Inflammation, negative affect, and amyloid burden in Alzheimer's disease: Insights from the kynurenine pathway.
Alzheimer’s disease
Depression
Inflammation
Kynurenine
Serotonin
Tryptophan
Journal
Brain, behavior, and immunity
ISSN: 1090-2139
Titre abrégé: Brain Behav Immun
Pays: Netherlands
ID NLM: 8800478
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
21
01
2021
revised:
17
03
2021
accepted:
22
03
2021
pubmed:
30
3
2021
medline:
24
6
2021
entrez:
29
3
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33775832
pii: S0889-1591(21)00121-5
doi: 10.1016/j.bbi.2021.03.019
pmc: PMC8187283
mid: NIHMS1687789
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Kynurenine
343-65-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
216-225Subventions
Organisme : NIA NIH HHS
ID : K99 AG047282
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG047282
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Références
Brain. 2020 May 1;143(5):1588-1602
pubmed: 32380523
Acta Orthop Traumatol Turc. 2010;44(1):63-9
pubmed: 20513993
Brain Imaging Behav. 2012 Dec;6(4):517-27
pubmed: 22644789
Brain Behav Immun. 2016 Mar;53:39-48
pubmed: 26546831
Exp Gerontol. 2007 Jul;42(7):693-701
pubmed: 17350781
Glia. 2003 Mar;41(4):371-81
pubmed: 12555204
Brain Behav Immun. 2005 Jul;19(4):345-50
pubmed: 15944074
Lung Cancer. 2010 Mar;67(3):361-5
pubmed: 19487045
Am J Psychiatry. 1989 May;146(5):577-87
pubmed: 2653053
Alzheimers Dement. 2015 May;11(5):504-510.e1
pubmed: 25043908
Neuropsychopharmacology. 2020 May;45(6):998-1007
pubmed: 31940661
Clin Chem. 1998 Apr;44(4):858-62
pubmed: 9554499
J Neurochem. 2010 Jan;112(1):66-76
pubmed: 19818105
Neurobiol Aging. 2010 Aug;31(8):1340-54
pubmed: 20570401
Gene. 2007 Jul 1;396(1):203-13
pubmed: 17499941
Psychosom Med. 2012 Jun;74(5):476-82
pubmed: 22434915
Int J Geriatr Psychiatry. 2021 May;36(5):713-721
pubmed: 33176024
Stress. 2009 May;12(3):206-14
pubmed: 19006008
Biol Psychiatry. 2011 Jul 15;70(2):175-82
pubmed: 21277567
Arch Gen Psychiatry. 2012 May;69(5):493-8
pubmed: 22566581
Psychosom Med. 2009 Feb;71(2):171-86
pubmed: 19188531
Life Sci. 2002 Sep 6;71(16):1837-48
pubmed: 12175700
Brain. 2013 Jul;136(Pt 7):2228-38
pubmed: 23775979
Brain Imaging Behav. 2012 Dec;6(4):502-16
pubmed: 22782295
Eur J Nucl Med Mol Imaging. 2014 Apr;41(4):714-22
pubmed: 24233127
Ann Neurol. 2009 Apr;65(4):403-13
pubmed: 19296504
Psychoneuroendocrinology. 2015 Dec;62:54-8
pubmed: 26232650
J Neuroinflammation. 2008 Aug 29;5:37
pubmed: 18759972
Brain. 2009 Aug;132(Pt 8):2036-47
pubmed: 19439419
Proc Natl Acad Sci U S A. 1947 Jun;33(6):155-8
pubmed: 16588735
J Psychosom Res. 2002 Dec;53(6):1053-60
pubmed: 12479986
Neurotox Res. 2009 Jul;16(1):77-86
pubmed: 19526301
Brain Behav Immun. 2016 Aug;56:335-42
pubmed: 27091600
J Neural Transm (Vienna). 2000;107(3):343-53
pubmed: 10821443
Alzheimers Dement. 2018 Feb;14(2):243-252
pubmed: 28755839
J Magn Reson Imaging. 2008 Apr;27(4):685-91
pubmed: 18302232
Lancet Neurol. 2015 Apr;14(4):388-405
pubmed: 25792098
Lancet. 2007 Sep 8;370(9590):851-8
pubmed: 17826170
Psychoneuroendocrinology. 2012 Jul;37(7):903-16
pubmed: 22119476
Nat Rev Neurosci. 2012 Jul;13(7):465-77
pubmed: 22678511
Nat Med. 2019 Mar;25(3):496-506
pubmed: 30692699
Neuropsychopharmacology. 2012 Mar;37(4):939-49
pubmed: 22071871
Biol Psychiatry. 2010 Mar 1;67(5):446-57
pubmed: 20015486
Psychol Med. 2003 Jan;33(1):41-9
pubmed: 12537035
Cereb Cortex. 2004 Jan;14(1):11-22
pubmed: 14654453
Psychopharmacol Bull. 1988;24(4):709-11
pubmed: 3249773
Arch Gen Psychiatry. 2001 May;58(5):445-52
pubmed: 11343523
Acta Neuropathol. 2009 Oct;118(4):475-85
pubmed: 19513731
Psychoneuroendocrinology. 2008 Jan;33(1):18-29
pubmed: 18061362
Psychoneuroendocrinology. 2015 Feb;52:200-11
pubmed: 25486577
Int J Geriatr Psychiatry. 2011 Nov;26(11):1109-18
pubmed: 21370276
Brain Behav Immun. 2015 Aug;48:8-18
pubmed: 25683698
Nat Rev Neurosci. 2008 Jan;9(1):46-56
pubmed: 18073775
Acta Neuropathol Commun. 2016 Jun 29;4(1):65
pubmed: 27357286
Neurology. 1997 May;48(5 Suppl 6):S10-6
pubmed: 9153155
Obesity (Silver Spring). 2015 Oct;23(10):2066-74
pubmed: 26347385
Front Neurosci. 2014 Feb 06;8:12
pubmed: 24567701
Front Cell Neurosci. 2015 Dec 17;9:476
pubmed: 26733805
PLoS One. 2013 Apr 22;8(4):e59749
pubmed: 23630570
Brain Behav Immun. 2002 Oct;16(5):581-9
pubmed: 12401472
Adv Med Sci. 2010;55(2):204-11
pubmed: 20639188
Neuroimage. 2008 Jul 15;41(4):1177-83
pubmed: 18486492
Neurobiol Dis. 2010 Mar;37(3):519-33
pubmed: 19944762
Neuropharmacology. 1994 Mar-Apr;33(3-4):575-88
pubmed: 7984295
Brain Res. 2006 Feb 16;1073-1074:25-37
pubmed: 16448631
Behav Res Methods. 2009 May;41(2):486-98
pubmed: 19363189
Neurochem Res. 2007 Oct;32(10):1749-56
pubmed: 17705097
Psychiatry Res. 2012 Jul 30;198(2):263-8
pubmed: 22406390
Nat Genet. 2009 Oct;41(10):1094-9
pubmed: 19734903