Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
J Alzheimers Dis. 2019;71(1):21-31. doi: 10.3233/JAD-190202.
Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1.
To assess whether 24S-OHC was associated with agitation severity and response to nabilone.
24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression).
24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03).
24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone.
躁动是阿尔茨海默病（AD）的一种常见且难以治疗的症状。内源性大麻素系统（ECS）一直是治疗躁动的目标。然而，ECS 信号可能与 AD 相关的大脑胆固醇代谢变化相互作用。大脑胆固醇升高，表现为血清 24-S-羟基胆固醇（24S-OHC）降低，与膜流动性降低有关，从而阻止配体与大麻素受体 1 结合。
评估 24S-OHC 是否与躁动严重程度和纳布啡治疗反应相关。
在纳布啡临床试验中，从开始和结束时收集 AD 患者的 24S-OHC。这允许在 24S-OHC 与躁动（科恩·曼斯菲尔德躁动量表，CMAI）之间进行横断面和纵向研究。事后分析包括对基线标准化简易精神状态检查（sMMSE）进行调整，以及与国际心理老年学协会（IPA）躁动定义一致的 CMAI 分量分析（身体攻击和非攻击，以及言语攻击）。
24S-OHC 与 CMAI 评分在未调整基线 sMMSE 之前和之后均无横断面或纵向相关性。然而，24S-OHC 与基线时 IPA 评分较高的 CMAI 评分相关（F（1，36）=4.95，p=0.03）。仅在安慰剂阶段，基线时较低的 24S-OHC 与 CMAI IPA 评分升高相关（b=-35.2，95%CI-65.6 至-5.0，p=0.02），而 24S-OHC 的降低与 CMAI IPA 评分升高相关（b=-20.94，95%CI-57.9 至-4.01，p=0.03）。
24S-OHC 与 AD 患者的躁动严重程度呈横断面相关，纵向相关。然而，24S-OHC 不能预测治疗反应，并且随着纳布啡的使用，它不会随时间而改变。
