COMT
Catechol O-methyltransferase (EC 2.1.1.6)
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Dopamine (DA) signaling is critical for optimal cognitive performance. Aging is accompanied by a change in the strength of this signaling, with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning (EF), but also high extrastriatal binding potential. Here, we investigated in 176 participants aged 20-94 years whether: (1) DRD2 C carriers differ from T carriers in cortical thickness or subcortical volume in areas of high concentrations of D2 receptors that receive projections from mesocortical or nigrostriatal dopaminergic pathways; (2) whether the DRD2*COMT relationship has any synergistic effects on cortical thickness; (3) whether the effect of DRD2 on brain structure depends upon age; and (4) whether DRD2-related regional thinning affects executive function performance. We show that DRD2 impacts cortical thickness in the superior parietal lobule, precuneus, and anterior cingulate (marginal after FDR correction), while statistically controlling sex, age, and COMT genotype. Specifically, C homozygotes demonstrated thinner cortices than both heterozygotes and/or T homozygotes in an age-invariant manner. Additionally, DRD2 predicted executive function performance via cortical thickness. The results highlight that genetic influences on dopamine availability impact cognitive performance via the contribution of brain structure in cortical regions influenced by DRD2.
Keywords
- Aging
- Cortical thickness
- DRD2
- Dopamine
- Executive function
Older individuals have an elevated risk for chronic pain as half of all individuals over 65 years old have at least one chronic pain condition. Unfortunately, relevant assessment tools and recommendations for chronic pain management targeting older adults are lacking. This study explores changes in response to pain between young (2-3 months old) and geriatric (20-24 months old) ages using mice. Although cutaneous thresholds to brisk stimuli (von Frey and radiant heat assays) were not affected, behavioral responses to tonic stimuli (acetone and capsaicin assays) were more pronounced in geriatric animals. After nerve injury, geriatric mice present an altered neuropathic pain profile with hypersensitivity to mechanical stimuli but not acetone and an impairment in conditioned noxious stimuli avoidance. This altered behavioral response pattern was associated with an abnormal monoaminergic signature in the medial prefrontal cortex, suggesting decreased COMT function. We conclude that young and geriatric mice exhibit different behavioral and physiological responses to the experience of pain, suggesting that knowledge and practices must be adjusted for geriatric populations.
MeSH Terms
- Acetone
- Aging
- Animals
- Behavior
- Biogenic Monoamines
- Capsaicin
- Chronic Pain
- Disease Models, Animal
- Male
- Mice, Inbred C57BL
- Peripheral Nerve Injuries
- Physical Stimulation
- Prefrontal Cortex
- Sensory Thresholds
Keywords
- Geriatric pain
- Healthy aging
- Mice
- Sensory thresholds
- Supraspinal plasticity
- Tonic and chronic pain response
While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS). We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model. One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05). Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.
MeSH Terms
- Aged
- Alzheimer Disease
- Apolipoproteins E
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Cognitive Dysfunction
- Dementia
- Female
- Genetic Predisposition to Disease
- Humans
- Intracellular Signaling Peptides and Proteins
- LDL-Receptor Related Proteins
- Membrane Transport Proteins
- Middle Aged
- Polymorphism, Single Nucleotide
- Postmenopause
- Women's Health
Keywords
- AD
- Alzheimer's disease
- MCI
- aging
- hormone therapy
Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared to COMT Met carriers. Furthermore, dopamine receptors and postsynaptic availability are drastically reduced with aging, as is executive function performance that ostensibly relies on these pathways. Here, we investigated in 176 individuals aged 20-94 years whether: (1) COMT Val carriers differ from their Met counterparts in thickness of regional cortices receiving D1 receptor pathways: prefrontal, parietal, cingulate cortices; (2) this gene-brain association differs across the adult lifespan; and (3) COMT-related regional thinning evidences cognitive consequences. We found that COMT Val carriers evidenced thinner cortex in prefrontal, parietal, and posterior cingulate cortices than COMT Met carriers and this effect was not age-dependent. Further, we demonstrate that thickness of these regions significantly mediates the effect of COMT genotype on an executive function composite measure. These results suggest that poorer executive function performance is due partly to thinner association cortex in dopaminergic-rich regions, and particularly so in individuals who are genetically predisposed to lower postsynaptic dopamine availability, regardless of age.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Catechol O-Methyltransferase
- Dopamine
- Executive Function
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
- Somatosensory Cortex
- Young Adult
Keywords
- Aging
- COMT
- Cortical thickness
- Dopamine
- Executive function
Extrapineal and pineal melatonin is the marker of the aging rate of organism making it possible to characterize functional condition of the neuro-immuno-endocrine system. In this article we have used the new method for non-invasive diagnostics of melatonin expression in buccal epithelium and determination of the main melatonin metabolite 6-hydroxymelatonin sulfate (6-HMS) in urine of elderly people. Normal, impaired and enhanced melatonin expression was documented in 20.5%, 43.2% and 36.30% of the patients respectively. Such comprehensive melatonin and 6-COMT studies can be recommended for elderly patients with oncological, neurodegenerative, cardiovascular diseases, and ageing macular dystrophy. Moreover, melatonin expression analysis in buccal cells can be used for integral investigation of biorhythms in elderly people.
