Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease

Lin, Chin-Hsien; Fan, Jun‐Yu; Lin, Han-I; Chang, Chia-Wen; Wu, Yih‐Ru

doi:10.1016/j.parkreldis.2018.02.015

Cited by 16 publications

(8 citation statements)

References 34 publications

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“… 100 , 101 Both variants have been linked to a lessened cognitive decline in some systemic diseases. 102 , 103 …”

Section: Discussionmentioning

confidence: 99%

“…These genes are widely expressed in the CNS, and they code respectively for a neurotrophin that regulates several neurological processes and an enzyme that catabolizes monoamine 100,101 . Both variants have been linked to a lessened cognitive decline in some systemic diseases 102,103 …”

Section: Discussionmentioning

confidence: 99%

“…100,101 Both variants have been linked to a lessened cognitive decline in some systemic diseases. 102,103 An important limitation is that each of the three articles used different tools for toxicity identification. To be able to study associated genetic markers more systematically, a universal definition of taxane-induced central neurotoxicity is needed.…”

Section: Central Neurotoxicitymentioning

confidence: 99%

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Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

Guijosa

Freyria

Espinosa-Fernandez

et al. 2022

Clinical Translational Sci

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Taxane‐based chemotherapy regimens are used as first‐line treatment for breast cancer. Neurotoxicity, mainly taxane‐induced peripheral neuropathy (TIPN), remains the most important dose‐limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random‐effects gene meta‐analyses and examined interstudy heterogeneity with meta‐regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single‐nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta‐analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1‐rs2032582, ABCB1‐rs3213619, BCL6/‐rs1903216, /CAND1‐rs17781082, CYP1B1‐rs1056836, CYP2C8‐rs10509681, CYP2C8‐rs11572080, EPHA5‐rs7349683, EPHA6‐rs301927, FZD3‐rs7001034, GSTP1‐rs1138272, TUBB2A‐rs9501929, and XKR4‐rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta‐analysis. In conclusion, through systematic review and meta‐analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

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“… 100 , 101 Both variants have been linked to a lessened cognitive decline in some systemic diseases. 102 , 103 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Central Neurotoxicitymentioning

confidence: 99%

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Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

Guijosa

Freyria

Espinosa-Fernandez

et al. 2022

Clinical Translational Sci

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“…The activity of COMT is associated with the degradation of catecholamines, where lower activity can potentially lead to elevated neurotransmitter levels, while higher activity can potentially result in decreased neurotransmitter levels [127][128][129]. Indeed, COMT gene variants that alter dopamine levels are associated with cognitive decline in PD [130,131] and, similarly, impaired cognitive flexibility following TBI [127,132]. The investigation of COMT protein level following TBI is limited, with one study demonstrating that following focal TBI, both sCOMT and mbCOMT were increased in the ipsilateral cortex at 3 and 14 days post-injury [133], but longer time points have not been assessed to date.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson’s Disease Risk

Wee,

Arulsamy,

Corrigan

et al. 2024

Molecules

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Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson’s disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou’s impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate–severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DβH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

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“…COMT polymorphisms are denoted as a valine (Val or G) and methionine (Met or A) substitution at codon 108/158. The activity of the COMT enzyme with the A/A genotype was 3- to 4-fold lower than that with the G/G genotype, resulting in reduced dopamine degradation [ 40 ]. The COMT Val158Met polymorphism has been shown to modulate the cognitive and symptom profiles in patients with schizophrenia, with more negative outcomes related to adverse childhood experiences in Met carriers [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-Methyltransferase Gene Polymorphisms and the Risk of Chemotherapy-Induced Prospective Memory Impairment in Breast Cancer Patients with Varying Tumor Hormonal Receptor Expression

Zhao

Ding

et al. 2020

Med Sci Monit

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Background Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). Material/Methods A total of 232 patients with breast cancer (113 with ER−/PR− and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). Results The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER−/PR− group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=−7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (β=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. Conclusions The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.

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Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease

Abstract: Our findings suggest that the high-COMT activity haplotype is associated with cognitive decline in patients with PD.

Cited by 16 publications

References 34 publications

Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson’s Disease Risk

Catechol-O-Methyltransferase Gene Polymorphisms and the Risk of Chemotherapy-Induced Prospective Memory Impairment in Breast Cancer Patients with Varying Tumor Hormonal Receptor Expression

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