Cognition in healthy aging is related to regional white matter integrity, but not cortical thickness

It is well established that healthy aging is accompanied by structural changes in many brain regions and functional decline in a number of cognitive domains. The goal of this study was to determine (1) whether the regional distribution of age-related brain changes is similar in gray matter (GM) and white matter (WM) regions, or whether these two tissue types are affected differently by aging, and (2) whether measures of cognitive performance are more closely linked to alterations in the cerebral cortex or in the underlying WM in older adults (OA). To address these questions, we collected high-resolution magnetic resonance imaging (MRI) data from a large sample of healthy young adults (YA; aged 18-28) and OA (aged 61-86 years). In addition, the OA completed a series of tasks selected to assess cognition in three domains: cognitive control, episodic memory, and semantic memory. Using advanced techniques for measuring cortical thickness and WM integrity, we found that healthy aging was accompanied by deterioration of both GM and WM, but with distinct patterns of change: Cortical thinning occurred primarily in primary sensory and motor cortices, whereas WM changes were localized to regions underlying association cortices. Further, in OA, we found a striking pattern of region-specific correlations between measures of cognitive performance and WM integrity, but not cortical thickness. Specifically, cognitive control correlated with integrity of frontal lobe WM, whereas episodic memory was related to integrity of temporal and parietal lobe WM. Thus, age-related impairments in specific cognitive capacities may arise from degenerative processes that affect the underlying connections of their respective neural networks.

[1]  J. Sandell,et al.  Effects of age on nerve fibers in the rhesus monkey optic nerve , 2001, The Journal of comparative neurology.

[2]  D L Rosene,et al.  Feature article: are neurons lost from the primate cerebral cortex during normal aging? , 1998, Cerebral cortex.

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

[4]  Fabrice Crivello,et al.  Age- and sex-related effects on the neuroanatomy of healthy elderly , 2005, NeuroImage.

[5]  L. Ketonen Neuroimaging of the aging brain. , 1998, Neurologic clinics.

[6]  M Rovaris,et al.  Influence of aging on brain gray and white matter changes assessed by conventional, MT, and DT MRI , 2006, Neurology.

[7]  Jens C. Pruessner,et al.  Regional Frontal Cortical Volumes Decrease Differentially in Aging: An MRI Study to Compare Volumetric Approaches and Voxel-Based Morphometry , 2002, NeuroImage.

[8]  John O. Willis,et al.  Wechsler Adult Intelligence Scale–Third Edition , 2008 .

[9]  K. Lim,et al.  Age‐related decline in brain white matter anisotropy measured with spatially corrected echo‐planar diffusion tensor imaging , 2000, Magnetic resonance in medicine.

[10]  L. J. Whalley,et al.  White matter integrity and cognition in childhood and old age , 2006, Neurology.

[11]  M S Buchsbaum,et al.  Regional and global changes in cerebral diffusion with normal aging. , 2001, AJNR. American journal of neuroradiology.

[12]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

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

[14]  C. Fennema-Notestine,et al.  Effects of age on tissues and regions of the cerebrum and cerebellum , 2001, Neurobiology of Aging.

[15]  K. Krishnan,et al.  Widespread effects of hyperintense lesions on cerebral white matter structure. , 2007, AJR. American journal of roentgenology.

[16]  A. Peters,et al.  The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey. , 1998, Cerebral cortex.

[17]  Jonas Persson,et al.  Structure-function correlates of cognitive decline in aging. , 2006, Cerebral cortex.

[18]  Alan C. Evans,et al.  A voxel-based morphometric study to determine individual differences in gray matter density associated with age and cognitive change over time. , 2004, Cerebral cortex.

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

[20]  S. Markwell,et al.  A Cross-Sectional Study of the Effects of Age, Education, and Gender on the Boston Naming Test , 2007, The Clinical neuropsychologist.

[21]  Sheryl Feinstein Learning and the brain : a comprehensive guide for educators, parents, and teachers , 2007 .

[22]  M. O’Sullivan,et al.  Activate your online subscription , 2001, Neurology.

[23]  J. Rosenbluth REDUNDANT MYELIN SHEATHS AND OTHER ULTRASTRUCTURAL FEATURES OF THE TOAD CEREBELLUM , 1966, The Journal of cell biology.

[24]  L. Jäger,et al.  Evidence of subcortical and cortical aging of the acoustic pathway: a diffusion tensor imaging (DTI) study. , 2007, Academic radiology.

[25]  P. Basser,et al.  Estimation of the effective self-diffusion tensor from the NMR spin echo. , 1994, Journal of magnetic resonance. Series B.

[26]  R. Henson,et al.  The neural basis of episodic memory: evidence from functional neuroimaging. , 2002, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[27]  R. Reitan Validity of the Trail Making Test as an Indicator of Organic Brain Damage , 1958 .

