Differential effects of COMT on gait and executive control in aging

Walking speed is associated with attention and executive control processes subserved by the prefrontal cortex. Because polymorphisms in catechol-O-methyltransferase (COMT) influence these cognitive processes we hypothesized that the same polymorphisms may influence gait velocity. We examined the associations between the Val(158)Met polymorphism in COMT and gait velocity as well as attention and executive function. Participants were 278 non-demented older adults. The results revealed that methionine (Met)/valine (Val) was associated with faster gait velocity. This association can be explained by the putative role of the Val allele in regulating tonic dopamine release in the striatum. In contrast, Met/Met was associated with better attention and executive function. Stratification by gender revealed that the association between COMT genotype and gait was significant only in men. Conversely, the association between COMT genotype and attention and executive function was significant only in women. These findings suggest a differential effect in relating the Val(158)Met polymorphism to gait and to cognitive function while supporting the previously described sexual dimorphism in the phenotypic expressions of COMT.

[1]  K. Nolan,et al.  Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: A replication study , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[2]  R. Ebstein,et al.  Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) , 2000, Molecular Psychiatry.

[3]  T. Goldberg,et al.  Genes and the parsing of cognitive processes , 2004, Trends in Cognitive Sciences.

[4]  M. Morris,et al.  Concurrent related validity of the GAITRite walkway system for quantification of the spatial and temporal parameters of gait. , 2003, Gait & posture.

[5]  Hans-Jürgen Möller,et al.  A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits , 2003, Biological Psychiatry.

[6]  M. Koulu,et al.  Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism , 1999, Molecular Psychiatry.

[7]  R. Abbott,et al.  Walking and dementia in physically capable elderly men. , 2004, JAMA.

[8]  A. Arnsten,et al.  Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. , 1997, The Journal of pharmacology and experimental therapeutics.

[9]  S. Ho,et al.  Human catechol-O-methyltransferase down-regulation by estradiol , 2003, Neuropharmacology.

[10]  M. Ronaghi.  Pyrosequencing for SNP genotyping. , 2003, Methods in molecular biology.

[11]  Nils Lid Hjort,et al.  Goodness‐of‐fit processes for logistic regression: simulation results , 2002, Statistics in medicine.

[12]  H. Buschke,et al.  The effect of dementia risk factors on comparative and diagnostic selective reminding norms , 1997, Journal of the International Neuropsychological Society.

[13]  P. Goldman-Rakic,et al.  Modulation of memory fields by dopamine Dl receptors in prefrontal cortex , 1995, Nature.

[14]  M. Egan,et al.  Effect of Catechol-O-Methyltransferase val158met Genotype on Attentional Control , 2005, The Journal of Neuroscience.

[15]  B. Bloem,et al.  Neurological gait disorders in elderly people: clinical approach and classification , 2007, The Lancet Neurology.

[16]  J Ormel,et al.  Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA , 2007, Molecular Psychiatry.

[17]  Harvey J. Motulsky,et al.  Detecting outliers when fitting data with nonlinear regression – a new method based on robust nonlinear regression and the false discovery rate , 2006, BMC Bioinformatics.

[18]  L. Talbot,et al.  Relationship between muscle strength and the time taken to complete a standardized walk-turn-walk test. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[19]  Paul J. Harrison,et al.  Catechol-o-Methyltransferase, Cognition, and Psychosis: Val158Met and Beyond , 2006, Biological Psychiatry.

[20]  M. Inzitari,et al.  Impaired attention predicts motor performance decline in older community-dwellers with normal baseline mobility: results from the Italian Longitudinal Study on Aging (ILSA). , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[21]  N. Hayward,et al.  Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia , 2005, Molecular Psychiatry.

[22]  T. Robbins,et al.  Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls , 2007, Molecular Psychiatry.

[23]  L. Nyberg,et al.  The correlative triad among aging, dopamine, and cognition: Current status and future prospects , 2006, Neuroscience & Biobehavioral Reviews.

[24]  T. Lehtimäki,et al.  Catechol-O-methyltransferase and Monoamine Oxidase A Genotypes and Drug Response to Conventional Neuroleptics in Schizophrenia , 2003, Journal of clinical psychopharmacology.

[25]  M. Sliwinski,et al.  Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons , 1994, Neurology.

[26]  H Morgenstern,et al.  Development of dementing illnesses in an 80‐year‐old volunteer cohort , 1989, Annals of neurology.

[27]  B. Lipska,et al.  Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function , 2003, Neuroscience.

[28]  R. Lipton,et al.  Epidemiology of Gait Disorders in Community‐Residing Older Adults , 2006, Journal of the American Geriatrics Society.

[29]  S. Ho,et al.  Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. , 1999, Molecular pharmacology.

