Adverse effect of catechol-O-methyltransferase (COMT) Val158Met met/met genotype in methamphetamine-related executive dysfunction

Cherner, Mariana; Watson, Caitlin; Saloner, Rowan; Halpin, Laura E.; Minassian, Arpi; Murray, Sarah; Vaida, Florin; Bousman, Chad; Everall, Ian

doi:10.1016/j.addbeh.2019.06.012

Cited by 7 publications

(10 citation statements)

References 53 publications

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“…The relationship between CSF NE and neurocognition is also likely influenced by brain regional differences in the rate of NE metabolism, which is primarily carried out by the monoamine oxidase A and catechol-omethyltransferase (COMT) enzymes 17 . COMT, for example, is particularly active in clearing catecholamines from the prefrontal cortex and we have previously reported that the neurocognitive effects of HIV and METH are moderated by genetic variation in COMT 73,79,80 . The neurobehavioral effects of COMT are often attributed to the processing of dopamine, which may be increased or decreased in HIV and METH depending on disease stage and abstinence [81][82][83] .…”

Section: Discussionmentioning

confidence: 95%

“…Consistent with this variability, parameters of METH use are not predictive of neuropsychological performance and it has been suggested that substance use during adolescence or young adulthood can interfere with educational quality, which may obscure the detection of brain-behavior relationships in adulthood 70,71 . Other factors such as host genetics, including those involved in the metabolism of METH and catecholamines 72,73 , may also help clarify the role of NE in METH-associated neurobehavioral function.…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Saloner

Cherner

Iudicello

et al. 2020

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective: HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition.Methods: Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson's correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores.Results: HIV significantly interacted with METH (p<.001) such that compared to HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d=0.96; HIV-/METH+: d=0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d=0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r=−0.19), learning (r=−0.23), and delayed recall (r=−0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH-groups (i.e., HIV-/METH-and HIV+/ METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (i.e., HIV-/METH+, HIV+/METH+).

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Saloner

Cherner

Iudicello

et al. 2020

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…In people with methamphetamine dependence having the Val allele, EF is protected due to greater inactivation of dopamine, which suggests that vulnerability to executive dysfunction among methamphetamine users is driven by genetics. Additionally, COMT genotyping could lead to personalized management of neurocognitive effects among methamphetamine users [ 26 ].…”

Section: Reviewmentioning

confidence: 99%

Effect of Catechol-O-Methyltransferase Genotype Polymorphism on Neurological and Psychiatric Disorders: Progressing Towards Personalized Medicine

Srivastava¹,

Ochuba²,

Sandhu³

et al. 2021

Cureus

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Different polymorphisms of the catechol-O-methyltransferase (COMT) gene affect the COMT enzyme activity. The COMT enzyme plays a major role in the pathophysiology of various neurological and psychiatric disorders. This review article aims to discuss what recent research has discovered about the association of COMT genotype polymorphism with neurological and psychiatric disorders and the scope for the knowledge to be applied for advancement in therapeutics. We searched PubMed and Google Scholar databases and found 1656 articles. We included observational studies, clinical trials, and meta-analyses in the English language published between 2019 and 2021. We screened the articles based on the title and the abstract and found 26 relevant articles. Diseases or conditions studied primarily were schizophrenia, Parkinson's disease, Alzheimer's disease, substance use, and depression. This article highlights how genetics influences the susceptibility of an individual to neurological and psychiatric diseases and the variations in the specific symptoms of those diseases. The review showed that the variability in individual response to therapeutic interventions stems from the gene level. This knowledge can contribute towards the dawn of a new era of personalized medicine.

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“…These demographically-corrected individual test T scores were averaged within each neurocognitive ability domain to generate domain-specific T scores. Given the relevance of COMT to DAergic activity in the PFC (Meyer-Lindenberg et al, 2006) and our prior findings that COMT interacts with METH status to predict executive function, secondary analyses focused on the relationship between CSF DA and executive function T scores (Cherner et al, 2019). The executive function composite was composed of the Wisconsin Card Sorting Test 64-item-computerized version, Stroop Color-Word Test, and Trail Making Test Part B.…”

Section: Neurocognitive Assessmentmentioning

confidence: 99%

“…It is hypothesized that higher DA bioavailability conferred by the Met allele underlies this Metassociated neurocognitive 'advantage' in healthy adults. However, we have previously demonstrated that in chronic METH users (both HIV-seropositive and HIV-seronegative), whose PFC is repeatedly exposed to excessive levels of DA, the Met/Met genotype is no longer associated with better executive function and may in fact confer risk for executive dysfunction (Bousman et al, 2010;Cherner et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings

Saloner

Cherner

Sundermann

et al. 2020

Psychiatry Research

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The Met allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val allele. Healthy Metcarriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH-men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met or Val/Val. Met/Met exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met and Val-carriers among METH+. Higher DA correlated with better EF in METH-Met/Met, but did not predict EF *

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Adverse effect of catechol-O-methyltransferase (COMT) Val158Met met/met genotype in methamphetamine-related executive dysfunction

Cited by 7 publications

References 53 publications

Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Effect of Catechol-O-Methyltransferase Genotype Polymorphism on Neurological and Psychiatric Disorders: Progressing Towards Personalized Medicine

COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings

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