[28]  Evan Fletcher,et al.  White Matter Changes Compromise Prefrontal Cortex Function in Healthy Elderly Individuals , 2006, Journal of Cognitive Neuroscience.

[29]  G. M. Halliday,et al.  White matter loss in healthy ageing: A postmortem analysis , 2009, Neurobiology of Aging.

[30]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[31]  R. Sturrock Changes in neurologia and myelination in the white matter of aging mice. , 1976, Journal of gerontology.

[32]  B. Turetsky,et al.  Sex differences in aging of the human frontal and temporal lobes , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  Faith M. Gunning-Dixon,et al.  Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume , 2004, Neurobiology of Aging.

[34]  H. C. Chui,et al.  White matter lesions impair frontal lobe function regardless of their location , 2004, Neurology.

[35]  Wiro J. Niessen,et al.  Brain tissue volumes in the general elderly population The Rotterdam Scan Study , 2008, Neurobiology of Aging.

[36]  F. Gunning-Dixon,et al.  The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. , 2000, Neuropsychology.

[37]  C. Beaulieu,et al.  The basis of anisotropic water diffusion in the nervous system – a technical review , 2002, NMR in biomedicine.

[38]  V. Wedeen,et al.  Reduction of eddy‐current‐induced distortion in diffusion MRI using a twice‐refocused spin echo , 2003, Magnetic resonance in medicine.

[39]  Benjamin J. Shannon,et al.  Parietal lobe contributions to episodic memory retrieval , 2005, Trends in Cognitive Sciences.

[40]  Jim Mintz,et al.  Brain ferritin iron may influence age- and gender-related risks of neurodegeneration , 2007, Neurobiology of Aging.

[41]  G. Bartzokis,et al.  In vivo MR evaluation of age-related increases in brain iron. , 1994, AJNR. American journal of neuroradiology.

[42]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[43]  A M Dale,et al.  Measuring the thickness of the human cerebral cortex from magnetic resonance images. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Danielle J. Tisserand,et al.  On the Involvement of Prefrontal Networks in Cognitive Ageing , 2003, Cortex.

[45]  D. Head,et al.  Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. , 1997, Cerebral cortex.

[46]  J. Hinman,et al.  What’s Behind the Decline? The Role of White Matter in Brain Aging , 2007, Neurochemical Research.

[47]  S. Resnick,et al.  Longitudinal Magnetic Resonance Imaging Studies of Older Adults: A Shrinking Brain , 2003, The Journal of Neuroscience.

[48]  Vladimir V. Frolkis,et al.  Neurobiology of Aging , 2019, Psychobiology of Behaviour.

[49]  M J de Leon,et al.  Hippocampal formation size predicts declining memory performance in normal aging , 1996, Neurology.

[50]  Benjamin J. Shannon,et al.  Functional-Anatomic Correlates of Memory Retrieval That Suggest Nontraditional Processing Roles for Multiple Distinct Regions within Posterior Parietal Cortex , 2004, The Journal of Neuroscience.

[51]  E. Glisky,et al.  Double dissociation between item and source memory. , 1995 .

[52]  R. Luján Fiber Pathways of the Brain, J.D. Schmahmann, D.N. Pandya (Eds.). Oxford University Press (2006), ISBN: 0-19-510423-4 , 2008 .

[53]  E. Kaplan,et al.  The Boston naming test , 2001 .

[54]  F. Aboitiz,et al.  One hundred million years of interhemispheric communication: the history of the corpus callosum. , 2003, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[55]  Ron Dumont,et al.  Wechsler Memory Scale–Third Edition , 2008 .

[56]  Tao Lu,et al.  The aging brain. , 2008, Annual review of pathology.

[57]  Arthur W. Toga,et al.  A Probabilistic Atlas of the Human Brain: Theory and Rationale for Its Development The International Consortium for Brain Mapping (ICBM) , 1995, NeuroImage.

[58]  P. Greenwood,et al.  The frontal aging hypothesis evaluated , 2000, Journal of the International Neuropsychological Society.

[59]  M. O’Sullivan,et al.  White matter damage on diffusion tensor imaging correlates with age-related cognitive decline , 2006, Neurology.

[60]  D. Salat,et al.  Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease. , 1999, Archives of neurology.

[61]  B. Pakkenberg,et al.  Age-Induced White Matter Changes in the Human Brain: A Stereological Investigation , 1997, Neurobiology of Aging.

[62]  Cindy Lustig,et al.  Evidence for frontally mediated controlled processing differences in older adults. , 2006, Cerebral cortex.