MeSH Terms
- Aged
- Aging
- Biomarkers
- Cardiovascular Diseases
- Female
- Humans
- Macular Degeneration
- Male
- Melatonin
- Mouth Mucosa
- Neoplasms
- Neurodegenerative Diseases
- Reproducibility of Results
- Urinalysis
Given the increase in research suggesting benefit following cognitive training in older adults, researchers have started to investigate the potential moderating role of genetic polymorphisms on transfer effects. The objective of this study was to evaluate the moderating effect of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) polymorphisms on transfer effects following a single-domain or multi-domain training intervention in healthy community-dwelling older adults. A total of 104 men and women living in Shanghai were randomized to a multi-domain or a single-domain cognitive training (SDCT) group. COMT rs4818 SNP and the BDNF rs6265 SNP were analyzed from blood. At pre-intervention, post-intervention and at 6-month follow-up, participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Color-Word Stroop Test (CWST), the Trails Making Test (TMT) and the Visual Reasoning Test (VRT). COMT was found to moderate immediate memory transfer effects following single-domain training only, with G/- carriers displaying greater benefits than C/C carriers. BDNF was found to moderate attention and inhibition independent of the training, with Met/- carriers displaying better performance than Val/Val carriers. Overall, individualizing training methods with full consideration of genetic polymorphisms may promote the maximization of cognitive training benefits.
Keywords
- brain-derived neurotrophic factor
- catechol-O-methyltransferase
- cognitive training
- single nucleotide polymorphism
- successful aging
Alzheimer's disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.
MeSH Terms
- Adult
- Aging
- Analysis of Variance
- Apolipoproteins E
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Cognitive Dysfunction
- Executive Function
- Female
- Genotype
- Humans
- Independent Living
- Intracellular Signaling Peptides and Proteins
- LDL-Receptor Related Proteins
- Male
- Maze Learning
- Membrane Transport Proteins
- Middle Aged
- Phosphoproteins
- Polymorphism, Single Nucleotide
- Reaction Time
- User-Computer Interface
Keywords
- Aging
- Alzheimer’s disease
- apolipoproteins E
- brain-derived neurotrophic factor
- cognition
- hippocampus
- middle age
- prefrontal cortex
To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). Multicenter study, 8 U.S. Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). Structured PA versus health education (HE) for an average of 2.6 years. Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. clinicaltrials.gov Identifier: NCT01072500.
MeSH Terms
- Accelerometry
- Aged
- Catechol O-Methyltransferase
- Dopamine
- Exercise
- Exercise Therapy
- Female
- Humans
- Life Style
- Male
- Middle Aged
- Mobility Limitation
- Polymorphism, Single Nucleotide
- Receptors, Dopamine D2
- Risk Reduction Behavior
- Sedentary Behavior
- Signal Transduction
- Walking Speed
Keywords
- aging
- dopamine
- physical activity
- randomized controlled trial
With ever-increasing elder populations, age-related cognitive decline, which is characterized as a gradual decline in cognitive capacity in the aging process, has turned out to be a mammoth public health concern. Since genetic information has become increasingly important to explore the biological mechanisms of cognitive decline, the search for genetic biomarkers of cognitive aging has received much attention. There is growing evidence that single-nucleotide polymorphisms (SNPs) within the [i]ADAMTS9, BDNF, CASS4, COMT, CR1, DNMT3A, DTNBP1, REST, SRR, TOMM40[/i], circadian clock, and Alzheimer's diseases-associated genes may contribute to susceptibility to cognitive aging. In this review, we first illustrated evidence of the genetic contribution to disease susceptibility to age-related cognitive decline in recent studies ranging from approaches of candidate genes to genome-wide association studies. We then surveyed a variety of association studies regarding age-related cognitive decline with consideration of gene-gene and gene-environment interactions. Finally, we highlighted their limitations and future directions. In light of advances in precision medicine and multi-omics technologies, future research in genomic medicine promises to lead to innovative ideas that are relevant to disease prevention and novel drugs for cognitive aging.
