有限的结果测量指标，评估了少数 eCB 化合物，而在很大程度上忽略了 eCB 系统的复杂性。我们研究了多种循环 eCB 和 eCB 样分子与神经退行性变和神经损伤的早期标志物之间的相关性，并测试了性别对其的影响。
本探索性横断面研究纳入了弗雷明汉心脏研究后代队列中 237 名无痴呆的老年参与者的随机样本，这些参与者参加了第 9 次检查周期（2011-2014 年），年龄在 65 岁或以上，认知健康。通过液相色谱-高分辨率质谱法在血清中定量了 44 种 eCB 化合物。线性回归模型用于研究 eCB 水平与脑 MRI 测量值（即总脑容量、灰质体积、海马体积和白质高信号体积）以及阿尔茨海默病和神经损伤的血液生物标志物（即总 tau、神经丝轻链、神经胶质纤维酸性蛋白和泛素 C 端水解酶 L1）之间的相关性。所有模型均调整了潜在混杂因素，并检查了性别对其的影响。
参与者的平均年龄为 73.3±6.2 岁，其中 40%为男性。在调整潜在混杂因素并进行多次比较校正后，eCB 水平与研究结果之间未观察到统计学显著相关性。然而，我们在 eCB 水平与各种研究结果之间发现了多种性别特异性关联。例如，高亚油酸乙醇酰胺（LEA）水平与男性的海马体体积减少有关，与女性的海马体体积增加有关（β±SE= -0.12±0.06，p=0.034 和 β±SE=0.08±0.04，p=0.026，分别）。
循环 eCB 可能在神经损伤中起作用，并可能解释女性对加速大脑衰老的易感性差异。特别是，我们的结果突出了 N-酰基氨基酸和脂肪酸乙醇酰胺类的 eCBs 可能参与大脑衰老的可能性，并提出了可能与大脑衰老有关的特定新型脂肪酸化合物。此外，在人类中研究 eCB 对神经退行性疾病（如阿尔茨海默病）的贡献是合理的，特别是采用前瞻性研究设计和包括绝经前妇女在内的不同人群。
