Abstract # 1937Neuroinflammation, depression and Alzheimer’s disease: Insights from the Kynurenine pathway
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Abstract:

BackgroundDepressive symptoms in Alzheimer’s disease (AD) predict worse cognitive and neural outcomes. Neuroinflammation activates the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO), leading to increased kynurenine (Kyn) production and neurotoxic metabolites instead of serotonin (5-HT), which may affect brain structure and function in depression and AD. The neural and cognitive correlates of Kyn overproduction remain unknown in subjects across the AD spectrum. We determined if an imbalance in Kyn/5-HT correlated with AD neuropathology and depressive symptoms.MethodsIn 643 Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a CSF Kyn/5-HT ratio was regressed on behavioral, neural, and immunologic outcomes, as well as CSF amyloid and tau which are AD hallmarks. Voxel-wise analyses gauged regional associations with brain volume and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), which reflects glucose metabolism.ResultsHigher Kyn/5-HT significantly predicted worse scores on the Geriatric Depression Scale (R2 = 0.667), worse factor scores for verbal memory (R2 = 0.368) and executive function (R2 = 0.428), more amyloid (R2 = 0.703) and tau (R2 = 0.441) deposition, and higher CSF cytokine levels for IL-1 receptor (R2 = 0.546), IL-12 (R2 = 0.702), and IL-18 (R2 = 0.535). These cytokines fully mediated Kyn/5-HT and affect associations. Higher Kyn/5-HT predicted less grey matter and glucose metabolism in the hippocampus, precuneus, and prefrontal cortex, areas affected in depression and AD.DiscussionThese findings suggest that aberrant Kyn metabolism, perhaps due to neuroinflammation, may be related to AD-like neuropathology and depressive symptoms.

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