Keywords
- Alzheimer’s diseases
- SNP–SNP interactions
- age-related cognitive decline
- biomarker
- cognitive aging
- gene–gene interactions
- neurodegeneration
- single-nucleotide polymorphisms
Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs).We included 5064 subjects (age: 40-82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP.All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P < .05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (ValMet) in COMT was significantly associated with lower SBP in participants treated with CCBs (P = .009) with an especially strong impact in elderly individuals (age ≥ 70) alone (Δ = -14.08 mm Hg, P = .0005).These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Antihypertensive Agents
- Aromatase
- Blood Pressure
- Calcium Channel Blockers
- Catechol O-Methyltransferase
- Cohort Studies
- Female
- Genotyping Techniques
- Glucuronosyltransferase
- Humans
- Male
- Middle Aged
- Pharmacogenomic Variants
- Switzerland
To determine the association between catechol-O-methyltransferase (COMT) genotype and 6-m walk time and to determine whether these associations are quadratic in nature, similar to previously reported U-shaped associations between dopamine and gait and cognition. Prospective cohort study. Health, Aging and Body Composition Study. Black (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 ± 2.85 at baseline. Mixed models were used to assess the association between the COMT genotype and 6-m walk time, cross-sectionally and longitudinally over 10 years. Models were assessed unstratified and stratified according to race because allele distributions were different between white and black participants. There was a significant U-shaped association between COMT genotype and 6-m walk time: those with higher (Val/Val) and lower (Met/Met) dopamine slowed more over 10 years (0.22 ± 0.02 seconds per visit and 0.23 ± 0.02 seconds per visit, respectively) than those with the intermediate (Met/Val) dopamine (0.20 ± 0.02 seconds per visit) (P = .005). Stratified results showed a significant relationship in black (P = .01) but not white (P = .15) participants. These findings indicate a role of dopaminergic regulation of gait speed in community-dwelling older adults and of prefrontal cortex involvement in gait performance. Future work should investigate the molecular integrity of dopaminergic networks and gait changes over time and structural changes in the brain with COMT and gait decline in older adults.
MeSH Terms
- Aged
- Aging
- Alleles
- Catechol O-Methyltransferase
- Ethnic Groups
- Gait
- Genotype
- Health Surveys
- Humans
- Independent Living
- Longitudinal Studies
- Prospective Studies
- Walking
Keywords
- aging
- catechol-O-methyltransferase
- dopamine
- mobility disability
- physical function
The review has described melatonin as a prognostic marker of invasive and non-invasive diagnostic of organism aging time and age-related pathology. Decreasing of melatonin level in buccal cells has correlated with patient age. Melatonin level in patients with Alzheimer disease has decreased. Melatonin level in blood plasma has correlated with severity of menopausal syndrome. Melatonin secretion in enterocytes increased during gastric ulcer. In oncology patients was described changes of 6-COMT - metabolite of melatonin in urine in dependent of histology type and stage of disease. Thus, melatonin is the molecular marker, which characterized integral processes in neuro-immuno-endocrine system and can be verified by non-invasive methods in peripheral tissues and biological fluids of organism.
MeSH Terms
- Age Factors
- Alzheimer Disease
- Biomarkers
- Circadian Rhythm
- Enterocytes
- Humans
- Melatonin
- Mouth Mucosa
- Neoplasms
- Stomach Ulcer
Keywords
- Alzheimer’s disease
- aging
- cancer
- melatonin
- menopausal syndrome
- molecular marker
Recent analyses of the enzymatic features of various melatonin biosynthetic genes from bacteria, animals, and plants have led to the hypothesis that melatonin could be synthesized via the 5-methoxytryptamine (5-MT) pathway. 5-MT is known to be synthesized in vitro from serotonin by the enzymatic action of O-methyltransferases, including N-acetylserotonin methyltransferase (ASMT) and caffeic acid O-methyltransferase (COMT), leading to melatonin synthesis by the subsequent enzymatic reaction with serotonin N-acetyltransferase (SNAT). Here, we show that 5-MT was produced and served as a precursor for melatonin synthesis in plants. When rice seedlings were challenged with senescence treatment, 5-MT levels and melatonin production were increased in transgenic rice seedlings overexpressing the rice COMT in chloroplasts, while no such increases were observed in wild-type or transgenic seedlings overexpressing the rice COMT in the cytosol, suggesting a 5-MT transport limitation from the cytosol to chloroplasts. In contrast, cadmium treatment led to results different from those in senescence. The enhanced melatonin production was not observed in the chloroplast COMT lines relative over the cytosol COMT lines although 5-MT levels were equally induced in all genotypes upon cadmium treatment. The transgenic seedlings with enhanced melatonin in their chloroplasts exhibited improved seedling growth vs the wild type under continuous light conditions. This is the first report describing enhanced melatonin production in chloroplasts via the 5-MT pathway with the ectopic overexpression of COMT in chloroplasts in plants.
