Agitation is challenging to treat in Alzheimer’s disease (AD) and has significant implications for patients and caregivers. A major source of difficulty in identifying safe and effective treatments for agitation is the lack of validated biomarkers. The goal of this work was to investigate biomarkers of agitation in patients with AD.
Study 1: This study systematically reviewed 57 papers investigating biomarkers of agitation in AD.
Studies 2-5: Blood samples were collected from 38 participants enrolled in a randomized, placebo-controlled trial investigating nabilone, a synthetic cannabinoid, for the treatment of agitation in AD. The cross-sectional and longitudinal associations between agitation and 24-S-hydroxycholesterol (cerebrocholesterol (Cchol) (study 2), lipid peroxidation markers of oxidative stress (OS) (study 3), and inflammatory cytokines (study 4) and a biosignature of response to nabilone (study 5) were investigated. These processes are altered in AD and may be associated with agitation and/or endocannabinoid signalling.
Study 1: Of six classes of biomarkers identified, most were diagnostic in nature, substantiating the need for studies investigating the longitudinal associations between biomarkers and agitation in AD.
Study 2: Cchol was associated with agitation severity cross-sectionally, and longitudinally. However, Cchol did not predict response to nabilone, and did not change over time with nabilone.
Study 3: Baseline levels of the late-stage lipid-peroxidation marker, 4-hydroxynonenal (4-HNE) were associated with agitation severity cross-sectionally, and longitudinally. However changes in 4-HNE were not associated with changes in agitation severity in either phase.
Study 4: The pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was associated with agitation severity cross-sectionally. Lower baseline and decreases in TNF-α were associated with decreases in agitation severity in the nabilone phase only.
Study 5: Inflammatory cytokines, and markers of OS predicted response to nabilone based on symptoms of verbal and physical agitation, respectively.
Findings from the nabilone trial suggest that Cchol, 4-HNE and TNF-α may be useful markers of agitation severity. Additionally, response to nabilone may be influenced by the degree of OS and neuroinflammation a patient may have. As there are no validated biomarkers of agitation, identifying markers of agitation and response would assist in identifying patients who may benefit from treatment with nabilone.Ph.D
