Top

Published in:

01-09-2015 | Original Article

Magnified effects of the COMT gene on white-matter microstructure in very old age

Authors: Goran Papenberg, Martin Lövdén, Erika J. Laukka, Grégoria Kalpouzos, Lina Keller, Caroline Graff, Ylva Köhncke, Tie-Qiang Li, Laura Fratiglioni, Lars Bäckman

Published in: Brain Structure and Function | Issue 5/2015

Abstract

Genetic factors may partly account for between-person differences in brain integrity in old age. Evidence from human and animal studies suggests that the dopaminergic system is implicated in the modulation of white-matter integrity. We investigated whether a genetic variation in the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences dopamine availability in prefrontal cortex, contributes to interindividual differences in white-matter microstructure, as measured with diffusion-tensor imaging. In a sample of older adults from a population-based study (60–87 years; n = 238), we found that the COMT polymorphism affects white-matter microstructure, indexed by fractional anisotropy and mean diffusivity, of several white-matter tracts in the oldest age group (81–87 years), although there were no reliable associations between COMT and white-matter microstructure in the two younger age groups (60–66 and 72–78 years). These findings extend previous observations of magnified genetic effects on cognition in old age to white-matter integrity.

Available only for authorised users

Andersson JLR, Jenkinson M, Smith S (2007a) Non-linear registration, aka Spatial normalisation. FMRIB Technical Report TR07JA2. Available at: http://www.fmrib.ox.ac.uk/analysis/techrep

Andersson JLR, Jenkinson M, Smith S (2007b) Nonlinear optimisation. FMRIB Technical Report TR07JA1. Available at: http://www.fmrib.ox.ac.uk/analysis/techrep

Bäckman L, Nyberg L, Lindenberger U, Li S-C, Farde L (2006) The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neurosci Biobehav Rev 30:791–807CrossRefPubMed

Bäckman L, Lindenberger U, Li S-C, Nyberg L (2010) Linking cognitive aging to alterations in dopamine neurotransmitter functioning: recent data and future avenues. Neurosci Biobehav Rev 34:670–677CrossRefPubMed

Basser PJ, Pierpaoli C (1996) Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 111:209–219CrossRefPubMed

Bongarzone ER, Howard SG, Schonmann V, Campagnoni AT (1998) Identification of the dopamine D3 receptor in oligodendrocyte precursors: potential role in regulating differentiation and myelin formation. J Neurosci 18:5344–5353PubMed

Catani M, Thiebaut de Schotten M (2008) A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex 44:1105–1132CrossRefPubMed

Colzato LS, Waszack F, Nieuwenhuis ST, Posthuma D, Hommel B (2010) The flexible mind is associated with the Catechol-O-methyltransferase (COMT) Val158Met polymorphism: evidence for a role of dopamine in the control of task switching. Neuropsychologia 48:2764–2768CrossRefPubMed

Colzato LS, van den Wildenberg WP, Hommel B (2013) The genetic impact (C957T-DRD2) on inhibitory control is magnified by aging. Neuropsychologia 51:1377–1381CrossRefPubMed

Dahl M, Allwood CM, Hagberg B (2009) The realism in older people’s confidence judgments of answers to general knowledge questions. Psychol Aging 24:234–238CrossRefPubMed

Daki F, Peyrard-Janvid M, Matsson H, Kere J, Klingberg T (2012) Three dyslexia susceptibility genes, DYX1C1, DCDC2, and KIAA0319, affect temporo-parietal white matter structure. Biol Psychiatry 72:671–676CrossRef

de Frias CM, Lövdén M, Lindenberger U, Nilsson LG (2007) Revisiting the dedifferentiation hypothesis with longitudinal multi-cohort data. Intelligence 35:381–392CrossRef

de Frias CM, Marklund P, Eriksson E, Larsson A, Öhman L, Annerbrink K, Bäckman L, Nilsson L-G, Nyberg L (2010) Influence of COMT gene polymorphism on fMRI-assessed sustained and transient activity during a working memory task. J Cog Neurosci 22:1614–1622CrossRef

Dureman I (1960) SRB:1. Stockholm, Sweden: Psykologiförlaget

Hua K, Zhang J, Wakana S, Jiang H, Li X, Reich DS, Calabresi PA, Pekar JJ, van Zijl PC, Mori S (2008) Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification. Neuroimage 39:336–347PubMedCentralCrossRefPubMed

