Human Neuroscience

Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms.

[1]  H. Vankova.  Mini Mental State , 2010 .

[2]  Roberto Cabeza,et al.  Assessing the effects of age on long white matter tracts using diffusion tensor tractography , 2009, NeuroImage.

[3]  J. Duncan,et al.  Effects of the Brain-Derived Neurotrophic Growth Factor Val66Met Variation on Hippocampus Morphology in Bipolar Disorder , 2009, Neuropsychopharmacology.

[4]  N. Raz,et al.  Aging white matter and cognition: Differential effects of regional variations in diffusion properties on memory, executive functions, and speed , 2009, Neuropsychologia.

[5]  Karen M Rodrigue,et al.  Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension. , 2009, Neuropsychology.

[6]  A M McIntosh,et al.  The effects of a neuregulin 1 variant on white matter density and integrity , 2008, Molecular Psychiatry.

[7]  J. John Mann,et al.  Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  Dorret I. Boomsma,et al.  Imaging the genetics of brain structure and function , 2008, Biological Psychology.

[9]  Terry E. Goldberg,et al.  Neurobiology of cognitive aging: Insights from imaging genetics , 2008, Biological Psychology.

[10]  Adam E. Green,et al.  Using genetic data in cognitive neuroscience: from growing pains to genuine insights , 2008, Nature Reviews Neuroscience.

[11]  Larry A. Kramer,et al.  Diffusion tensor quantification of the human midsagittal corpus callosum subdivisions across the lifespan , 2008, Brain Research.

[12]  P Rabbitt,et al.  Brain‐derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly , 2008, Genes, brain, and behavior.

[13]  K. Tanonaka,et al.  Injection of neural progenitor cells improved learning and memory dysfunction after cerebral ischemia , 2008, Experimental Neurology.

[14]  Y. Kawasaki,et al.  Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons , 2008, Neuroscience Letters.

[15]  Oliver Ganslandt,et al.  Age-related degradation in the central nervous system: assessment with diffusion-tensor imaging and quantitative fiber tracking. , 2008, Radiology.

[16]  Peter Stoeter,et al.  Association of 5′ end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans , 2008, NeuroImage.

[17]  A. Karni,et al.  Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection , 2008, Journal of Neuroimmunology.

[18]  R. Kraft,et al.  Relating imaging indices of white matter integrity and volume in healthy older adults. , 2008, Cerebral cortex.

[19]  Docent Jarmo Jääskeläinen,et al.  Genetic Regulation , 2008 .

[20]  Robert Zivadinov,et al.  Immune cell BDNF secretion is associated with white matter volume in multiple sclerosis , 2007, Journal of Neuroimmunology.

[21]  C. Sommer,et al.  Intravenous Brain-Derived Neurotrophic Factor Enhances Poststroke Sensorimotor Recovery and Stimulates Neurogenesis , 2007, Stroke.

[22]  Paul M. Thompson,et al.  Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: Tract-based spatial statistics study of aging , 2007, NeuroImage.

[23]  Karen M Rodrigue,et al.  Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. , 2007, Neuropsychology.

[24]  L. White,et al.  Adult age differences in the functional neuroanatomy of visual attention: A combined fMRI and DTI study , 2007, Neurobiology of Aging.

[25]  Usha Sinha,et al.  Exploratory voxel-based analysis of diffusion indices and hemispheric asymmetry in normal aging. , 2007, Magnetic resonance imaging.

[26]  N. Secher,et al.  Brain-derived neurotrophic factor (BDNF) and type 2 diabetes , 2007, Diabetologia.

[27]  A. Pfefferbaum,et al.  Diffusion tensor imaging and aging , 2006, Neuroscience & Biobehavioral Reviews.

[28]  F. Sohrabji,et al.  Estrogen–BDNF interactions: Implications for neurodegenerative diseases , 2006, Frontiers in Neuroendocrinology.

[29]  Tsong-Hai Lee,et al.  Hypertension downregulates the expression of brain-derived neurotrophic factor in the ischemia-vulnerable hippocampal CA1 and cortical areas after carotid artery occlusion , 2006, Brain Research.

[30]  A. Jean,et al.  Brain-derived neurotrophic factor (BDNF) and food intake regulation: A minireview , 2006, Autonomic Neuroscience.