MeSH Terms
- 5-Methoxytryptamine
- Cadmium
- Chloroplasts
- Cloning, Molecular
- Melatonin
- Methyltransferases
- Oryza
- Plants, Genetically Modified
- Seedlings
Keywords
- 5-methoxytryptamine
- caffeic acid O-methyltransferase
- chloroplast targeting
- melatonin
- senescence
- transgenic rice
Little is known about the effects of risk factors on attention-deficit/hyperactivity disorder (ADHD) symptom over time. Here, we longitudinally studied the role of candidate genes, pre- and perinatal factors, and their interactions on ADHD symptoms between ages 10 and 18 years. Subjects were part of the general population or clinic-referred cohort of the TRacking Adolescents' Individual Lives Survey (n = 1667). At mean ages of 11.1 (T1), 13.4 (T2), and 16.2 years (T3), ADHD symptoms were assessed with the Child Behavior Checklist. Linear Mixed Models were used to examine the association of candidate genes (i.e., DRD4, DRD2, 5-HTTLPR, COMT, and MAOA), pre- and perinatal factors (i.e., index measure of various pregnancy and delivery complications, maternal smoking, maternal drinking, and low birth weight), and their interactions with ADHD symptoms across adolescence. Pregnancy and delivery complications were associated with a higher level of ADHD symptoms across all time points, but with a significantly declining influence over time (p = 0.006). We found no main effects of the candidate genes on ADHD symptoms throughout adolescence. The simultaneous presence of the low activity MAOA genotype and low birth weight (p < 0.001) and of the 5-HTTLPR LL-allele and respectively pregnancy and delivery complications (p = 0.04) and maternal smoking (p = 0.04) were associated with more ADHD symptoms particularly during early adolescence, and these influences significantly decreased over time. Findings suggest an age-dependent role of gene-environment interactions on ADHD symptoms across adolescence.
MeSH Terms
- Adolescent
- Aging
- Attention Deficit Disorder with Hyperactivity
- Child
- Female
- Gene-Environment Interaction
- Genotype
- Humans
- Male
- Monoamine Oxidase
- Polymorphism, Single Nucleotide
- Pregnancy
- Pregnancy Complications
- Prenatal Exposure Delayed Effects
- Psychiatric Status Rating Scales
- Serotonin Plasma Membrane Transport Proteins
Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aging
- Apolipoprotein E4
- Arteries
- Blood Flow Velocity
- Catechol O-Methyltransferase
- Cerebrovascular Circulation
- Cross-Sectional Studies
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Peptidyl-Dipeptidase A
- Phenotype
- Regional Blood Flow
- Risk Assessment
- Risk Factors
- Vascular Diseases
- Veins
- Young Adult
Keywords
- ACE
- COMT
- Internal carotid artery
- Jugular vein
- Phase-contrast MRI
- Vertebral artery
Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4 carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4 carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoproteins E
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Executive Function
- Female
- Genetic Association Studies
- Humans
- Life Style
- Longitudinal Studies
- Male
- Middle Aged
- Polymorphism, Genetic
Keywords
- Aging
- Apolipoprotein E
- Brain-derived neurotrophic factor
- Catechol-O-methyltransferase
- Executive function
- Victoria Longitudinal Study
The genetic basis controlling language development remains elusive. Previous studies of the catechol-O-methyltransferase (COMT) Val158Met genotype and cognition have focused on prefrontally guided executive functions involving dopamine. However, COMT may further influence posterior cortical regions implicated in language perception. We investigated whether COMT influences language ability and cortical language processing involving the posterior language regions in 246 children aged 6-10 years. We assessed language ability using a language test and cortical responses recorded during language processing using a word repetition task and functional near-infrared spectroscopy. The COMT genotype had significant effects on language performance and processing. Importantly, Met carriers outperformed Val homozygotes in language ability during the early elementary school years (6-8 years), whereas Val homozygotes exhibited significant language development during the later elementary school years. Both genotype groups exhibited equal language performance at approximately 10 years of age. Val homozygotes exhibited significantly less cortical activation compared with Met carriers during word processing, particularly at older ages. These findings regarding dopamine transmission efficacy may be explained by a hypothetical inverted U-shaped curve. Our findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change in a narrow age window of 6-10 years.