[63]  B. Yoon,et al.  Region-specific changes of cerebral white matter during normal aging: a diffusion-tensor analysis. , 2008, Archives of gerontology and geriatrics.

[64]  N. Prins,et al.  Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[65]  W. Sturm,et al.  Neuropsychological assessment , 2007, Journal of Neurology.

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

[67]  J. Connor,et al.  Iron, brain ageing and neurodegenerative disorders , 2004, Nature Reviews Neuroscience.

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

[69]  A. Dale,et al.  Cortical Surface-Based Analysis II: Inflation, Flattening, and a Surface-Based Coordinate System , 1999, NeuroImage.

[70]  N. Raz,et al.  Differential Aging of the Brain: Patterns, Cognitive Correlates and Modifiers , 2022 .

[71]  Takayuki Obata,et al.  Age-related degeneration of corpus callosum measured with diffusion tensor imaging , 2006, NeuroImage.

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

[73]  B. Hallgren,et al.  THE EFFECT OF AGE ON THE NON‐HAEMIN IRON IN THE HUMAN BRAIN , 1958, Journal of neurochemistry.

[74]  A. Dale,et al.  High‐resolution intersubject averaging and a coordinate system for the cortical surface , 1999, Human brain mapping.

[75]  A. Hofman,et al.  Cerebral white matter lesions and cognitive function: The Rotterdam scan study , 2000, Annals of neurology.

[76]  David J. Madden,et al.  Adult Age Differences in Regional Cerebral Blood Flow during Visual Word Identification: Evidence from H2 15O PET , 1996, NeuroImage.

[77]  H. Brody,et al.  The aging brain , 1992, Acta neurologica Scandinavica. Supplementum.

[78]  D. Salat,et al.  Greater orbital prefrontal volume selectively predicts worse working memory performance in older adults. , 2002, Cerebral cortex.

[79]  Michael W Weiner,et al.  Longitudinal MRI and cognitive change in healthy elderly. , 2007, Neuropsychology.

[80]  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.

[81]  Lars-Göran Nilsson,et al.  High Prevalence of White Matter Hyperintensities in Normal Aging: Relation to Blood Pressure and Cognition , 2003, Cortex.

[82]  R. Cabeza Cognitive neuroscience of aging: contributions of functional neuroimaging. , 2001, Scandinavian journal of psychology.

[83]  J. Ridley Studies of Interference in Serial Verbal Reactions , 2001 .

[84]  Leanne M Williams,et al.  Preservation of limbic and paralimbic structures in aging , 2005, Human brain mapping.

[85]  Jeffrey W. Cooney,et al.  Top-down suppression deficit underlies working memory impairment in normal aging , 2005, Nature Neuroscience.

[86]  R. Cabeza,et al.  Effects of aging on transient and sustained successful memory encoding activity , 2007, Neurobiology of Aging.

[87]  A. Dale,et al.  Effects of age on volumes of cortex, white matter and subcortical structures , 2005, Neurobiology of Aging.

[88]  Robert H. Paul,et al.  The relationship between frontal gray matter volume and cognition varies across the healthy adult lifespan. , 2006, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[89]  E. Gordon,et al.  Cognitive aging, executive function, and fractional anisotropy: a diffusion tensor MR imaging study. , 2007, AJNR. American journal of neuroradiology.

[90]  R. Killiany,et al.  Age-Related Cognitive Decline in the Rhesus Monkey , 1999 .

[91]  Anders M. Dale,et al.  Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex , 2001, IEEE Transactions on Medical Imaging.

[92]  T. Mexia,et al.  Author ' s personal copy , 2009 .

[93]  John S. Allen,et al.  Normal neuroanatomical variation due to age: The major lobes and a parcellation of the temporal region , 2005, Neurobiology of Aging.

[94]  Karl J. Friston,et al.  A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains , 2001, NeuroImage.

[95]  Scott A. Huettel,et al.  Diffusion tensor imaging of adult age differences in cerebral white matter: relation to response time , 2004, NeuroImage.

[96]  Anthony R. McIntosh,et al.  Age-Related Differences in Neural Activity during Memory Encoding and Retrieval: A Positron Emission Tomography Study , 1997, The Journal of Neuroscience.

[97]  A. Peters The effects of normal aging on myelin and nerve fibers: A review , 2002, Journal of neurocytology.

[98]  J. Gabrieli,et al.  Insights into the ageing mind: a view from cognitive neuroscience , 2004, Nature Reviews Neuroscience.

[99]  R. Buckner,et al.  THE COGNITIVE NEUROSCIENCE OF REMEMBERING , 2001 .

[100]  Anthony Randal McIntosh,et al.  Towards a network theory of cognition , 2000, Neural Networks.