[30]  Charles Hall,et al.  Validity of Divided Attention Tasks In Predicting Falls in Older Individuals: A Preliminary Study , 2002, Journal of the American Geriatrics Society.

[31]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[32]  Xiaonan Xue,et al.  The relationship between specific cognitive functions and falls in aging. , 2007, Neuropsychology.

[33]  Herman Buschke,et al.  Screening for Dementia by Telephone Using the Memory Impairment Screen , 2003, Journal of the American Geriatrics Society.

[34]  Sverker Sikström,et al.  Integrative neurocomputational perspectives on cognitive aging, neuromodulation, and representation , 2002, Neuroscience & Biobehavioral Reviews.

[35]  Xiaonan Xue,et al.  Cognitive processes related to gait velocity: results from the Einstein Aging Study. , 2006, Neuropsychology.

[36]  Katharina Domschke,et al.  Meta‐analysis of COMT val158met in panic disorder: Ethnic heterogeneity and gender specificity , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[37]  K. Yabe,et al.  Age-related changes in gait velocity and leg extension power in middle-aged and elderly people. , 2000, Journal of epidemiology.

[38]  Rose Anne Kenny,et al.  Prevalence and Severity of Gait Disorders in Alzheimer's and Non‐Alzheimer's Dementias , 2005, Journal of the American Geriatrics Society.

[39]  A. Grace.  Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia , 1991, Neuroscience.

[40]  M. Egan,et al.  Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Dc Washington.  Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. , 1994 .

[42]  R. Ebstein,et al.  Relationship between dopamine system genes and extraversion and novelty seeking , 2007, Neuroscience and Behavioral Physiology.

[43]  J. Lieberman,et al.  Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia , 2002, Biological Psychiatry.

[44]  Venkata S Mattay,et al.  Imaging genetic influences in human brain function , 2004, Current Opinion in Neurobiology.

[45]  J. Cummings,et al.  Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. , 2002, Journal of psychosomatic research.

[46]  Paul J. Harrison,et al.  The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis , 2007, Molecular Psychiatry.

[47]  Andreas Meyer-Lindenberg,et al.  Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function , 2007, Proceedings of the National Academy of Sciences.

[48]  D. Durstewitz,et al.  Bidirectional Dopamine Modulation of GABAergic Inhibition in Prefrontal Cortical Pyramidal Neurons , 2001, The Journal of Neuroscience.

[49]  C. Benkelfat,et al.  Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin Card Sorting Test. , 2002, Archives of general psychiatry.

[50]  Herman Buschke,et al.  Abnormality of gait as a predictor of non-Alzheimer's dementia. , 2002, The New England journal of medicine.

[51]  A. Hofman,et al.  The catechol-O-methyltransferase Met158 low-activity allele and association with nonvertebral fracture risk in elderly men. , 2007, The Journal of clinical endocrinology and metabolism.

[52]  T. Lehtimäki,et al.  Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics , 2003, European Neuropsychopharmacology.

[53]  M. Koulu,et al.  Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers. , 2000, Alcoholism, clinical and experimental research.

[54]  M. Roth,et al.  The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects , 1968, British Journal of Psychiatry.

[55]  David Balaban,et al.  Robust regression for high throughput drug screening , 2006, Comput. Methods Programs Biomed..

[56]  Dean F. Wong,et al.  Sex Differences in Striatal Dopamine Release in Healthy Adults , 2006, Biological Psychiatry.

[57]  Theo Mulder,et al.  Gait in ageing and associated dementias; its relationship with cognition , 2007, Neuroscience & Biobehavioral Reviews.

[58]  M. Leinonen,et al.  The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease , 2003, European journal of neurology.

[59]  R. Lipton,et al.  Reliability and validity of a telephone-based mobility assessment questionnaire. , 2004, Age and ageing.

[60]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Lars-Göran Nilsson,et al.  Catechol O-Methyltransferase Val158Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults , 2005, Journal of Cognitive Neuroscience.

[62]  B. Kolachana,et al.  Catechol-O-Methyltransferase Genotype and Dopamine Regulation in the Human Brain , 2003, The Journal of Neuroscience.

[63]  R. Nussbaum,et al.  Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype , 2005, Nature Neuroscience.

[64]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[65]  W. Boon,et al.  Estrogen Deficient Male Mice Develop Compulsive Behavior , 2007, Biological Psychiatry.

[66]  P. Goldman-Rakic,et al.  The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. , 1994, Journal of neurophysiology.

[67]  A. Grace,et al.  The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes , 2004, Neuropsychopharmacology.

[68]  Xiaonan Xue,et al.  Quantitative gait dysfunction and risk of cognitive decline and dementia , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[69]  J. Manson,et al.  Physical activity, including walking, and cognitive function in older women. , 2004, JAMA.

[70]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.