Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation

Abstract

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; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated ( F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .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, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

Agitation and impulsivity in mid and late life as possible risk markers for incident dementia

“…During the nabilone treatment phase, a lower baseline TNF‐α serum level demonstrated an association with decreases in agitation severity. Decreases in TNF‐α were also associated with decreases in agitation severity 164 …”

“…In total these studies suggest that several pro‐inflammatory cytokines levels directly correlate with agitation frequency 161,162 and severity, 163,164 while anti‐inflammatory cytokine levels inversely correlate with agitation, 161 and agitation treatment response to nabilone correlates with decreases in TNF‐α 164 (See Figure 2). It should be noted that most of the biomarker work that has been done in NPS focuses on people with dementia or at high risk of converting to dementia within 5 years.…”

The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases

“…1,24,48 Identifying biomarkers and genetic factors associated with specific behavioral symptoms and syndromes would further strengthen diagnostic criteria and the role of neuropsychiatric symptoms in support of diagnosis. 49,50 An important role for diagnostic criteria is their application in clinical trials and regulatory interactions. For clinical trials of disease-modifying therapies, criteria allow the construction of trial populations that have greater diagnostic homogeneity.…”

Endocannabinoidome and its role in neurological disorders-A comprehensive update of existing literature

“…Alzheimer's Disease (AD): Severity of agitation may be associated with oxidative stress and neuroin lammation, while nabilone may have anti-in lammatory effects [51]. Heteromerspeci ic feature suggests that adenosine receptor antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy [52].…”