[31]  Margit Burmeister,et al.  BDNF Val66Met Allele Is Associated with Reduced Hippocampal Volume in Healthy Subjects , 2006, Biological Psychiatry.

[32]  L Nyberg,et al.  Altered brain white matter integrity in healthy carriers of the APOE ε4 allele , 2006, Neurology.

[33]  Takashi Asada,et al.  The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology , 2006, Neuroscience Letters.

[34]  Kevin G Bath,et al.  Variant BDNF (Val66Met) impact on brain structure and function , 2006, Cognitive, affective & behavioral neuroscience.

[35]  L Nyberg,et al.  Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD? , 2006, Neurology.

[36]  Jim Mintz,et al.  Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. , 2006, Archives of general psychiatry.

[37]  K. Houkin,et al.  I.v. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat , 2005, Neuroscience.

[38]  Cheryl L. Dahle,et al.  Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. , 2005, Cerebral cortex.

[39]  John J Sidtis,et al.  Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers , 2005, Neuroreport.

[40]  A. Dale,et al.  Age-related alterations in white matter microstructure measured by diffusion tensor imaging , 2005, Neurobiology of Aging.

[41]  D Robinson,et al.  Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation , 2005, Molecular Psychiatry.

[42]  Edith V. Sullivan,et al.  Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging , 2005, NeuroImage.

[43]  N. Raz.  The Aging Brain Observed in Vivo: Differential Changes and Their Modifiers. , 2005 .

[44]  A. Meyer-Lindenberg,et al.  The Brain-derived Neurotrophic Factor Val66met Polymorphism and Variation in Human Cortical Morphology , 2022 .

[45]  Kenichi Murao,et al.  Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism , 2004, Brain Research.

[46]  H. Scharfman,et al.  Brain-derived neurotrophic factor. , 2004, Growth factors.

[47]  D. Head,et al.  Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. , 2004, Cerebral cortex.

[48]  M. B. Katan,et al.  Apolipoprotein E isoforms, serum cholesterol, and cancer , 2004 .

[49]  G. Bartzokis.  Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease , 2004, Neurobiology of Aging.

[50]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[51]  John Russell,et al.  Dysmyelination Revealed through MRI as Increased Radial (but Unchanged Axial) Diffusion of Water , 2002, NeuroImage.

[52]  Alan Peters,et al.  Structural changes in the normally aging cerebral cortex of primates. , 2002, Progress in brain research.

[53]  W. Brück,et al.  BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? , 2002, Brain : a journal of neurology.

[54]  Derek K. Jones,et al.  Evidence for cortical “disconnection” as a mechanism of age-related cognitive decline , 2001, Neurology.

[55]  A Pfefferbaum,et al.  Genetic regulation of regional microstructure of the corpus callosum in late life , 2001, Neuroreport.

[56]  Edith V. Sullivan,et al.  Equivalent disruption of regional white matter microstructure in ageing healthy men and women , 2001, Neuroreport.

[57]  J M Wardlaw,et al.  Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study: the Rotterdam Scan Study , 2001, Journal of neurology, neurosurgery, and psychiatry.

[58]  A. Toga,et al.  In vivo evidence for post-adolescent brain maturation in frontal and striatal regions , 1999, Nature Neuroscience.

[59]  R. Weinshilboum,et al.  The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. , 1997, Archives of internal medicine.

[60]  P. Basser,et al.  Toward a quantitative assessment of diffusion anisotropy , 1996, Magnetic resonance in medicine.

[61]  K. Irikura,et al.  Impaired autoregulation in an experimental model of chronic cerebral hypoperfusion in rats. , 1996, Stroke.

[62]  F. Aboitiz,et al.  Age-related changes in fibre composition of the human corpus callosum: sex differences. , 1996, Neuroreport.

[63]  D. Mathalon,et al.  A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. , 1994, Archives of neurology.

[64]  P. Rakić,et al.  Cytological and quantitative characteristics of four cerebral commissures in the rhesus monkey , 1990, The Journal of comparative neurology.

[65]  J. Fleiss,et al.  Intraclass correlations: uses in assessing rater reliability. , 1979, Psychological bulletin.

[66]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[67]  R. C. Oldfield.  THE ASSESSMENT AND ANALYSIS OF HANDEDNESS , 1971 .