MeSH Terms
- Aging
- Catechol O-Methyltransferase
- Child
- Child Development
- Executive Function
- Female
- Genetic Predisposition to Disease
- Humans
- Language
- Language Development Disorders
- Language Tests
- Male
- Polymorphism, Single Nucleotide
Keywords
- catechol-O-methyltransferase (COMT)
- catecholamine
- children
- default mode network (DMN)
- development
- dopamine
- functional near-infrared spectroscopy (fNIRS)
- genotype
- language
- preadolescence
Better memory for positive information compared to negative and neutral information has been repeatedly associated with successful aging. The main psychological explanations for this so-called "positivity effect" in memory principally rely on emotional, motivational, and cognitive mechanisms that make older adults' cognition highly sensitive to positive information according to ultimate goals of well-being. However, emerging evidence also delineates a genetic profile for positivity effects in memory, which may render some older adults more prone than others to encoding and remembering positive memories. First, we present a brief overview of behavioral and neuroimaging studies about the positivity effect in aging. Subsequently, we report studies on candidate genes associated with positive memories. In particular, we review work to date on several candidate genes that are sensitive to stimulus valence such as ADRA2B, COMT, and 5HTTLPR. Finally, we propose that the future approach to the study of genetic correlates of positivity effects in memory should also include mitochondrial functioning (TOMM40). Altogether, the study of genetics and cell biology of positivity effects in memory can help us to reveal the underlying bottom-up pathways to positive affect in healthy aging.
MeSH Terms
- Aging
- Catechol O-Methyltransferase
- Cognition
- Emotions
- Humans
- Membrane Transport Proteins
- Memory
- Receptors, Adrenergic, alpha-2
- Serotonin Plasma Membrane Transport Proteins
Keywords
- Emotion
- Gene
- Positivity effects
The catechol-O-methyltransferase (COMT_Val158Met) genetic polymorphism has been linked to variation in affective well-being. Compared with Val carriers, Met carriers experience lower affective well-being. In parallel, research on aging and affective experience finds that younger adults experience poorer affective well-being than older adults. This study examined how COMT and age may interact to shape daily affective experience across the life span. Results suggest that Met (vs. Val) carriers experience lower levels of affective well-being in younger but not in older ages. These findings suggest that age-related improvements in emotional functioning may offset genetic vulnerabilities to negative affective experience. (PsycINFO Database Record
MeSH Terms
- Adult
- Affect
- Aged
- Aged, 80 and over
- Aging
- Catechol O-Methyltransferase
- Emotions
- Female
- Heterozygote
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
Aging is associated with declines in cognitive performance and multiple changes in the brain, including reduced default mode functional connectivity (FC). However, conflicting results have been reported regarding age differences in FC between hippocampal and default mode regions. This discrepancy may stem from the variation in selection of hippocampal regions. We therefore examined the effect of age on resting state FC of anterior and posterior hippocampal regions in an adult life-span sample. Advanced age was associated with lower FC between the posterior hippocampus and three regions: the posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortex. In addition, age-related reductions of FC between the left and right posterior hippocampus, and bilaterally along the posterior to anterior hippocampal axis were noted. Age differences in medial prefrontal and inter-hemispheric FC significantly differed between anterior and posterior hippocampus. Older age was associated with lower performance in all cognitive domains, but we observed no associations between FC and cognitive performance after controlling for age. We observed a significant effect of gender and a linear effect of COMT val158met polymorphism on hippocampal FC. Females showed higher FC of anterior and posterior hippocampus and medial prefrontal cortex than males, and the dose of val allele was associated with lower posterior hippocampus - posterior cingulate FC, independent of age. Vascular and metabolic factors showed no significant effects on FC. These results suggest differential age-related reduction in the posterior hippocampal FC compared to the anterior hippocampus, and an age-independent effect of gender and COMT on hippocampal FC.
MeSH Terms
- Adolescent
- Adult
- Age Distribution
- Aged
- Aged, 80 and over
- Aging
- Cardiovascular Diseases
- Catechol O-Methyltransferase
- Cerebral Cortex
- Comorbidity
- Connectome
- Female
- Genetic Predisposition to Disease
- Hippocampus
- Humans
- Male
- Metabolic Diseases
- Michigan
- Middle Aged
- Nerve Net
- Neural Pathways
- Prevalence
- Risk Factors
- Sex Distribution
- Sex Factors
- Young Adult
Keywords
- Aging
- COMT val158met
- Functional connectivity
- Gender
- Hippocampus
- Vascular risk
We investigated whether a physiological marker of cardiovascular health, pulse pressure (PP), and age magnified the effect of the functional COMT Val(158)Met (rs4680) polymorphism on 15-years cognitive trajectories [episodic memory (EM), visuospatial ability, and semantic memory] using data from 1585 non-demented adults from the Betula study. A multiple-group latent growth curve model was specified to gauge individual differences in change, and average trends therein. The allelic variants showed negligible differences across the cognitive markers in average trends. The older portion of the sample selectively age-magnified the effects of Val(158)Met on EM changes, resulting in greater decline in Val compared to homozygote Met carriers. This effect was attenuated by statistical control for PP. Further, PP moderated the effects of COMT on 15-years EM trajectories, resulting in greater decline in Val carriers, even after accounting for the confounding effects of sex, education, cardiovascular diseases (diabetes, stroke, and hypertension), and chronological age, controlled for practice gains. The effect was still present after excluding individuals with a history of cardiovascular diseases. The effects of cognitive change were not moderated by any other covariates. This report underscores the importance of addressing synergistic effects in normal cognitive aging, as the addition thereof may place healthy individuals at greater risk for memory decline.
