TY - JOUR
T1 - Inflammation, negative affect, and amyloid burden in Alzheimer's disease
T2 - Insights from the kynurenine pathway
AU - for the Alzheimer's Disease Neuroimaging Initiative
AU - Willette, Auriel A.
AU - Pappas, Colleen
AU - Hoth, Nathan
AU - Wang, Qian
AU - Klinedinst, Brandon
AU - Willette, Sara A.
AU - Larsen, Brittany
AU - Pollpeter, Amy
AU - Li, Tianqi
AU - Le, Scott
AU - Collazo-Martinez, Ana D.
AU - Mochel, Jonathan P.
AU - Allenspach, Karin
AU - Dantzer, Robert
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Depression
KW - Inflammation
KW - Kynurenine
KW - Serotonin
KW - Tryptophan
UR - http://www.scopus.com/inward/record.url?scp=85104143399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104143399&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2021.03.019
DO - 10.1016/j.bbi.2021.03.019
M3 - Article
C2 - 33775832
AN - SCOPUS:85104143399
SN - 0889-1591
VL - 95
SP - 216
EP - 225
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -