The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05). Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

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APOE genotype regulates pathology and disease progression in synucleinopathy

Science Translational Medicine ◽

10.1126/scitranslmed.aay3069 ◽

2020 ◽

Vol 12 (529) ◽

pp. eaay3069 ◽

Cited By ~ 17

Author(s):

Albert A. Davis ◽

Casey E. Inman ◽

Zachary M. Wargel ◽

Umber Dube ◽

Brittany M. Freeberg ◽

...

Keyword(s):

Substantia Nigra ◽

Transgenic Mice ◽

Cognitive Decline ◽

Apolipoprotein E ◽

Motor Performance ◽

Apoe Genotype ◽

Amyloid Β ◽

Tau Pathology ◽

Increased Risk ◽

Over Time

Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson’s disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.

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Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

Cells ◽

10.3390/cells9061564 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1564 ◽

Cited By ~ 3

Author(s):

Tamás Biernacki ◽

Dániel Sandi ◽

Krisztina Bencsik ◽

László Vécsei

Keyword(s):

Multiple Sclerosis ◽

Immune System ◽

Quinolinic Acid ◽

Nicotinamide Adenine Dinucleotide ◽

Kynurenic Acid ◽

Picolinic Acid ◽

Kynurenine Pathway ◽

Current Evidence ◽

Therapeutic Approaches ◽

The Past

Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches.

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Apolipoprotein E genotype and lifetime cognitive decline

International Psychogeriatrics ◽

10.1017/s104161020700587x ◽

2008 ◽

Vol 20 (1) ◽

pp. 109-123 ◽

Cited By ~ 27

Author(s):

Nicholas A. Kozauer ◽

Michelle M. Mielke ◽

Gary Kwun Chuen Chan ◽

George W. Rebok ◽

Constantine G. Lyketsos

Keyword(s):

Cognitive Decline ◽

Apolipoprotein E ◽

Verbal Learning ◽

Apoe Genotype ◽

Recall Task ◽

Cognitive Testing ◽

Older Individuals ◽

Delayed Recall ◽

Epidemiologic Catchment Area Study ◽

The Relationship

ABSTRACTObjective: The relationship of apolipoprotein E (APOE) genotype to lifetime cognitive decline was examined over 22 years in a large community-based population study.Method: The sample for the present study was derived from follow-up of a probability sample of the adult household residents of East Baltimore. From the Baltimore cohort of the Epidemiologic Catchment Area Study, genotype data were collected on 818 participants at the study's fourth wave between 2003 and 2004. Participants were administered the Mini-mental State Examination (MMSE) at all four study waves. Three tests of verbal learning – immediate recall, delayed recall, and word recognition – were completed at waves 3 and 4. The 659 participants for whom genetic data were available had also completed cognitive testing at all time points. Test scores and changes in these scores were examined by APOE genotype group (x/x or 4/x) in younger and older subcohorts defined by age at wave 4 (< or ≥ age 65).Results: Cross-sectional wave 4 scores on all four cognitive tasks were lower in APOEε4 carriers when compared to non-carriers. In longitudinal univariate models ε4 carriers in the younger cohort demonstrated a greater annual rate of decline on a delayed recall task and MMSE. After adjusting for covariates only the decline in the delayed recall task was significant.Conclusion: We report an association between APOE genotype and decline in delayed recall and possibly MMSE over this extended time period limited to younger individuals. The lack of an association between APOE and decline in older individuals is likely to be the result of survival bias. Although a clear association exists between APOE genotype and cognitive decline or dementia in late life, these findings suggest that over the lifespan the relationship between APOE and cognitive decline is more complicated.

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Abstract 117: Apolipoprotein E and use of Statins in Intracerebral Hemorrhage

Stroke ◽

10.1161/str.44.suppl_1.a117 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Daniel Woo ◽

Ranjan Deka ◽

Jessica G Woo ◽

Sharyl Martini ◽

Matthew Flaherty ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Apolipoprotein E ◽

Statistical Significance ◽

Apoe Genotype ◽

P Value ◽

Secondary Prevention Trial ◽

Exact Test ◽

Increased Risk ◽

Apoe Genotypes ◽

Statin Use

Background: Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH), and HMG-CoA Reductase Inhibitors (statins) were associated with risk of ICH in a secondary prevention trial. Yet, large meta-analyses of statin use have not consistently identified an increased risk of ICH with statin use. We evaluated whether ApoE genotypes were differentially associated with ICH risk according to statin use. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study is a prospective ICH study which recruits cases and controls from the same population. Study physicians adjudicated cases and determined ICH location. Subjects were classified as normocholesterolemia (NC), hypercholesterolemia without statin (HC-NS), and hypercholesterolemia with statin use (HC-S) based on chart review. Genotyping for ApoE ( rs429358 and rs7412) was performed using standard methods. Statistical comparisons were performed using Fisher’s exact test and Mantel-Haenszel tests for homogeneity. Results: From 1997-2008, the study recruited 597 cases of ICH and 1,548 controls. Of these, 26 cases/ 8 controls were excluded for unknown history of hypercholesterolemia, and 13 cases/ 96 controls were excluded for missing ApoE result. Of the 554 cases included, 204 were lobar in location. For non-lobar ICH cases, no significant differences were observed in ApoE genotype and statin use between NC, HC-NS and HC-S cases and controls. However, for lobar ICH, a marked increased risk of ICH was seen in HC-S patients with Apo E4/E4 (OR=4.5; 95% CI 1.3-16; p=0.02) and E2/E4 (OR=11.3; 95%CI 2.0-64; p=0.005), and there was a trend for Apo E2/E3 (OR=2.8; 95% CI 1.1-7.5, p=0.06) compared with Apo E3/E3. Apo E4/E4 did not demonstrate an increased odds of ICH without statin use (OR=1.6; 95% CI 0.27-9.4; p=0.63). The p-value for heterogeneity of odds ratios did not reach statistical significance between the HC-NS vs. HC-S group. Conclusion: Our data support a gene-by-drug effect for lobar ICH and, if confirmed, may indicate a utility for ApoE genotyping to identify patients who would bear the highest risk of ICH with statin use. However, further study is required to determine if an interaction exists or if the finding is associative.

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Atheromatosis Extent in Coronary Artery Disease is not Correlated with Apolipoprotein-E Polymorphism and its Plasma Levels, but Associated with Cognitive Decline

Current Alzheimer Research ◽

10.2174/1567210204558632050 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Luciana Moreira Lima ◽

Maria das Gracas Carvalho ◽

Claudia Natalia Ferreira ◽

Ana Paula Fernandes ◽

Cirilo Pereira da Fonseca Neto ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cognitive Decline ◽

Apolipoprotein E ◽

Plasma Levels ◽

Apolipoprotein E Polymorphism ◽

Artery Disease

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Flexibility as a marker of early cognitive decline in humanized apolipoprotein E ε4 (ApoE4) mice

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.01.013 ◽

2021 ◽

Vol 102 ◽

pp. 129-138

Author(s):

Julien Schmitt ◽

Anne-Lise Paradis ◽

Mathieu Boucher ◽

Laurent Andrieu ◽

Pascal Barnéoud ◽

...

Keyword(s):

Cognitive Decline ◽

Apolipoprotein E

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Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

The Journal of Headache and Pain ◽

10.1186/s10194-021-01239-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Bernadett Tuka ◽

Aliz Nyári ◽

Edina Katalin Cseh ◽

Tamás Körtési ◽

Dániel Veréb ◽

...

Keyword(s):

Anthranilic Acid ◽

Clinical Relevance ◽

Kynurenic Acid ◽

Picolinic Acid ◽

Plasma Concentrations ◽

Episodic Migraine ◽

Kynurenine Pathway ◽

Xanthurenic Acid ◽

Control Subjects ◽

Healthy Control

Abstract Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

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