Keywords
- COMT
- SNP
- aging
- cognition
- hypertension
- longitudinal
- single nucleotide polymorphism
Catechol-O-methyltransferase (COMT), located on chromosome 22q11.2, encodes an enzyme critical for dopamine flux in the prefrontal cortex. Genetic variants of COMT have been suggested to functionally manipulate prefrontal morphology and function in healthy adults. This study aims to investigate modulative roles of individuals COMT SNPs (rs737865, val158met, rs165599) and its haplotypes in age-related brain morphology using an Asian sample with 174 adults aged from 21 to 80 years. We showed an age-related decline in cortical thickness of the dorsal visual pathway, including the left dorsolateral prefrontal cortex, bilateral angular gyrus, right superior frontal cortex, and age-related shape compression in the basal ganglia as a function of the genotypes of the individual COMT SNPs, especially COMT val158met. Using haplotype trend regression analysis, COMT haplotype probabilities were estimated and further revealed an age-related decline in cortical thickness in the default mode network (DMN), including the posterior cingulate, precuneus, supramarginal and paracentral cortex, and the ventral visual system, including the occipital cortex and left inferior temporal cortex, as a function of the COMT haplotype. Our results provided new evidence on an antagonistic pleiotropic effect in COMT, suggesting that genetically programmed neural benefits in early life may have a potential bearing towards neural susceptibility in later life. Hum Brain Mapp 37:2068-2082, 2016. © 2016 Wiley Periodicals, Inc.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain
- Catechol O-Methyltransferase
- Female
- Genotyping Techniques
- Haplotypes
- Humans
- Image Processing, Computer-Assisted
- Magnetic Resonance Imaging
- Male
- Mental Status Schedule
- Middle Aged
- Organ Size
- Polymorphism, Single Nucleotide
- Regression Analysis
- Young Adult
Keywords
- aging
- cortical thickness
- diffeomorphic mapping
- genetic variant
- haplotype
- subcortical shape
To see the possible relationship between COMT Val158Met polymorphism and blood pressure (BP) and serum lipid levels and its putative role in human longevity, we genotyped COMT Val158Met (rs4680) by PCR-RFLP for members from Bama long-lived families (BLF, n = 1538), Bama non-long-lived families (BNLF, n = 600), Pingguo (a county outside Bama region) long-lived families (PLF, n = 538) and Pingguo non-long-lived families (PNLF, n = 403) after anthropometric measures were collected and serum lipid levels were detected. The distribution of genotypes and alleles among four family groups was significantly different (all P < 0.01), with GA/AA genotype and minor allele A presenting more frequently in Bama population than Pingguo Population (P < 0.01). The systolic blood pressure (SBP), pulse pressure (PP), total cholesterol (TC), triglyceride (TG) and low density lipoprotein-cholesterol (LDL-C) levels of GG genotype carriers were dramatically higher than non-GG carriers in BNLF (P < 0.05); the SBP and PP levels of GG carriers were lower (P < 0.05) while TC, LDL-C level were higher (P < 0.01) than that of non-GG carriers in PLF; no difference in blood pressure and lipids were observed between genotypes in BLF and PNLF (P > 0.05). Correlation analyses revealed that COMT Val158Met was mainly correlated negatively with SBP, diastolic blood pressure (DBP) and LDL-C in BNLF and negatively with TC level in BLF, BNLF and PLF. These data suggest that COMT Val158Met polymorphism may have more impact on the modulation of BP and lipid profiles in the average families than in the long-lived families in Bama region. The association between this SNP and other phenotypes (e.g. cognition) and its roles in the longevity in Bama area thus warrant further investigation.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Asian Continental Ancestry Group
- Blood Pressure
- Catechol O-Methyltransferase
- China
- Family
- Female
- Genotype
- Humans
- Lipids
- Longevity
- Male
- Middle Aged
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- Polymorphism, Single Nucleotide
Keywords
- COMT
- blood lipid
- blood pressure
- longevity
Evolutionary theories of aging predict an antagonistic relationship between fertility and life span in humans, but the genetic basis of this phenomenon is not clear. The variation of three genes in steroid hormone metabolism--CYP17 (rs743572), HSD17B1 (rs 605059), and COMT (rs4680)--was examined to elucidate the genetic basis of the relationship between fertility and life span. A sample of 277 individuals (mean age, 82.9 years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving to over 90 years (long-lived) or not (controls). Fertility data (number of children) were collected in the same sample. The HSD17B1 AA genotype was found to be significantly associated (p = 0.0085) with longevity only in the females (estimated odds ratio = 3.77). Because the HSD17B1 AA genotype was also associated with a higher number of children (5.3 ± 2.1) than the other genotypes (p = 0.006), we may infer that HSD17B1 genotypes could exert a positive pleiotropic action on longevity and fertility. CYP17 and COMT gene variation did not influence either life span or fertility. We then searched the literature for genes studied in relation to both reproduction and aging. A review of the studies showed a pleiotropic action for six out of 16 genes and revealed that genes may exert positive, or negative, or antagonistic pleiotropic actions. These potential actions may be modified by such environmental factors such as changing reproductive behaviors, which seem to be able to mitigate or enhance a gene's phenotypic effects.
