Auriel A Willette1, Colleen Pappas2, Nathan Hoth2, Qian Wang2, Brandon Klinedinst3, Sara A Willette2, Brittany Larsen3, Amy Pollpeter4, Tianqi Li4, Scott Le2, Ana D Collazo-Martinez2, Jonathan P Mochel5, Karin Allenspach6, Robert Dantzer7. 1. Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA; Neuroscience Graduate Program, Iowa State University, Ames, IA, USA; Department of Psychology, Iowa State University, Ames, IA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA; Bioinformatics and Computational Biology Graduate Program, Iowa State University, Ames, IA, USA; Department of Biomedical Sciences, Iowa State University, Ames, IA, USA. Electronic address: awillett@iastate.edu. 2. Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA. 3. Neuroscience Graduate Program, Iowa State University, Ames, IA, USA. 4. Bioinformatics and Computational Biology Graduate Program, Iowa State University, Ames, IA, USA. 5. Department of Biomedical Sciences, Iowa State University, Ames, IA, USA. 6. Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA, USA. 7. Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aβ) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aβ (i.e., Aβ-), whereas such associations were fully mediated by Complement 3 in Aβ+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aβ and the complement system may be critical contributing factors in this process.
BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aβ) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aβ (i.e., Aβ-), whereas such associations were fully mediated by Complement 3 in Aβ+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aβ and the complement system may be critical contributing factors in this process.
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