Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
J Geriatr Psychiatry Neurol. 2020 Jul;33(4):175-184. doi: 10.1177/0891988719874118. Epub 2019 Sep 23.
The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; = 6.41, = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; = 3.97, = .06), were associated with agitation severity, and TNF-α remained significantly associated ( = 3.69, = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.
内源性大麻素系统一直是阿尔茨海默病（AD）激动的靶点，因为它可能具有行为影响，并且可能对 AD 中涉及的机制（如氧化应激（OS）和神经炎症）产生影响。我们探讨了 OS 和神经炎症的血清标志物是否与 AD 激越患者对大麻素纳比隆的反应有关（N=38）。所有参与者均参加了一项为期 14 周的双盲交叉试验，比较纳比隆与安慰剂（各 6 周），两阶段之间有 1 周洗脱期。在每个阶段的开始和结束时收集样本。研究了激越（科恩·曼斯菲尔德激越量表）和 OS 及炎症标志物的横断面关系，以选择感兴趣的标志物。然后，对有意义的标志物进行了探索，以研究其与反应的关系。OS 标志物 4-羟壬烯醛（4-HNE； = 6.41， =.016）和促炎细胞因子肿瘤坏死因子-α（TNF-α； = 3.97， =.06）与激越严重程度相关，调整认知后 TNF-α仍显著相关（ = 3.69， =.04）。在安慰剂阶段，较低的基线 4-HNE 仅与激越严重程度的降低相关（b = 0.01， =.01），而较低的基线 TNF-α仅与纳比隆阶段激越严重程度的降低相关（b = 1.14， =.045）。在两个阶段中，4-HNE 的变化均与激越严重程度的变化无关。在纳比隆阶段，较低的基线 TNF-α与激越严重程度的降低相关（b = 1.14， =.045），TNF-α 的降低与激越严重程度的降低相关（b = 1.12， =.006）。这些发现表明 OS 和神经炎症可能与激越严重程度相关，而纳比隆可能具有抗炎作用。