MeSH Terms
- Aged, 80 and over
- Case-Control Studies
- Catechol O-Methyltransferase
- Estradiol Dehydrogenases
- Female
- Fertility
- Gene Frequency
- Hormones
- Humans
- Longevity
- Male
- Polymorphism, Single Nucleotide
- Reproduction
- Steroid 17-alpha-Hydroxylase
- Steroids
Genetic differences play a significant role in generating individual differences in cognitive abilities. Studies have linked common polymorphisms (valine to methionine substitution; VAL/MET) in the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) to cognitive differences between individuals. However, not all studies support these associations and hence, the impact of these polymorphisms on cognition is unclear. Here, we investigated the effect of COMT VAL158MET and BDNF VAL66MET polymorphisms and their interaction on cognitive performance measured longitudinally over 8 years in a population-based sample of older adults (60-64 years at baseline; n = 400). We used multilevel models to examine differences between individuals with different genotypes in performance on psychometric tests while controlling for age, sex, and education. We observed significant main and interaction effects of COMT and BDNF genotypes on reaction time (RT) and intraindividual variability in RT (IIV-RT). Subjects with at least one copy of the COMT*MET allele (which is associated with higher prefrontal dopamine) had significantly faster RT (both simple and choice RT) and less IIV-RT in both tasks than those without the COMT*MET allele when they also carried one or more BDNF*MET alleles (which is associated with lower activity-dependent BDNF secretion). However, RT and IIV-RT did not differ significantly between the COMT genotypes in the absence of the BDNF*MET allele. These polymorphisms had no significant effect on within person change in RT or IIV-RT. Our findings indicate that the interaction between common variants of COMT and BDNF explain individual differences in RT and IIV-RT but do not explain age-related decline in these abilities.
MeSH Terms
- Adult
- Aged
- Aging
- Alleles
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Cognition
- Female
- Genotype
- Humans
- Individuality
- Longitudinal Studies
- Male
- Methionine
- Middle Aged
- Polymorphism, Genetic
- Reaction Time
- Valine
- Young Adult
We hypothesized that normal variation in genes influencing the bioavailability of dopamine in prefrontal cortex contribute to inter-individual differences in working memory (WM), particularly in healthy old age. To test this, 858 healthy young, middle-aged, and older people were tested on a spatial WM task and genotyped for catechol-O-methyltransferase (COMT VAL158MET) and dopamine betahydroxylase (DBH; C-1021T) single nucleotide polymorphisms (SNPs). Since these genes encode enzymes influencing levels of extracellular dopamine, important for WM, we reasoned that individuals with low activity alleles of each SNP (less efficient degradation of dopamine by COMT and less efficient conversion of dopamine to norepinephrine by DBH) would have higher levels of extracellular dopamine and therefore better WM performance. We predicted the poorest WM performance in people who are both COMT VAL/VAL and DBH C/C homozygotes, encoding enzymes with high activity. That prediction was borne out, but only in the older group under difficult discrimination. This suggests the high activity alleles of these 2 genes combine in reducing ability to manipulate information in WM among the old. Further, we predicted the best performance in people who inherited both low activity alleles. That prediction was not borne out. That we found genetic effects only among older people and not in midlife indicates that brain changes late in life heighten negative effects of chronically lower levels of extracellular dopamine due to normal genetic variation. We found that age increased the combined effect on WM of the COMT and DBH genes encoding enzymes controlling levels of extracellular dopamine.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Catechol O-Methyltransferase
- Cognition
- Dopamine
- Female
- Genotype
- Humans
- Male
- Memory, Short-Term
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Prefrontal Cortex
- Young Adult
Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and individual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation.