Josefsson M, de Luna X, Pudas S, Nilsson LG, Nyberg L (2012) Genetic and lifestyle predictors of 15-year longitudinal change in episodic memory. J Am Geriatr Soc 60:2308–2312CrossRefPubMed

Joseph B, Dyer CA (2003) Relationship between myelin production and dopamine synthesis in the PKU mouse brain. J Neurochem 86:615–626CrossRefPubMed

Jucaite A, Forssberg H, Karlsson P, Halldin C, Farde L (2010) Age-related reduction in dopamine D1 receptors in the human brain: from late childhood to adulthood, a positron emission tomography study. Neuroscience 167:104–110CrossRefPubMed

Kanchibhotla SC, Mather KA, Wen W, Schofield PR, Kwok JB, Sachdev PS (2013) Genetics of ageing-related changes in brain white matter integrity - A review. Ageing Res Rev 12:391–401CrossRefPubMed

Kim B, Yoo E, Lee JY, Lee KS, Choe AY, Lee JE, Kwack K, Yook KH, Choi TK, Lee SH (2013) The effects of the catechol-O-methyltransferase val158met polymorphism on white matter connectivity in patients with panic disorder. J Affect Disord 147:64–71CrossRefPubMed

Kline RB (2005) Principles and practice of structural equation modeling, 2nd edn. Guilford Press, New York

Kohannim O, Jahanshad N, Braskie MN, Stein JL, Chiang MC, Reese AH, Hibar DP, Toga AW, McMahon KL, de Zubicaray GI, Medland SE, Montgomery GW, Martin NG, Wright MJ, Thompson PM (2012) Predicting white matter integrity from multiple common genetic variants. Neuropsychopharmacology 37:2012–2019PubMedCentralCrossRefPubMed

Krugel LK, Biele G, Mohr PNC, Li S-C, Heekeren HR (2009) Genetic variation in dopaminergic neuromodulation influences the ability to rapidly and flexibly adapt decisions 106:17951–17956

Laukka EJ, Lövdén M, Herlitz A, Karlsson S, Ferencz B, Pantzar A, Keller L, Graff C, Fratiglioni L, Bäckman L (2013a) Genetic effects on old-age cognitive functioning: a population-based study. Psychol Aging 28:262–274CrossRefPubMed

Laukka EJ, Lövdén M, Kalpouzos G, Li T-Q, Jonsson T, Wahlund L-O, Fratiglioni L, Bäckman L (2013b) Associations between white matter microstructure and cognitive performance in old and very old age. PLoS One 8:e81419PubMedCentralCrossRefPubMed

Li S-C, Papenberg G, Nagel IE, Preuschhof C, Schröder J, Nietfeld W, Bertram L, Heekeren HR, Lindenberger U, Bäckman L (2012) Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory. Neurobiol Aging 34(358):e1–10

Lindenberger U, Nagel IE, Chicherio C, Li SC, Heekeren HR, Bäckman L (2008) Age-related decline in brain resources modulates genetic effects on cognitive functioning. Front Neurosci. 2:234–244PubMedCentralCrossRefPubMed

Lindenberger U, Burzynska AZ, Nagel IE (2013) Heterogeneity in frontal lobe aging. In: Stuss DT & Knight RT (Eds.), Principles of frontal lobe functions (Vol. 2nd. ed.). New York: New York: Oxford University Press

Lindholm E, Jazin E (2007) A possible link between dopamine action and myelin dysfunction in schizophrenia. Schizophr Res 96:271–272CrossRefPubMed

Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210CrossRefPubMed

Lövdén M, Laukka EJ, Rieckmann A, Kalpouzos G, Li TQ, Jonsson T, Wahlund L-O, Fratiglioni L, Bäckman L (2013) The dimensionality of between-person differences in white matter microstructure in old age. Hum Brain Mapp 34:1386–1398CrossRefPubMed

Madden DJ, Bennett IJ, Burzynska AZ, Potter GG, Chen NK, Song AW (2012) Diffusion tensor imaging of cerebral white matter integrity in cognitive aging. Biochim Biophys Acta 1822:386–400PubMedCentralCrossRefPubMed

Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116:127–137CrossRefPubMed

Nagel IE, Chicherio C, Li S-C, von Oertzen T, Sander T, Villringer A, Heekeren HR, Bäckman L, Lindenberger U (2008) Human aging magnifies genetic effects on executive functioning and working memory. Front Hum Neurosci. 2:1PubMedCentralCrossRefPubMed

Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25CrossRefPubMed

Nilsson L-G, Bäckman L, Erngrund K, Nyberg L, Adolfsson R, Bucht G, Karlsson S, Widing M, Winblad B (1997) The Betula prospective cohort study: memory, health, and aging. Aging Neuropsychol C 4:1–32CrossRef

Nyberg L, Lövdén M, Riklund K, Lindenberger U, Bäckman L (2012) Memory aging and brain maintenance. Trends Cogn Sci 16:292–305CrossRefPubMed

Papenberg G, Bäckman L, Nagel IE, Nietfeld W, Schröder J, Bertram L, Heekeren HR, Lindenberger U, Li S-C (2013a) COMT polymorphism and memory dedifferentiation in old age. Psychol Aging. Advanced [online publication]

Papenberg G, Bäckman L, Nagel IE, Nietfeld W, Schröder J, Bertram L, Heekeren HR, Lindenberger U, Li S-C (2013b) Dopaminergic Gene Polymorphisms Affect Long-term Forgetting in Old Age: further Support for the Magnification Hypothesis. J Cogn Neurosci 25:571–579CrossRefPubMed

Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, Dahle C, Gerstorf D, Acker JD (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15:1676–1689CrossRefPubMed

Rosin C, Colombo S, Calver AA, Bates TE, Skaper SD (2005) Dopamine D2 and D3 receptor agonists limit oligodendrocyte injury caused by glutamate oxidative stress and oxygen/glucose deprivation. Glia. 52:336–343CrossRefPubMed

Salthouse TA, Babcock RL (1991) Decomposing adult age differences in working memory. Dev Psychol 27:763–776CrossRef

Seok JH, Choi S, Lim HK, Lee SH, Kim I, Ham BJ (2013) Effect of the COMT val158met polymorphism on white matter connectivity in patients with major depressive disorder. Neurosci Lett 545:35–39CrossRefPubMed

Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage. 44:83–98CrossRefPubMed

Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23:S208–S219CrossRefPubMed

Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505CrossRefPubMed

Starr JM, Fox H, Harris SE, Deary IJ, Whalley LJ (2007) COMT genotype and cognitive ability: a longitudinal aging study. Neurosci Lett 421:57–61CrossRefPubMed

Störmer VS, Passow S, Biesenack J, Li S-C (2011) Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: insights from molecular genetic research and implications for adult cognitive development. Dev Psychol 48:875–889CrossRefPubMed

Thiebaut de Schotten M, Ffytche DH, Bizzi A, Dell’Acqua F, Allin M, Walshe M, Murray R, Williams SC, Murphy DG, Catani M (2011) Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. Neuroimage 54:49–59CrossRefPubMed

Thomason ME, Dougherty RF, Colich NL, Perry LM, Rykhlevskaia EI, Louro HM, Hallmayer JF, Waugh CE, Bammer R, Glover GH, Gotlib IH (2010) COMT genotype affects prefrontal white matter pathways in children and adolescents. NeuroImage 53:926–934PubMedCentralCrossRefPubMed

Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PC, Mori S (2004) Fiber tract-based atlas of human white matter anatomy. Radiology 230:77–87CrossRefPubMed

Welmer AK, Angleman S, Rydwik E, Fratiglioni L, Qui C (2013) Association of cardiovascular burden with mobility limitation among elderly people: a population-based study. PLoS ONE 8:e65815PubMedCentralCrossRefPubMed

Zazzo R (1974) Test des deux barrages. Actualités pédagogiques et psychologiques (Vol. 7). Neuchâtel, Switzerland: Delachaux et Nestlé

Title: Magnified effects of the COMT gene on white-matter microstructure in very old age
Authors: Goran Papenberg
Martin Lövdén
Erika J. Laukka
Grégoria Kalpouzos
Lina Keller
Caroline Graff
Ylva Köhncke
Tie-Qiang Li
Laura Fratiglioni
Lars Bäckman
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 5/2015
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-014-0835-4

At a glance: The STEP trials

Springer Medicine

Magnified effects of the COMT gene on white-matter microstructure in very old age

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2015

Genetic ablation of VIAAT in glycinergic neurons causes a severe respiratory phenotype and perinatal death

Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats

Localisation and stress-induced plasticity of GABAA receptor subunits within the cellular networks of the mouse dorsal raphe nucleus

A new myeloarchitectonic map of the human neocortex based on data from the Vogt–Vogt school

Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism

The superior paraolivary nucleus shapes temporal response properties of neurons in the inferior colliculus