MeSH Terms
- Aged
- Aging
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Cognition
- Female
- Genetic Association Studies
- Genotype
- Humans
- Longitudinal Studies
- Male
- Memory, Episodic
- Middle Aged
- Neuropsychological Tests
- Prospective Studies
Keywords
- Ageing
- BDNF
- COMT
- Cognition
- LEQ
- Memory
The dorsolateral pFC (DLPFC) is a key region for working memory. It has been proposed that the DLPFC is dynamically recruited depending on task demands. By this view, high DLPFC recruitment for low-demanding tasks along with weak DLPFC upregulation at higher task demands reflects low efficiency. Here, the fMRI BOLD signal during working memory maintenance and manipulation was examined in relation to aging and catechol-O-methyltransferase (COMT) Val(158)Met status in a large representative sample (n = 287). The efficiency hypothesis predicts a weaker DLPFC response during manipulation, along with a stronger response during maintenance for older adults and COMT Val carriers compared with younger adults and COMT Met carriers. Consistent with the hypothesis, younger adults and met carriers showed maximal DLPFC BOLD response during manipulation, whereas older adults and val carriers displayed elevated DLPFC responses during the less demanding maintenance condition. The observed inverted relations support a link between dopamine and DLPFC efficiency.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain Mapping
- Catechol O-Methyltransferase
- Education
- Female
- Frontal Lobe
- Genotype
- Humans
- Magnetic Resonance Imaging
- Male
- Memory, Short-Term
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Genetic
- Prefrontal Cortex
- Task Performance and Analysis
According to a neurocomputational theory of cognitive aging, senescent changes in dopaminergic modulation lead to noisier and less differentiated processing. The authors tested a corollary hypothesis of this theory, according to which genetic predispositions of individual differences in prefrontal dopamine (DA) signaling may affect associations between memory functions, particularly in old age. Latent correlations between factors of verbal episodic memory and spatial working memory were compared between individuals carrying different allelic variants of the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences DA availability in prefrontal cortex. In younger adults (n = 973), correlations between memory functions did not differ significantly among the 3 COMT genotypes (r = .35); in older adults (n = 1333), however, the correlation was significantly higher in Val homozygotes (r = .70), whose prefrontal DA availability is supposedly the lowest of all groups examined, than in heterozygotes and Met homozygotes (both rs = .29). Latent means of the episodic memory and working memory factors did not differ by COMT status within age groups. However, when restricting the analysis to the low-performing tertile of older adults (n = 443), we found that Val homozygotes showed lower levels of performance in both episodic memory and working memory than heterozygotes and Met homozygotes. In line with the neurocomputational theory, the observed dedifferentiation of memory functions in older Val homozygotes suggests that suboptimal dopaminergic modulation may underlie multiple facets of memory declines during aging. Future longitudinal work needs to test this conjecture more directly.
MeSH Terms
- Adult
- Aged
- Aging
- Catechol O-Methyltransferase
- Dopamine
- Female
- Genotype
- Humans
- Male
- Memory
- Memory, Episodic
- Memory, Short-Term
- Methionine
- Middle Aged
- Polymorphism, Genetic
- Prefrontal Cortex
- Valine
- Young Adult
Associations between genotypes and cognitive outcomes may provide clues as to which mechanisms cause individual differences in old-age cognitive performance. We investigated the effects of five polymorphisms on cognitive functioning in a population-based sample of 2,694 persons without dementia (60-102 years). A structural equation model (SEM) was fit to the cognitive data, yielding five specific latent factors (perceptual speed, episodic memory, semantic memory, category fluency, and letter fluency), as well as a global cognitive factor. These factors showed the expected associations with chronological age. Genotyping was performed for five single-nucleotide polymorphisms that have been associated with cognitive performance: APOE (rs429358), COMT (rs4680), BDNF (rs6265), KIBRA (rs17070145), and CLSTN2 (rs6439886). After controlling for age, gender, and education, as well as correcting for multiple comparisons, we observed negative effects of being an APOE ε4 carrier on episodic memory and perceptual speed. Furthermore, being a CLSTN2 TT carrier was associated with poorer semantic memory. For the global factor, the same pattern of results was observed. In addition, being a BDNF any A carrier was associated with better cognitive performance. Also, older age was associated with stronger genetic effects of APOE on global cognition. However, this interaction effect was partly driven by the presence of preclinical dementia cases in our sample. Similarly, excluding future dementia cases attenuated the effects of APOE on episodic memory and global cognition, suggesting that part of the effects of APOE on old-age cognitive performance may be driven by dementia-related processes.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Cognition
- Female
- Genotype
- Humans
- Male
- Memory
- Middle Aged
- Polymorphism, Single Nucleotide
- Sweden