[101]  A. Dale,et al.  Age‐Related Changes in Prefrontal White Matter Measured by Diffusion Tensor Imaging , 2005, Annals of the New York Academy of Sciences.

[102]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[103]  Janice E. Knoefel,et al.  Clinical neurology of aging , 1985 .

[104]  R. West,et al.  An application of prefrontal cortex function theory to cognitive aging. , 1996, Psychological bulletin.

[105]  G. Bartzokis,et al.  Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. , 2001, Archives of general psychiatry.

[106]  T. Kemper,et al.  Neuroanatomical and neuropathological changes during aging and dementia. , 1994 .

[107]  Anders M. Dale,et al.  Frontal connections and cognitive changes in normal aging rhesus monkeys: A DTI study , 2007, Neurobiology of Aging.

[108]  Matthijs Oudkerk,et al.  Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. , 2000 .

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

[110]  Suzanne E. Welcome,et al.  Mapping cortical change across the human life span , 2003, Nature Neuroscience.

[111]  K. Double,et al.  Topography of brain atrophy during normal aging and alzheimer's disease , 1996, Neurobiology of Aging.

[112]  S. Rose,et al.  Gray and white matter changes in Alzheimer's disease: A diffusion tensor imaging study , 2008, Journal of magnetic resonance imaging : JMRI.

[113]  Ya Ke,et al.  Iron misregulation in the brain: a primary cause of neurodegenerative disorders , 2003, The Lancet Neurology.

[114]  Faith M. Gunning-Dixon,et al.  Neuroanatomical correlates of cognitive aging: evidence from structural magnetic resonance imaging. , 1998, Neuropsychology.

[115]  David Wechsler,et al.  Wechsler Memory scale. , 2005 .

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

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

[118]  B. Fischl,et al.  White matter pathology isolates the hippocampal formation in Alzheimer's disease , 2010, Neurobiology of Aging.

[119]  G. V. Van Hoesen,et al.  Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. , 1984, Science.

[120]  F. Craik,et al.  The effects of age on the neural correlates of episodic encoding. , 1999, Cerebral cortex.

[121]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[122]  Anthony Randal McIntosh,et al.  Age-related Changes in Brain Activity across the Adult Lifespan , 2006, Journal of Cognitive Neuroscience.

[123]  E. Plante,et al.  Memory and executive function in older adults: relationships with temporal and prefrontal gray matter volumes and white matter hyperintensities , 2004, Neuropsychologia.

[124]  Scott A. Huettel,et al.  Age-related slowing of memory retrieval: Contributions of perceptual speed and cerebral white matter integrity , 2008, Neurobiology of Aging.

[125]  S. Markwell,et al.  A longitudinal study of confrontation naming in the “normal” elderly , 2005, Journal of the International Neuropsychological Society.

[126]  B. Pakkenberg,et al.  Neocortical neuron number in humans: Effect of sex and age , 1997, The Journal of comparative neurology.

[127]  J. Haxby,et al.  The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults , 1995, Neurology.

[128]  Gary Glover,et al.  Aging effects on memory encoding in the frontal lobes. , 2002, Psychology and aging.

[129]  Adolf Pfefferbaum,et al.  Effects of age and sex on volumes of the thalamus, pons, and cortex , 2004, Neurobiology of Aging.

[130]  R. Kikinis,et al.  White matter changes with normal aging , 1998, Neurology.

[131]  D. Harvey,et al.  Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD , 2006, Neurology.

[132]  M M Mesulam,et al.  Large‐scale neurocognitive networks and distributed processing for attention, language, and memory , 1990, Annals of neurology.

[133]  C. Petten Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis , 2004, Neuropsychologia.

[134]  Terry L. Jernigan,et al.  Cerebral structure on MRI, Part I: Localization of age-related changes , 1991, Biological Psychiatry.

[135]  A. Pfefferbaum,et al.  Selective age-related degradation of anterior callosal fiber bundles quantified in vivo with fiber tracking. , 2006, Cerebral cortex.

[136]  Osamu Abe,et al.  Aging in the CNS: Comparison of gray/white matter volume and diffusion tensor data , 2008, Neurobiology of Aging.

[137]  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.

[138]  B. Pakkenberg,et al.  Marked loss of myelinated nerve fibers in the human brain with age , 2003, The Journal of comparative neurology.

[139]  Anders M. Dale,et al.  Selective increase of cortical thickness in high-performing elderly—structural indices of optimal cognitive aging , 2006, NeuroImage.

[140]  A. Dale,et al.  Thinning of the cerebral cortex in aging. , 2004, Cerebral cortex.

[141]  J. Townsend,et al.  Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. , 2000, Radiology.

[142]  Anders M. Dale,et al.  Regional cortical thickness matters in recall after months more than minutes , 2006, NeuroImage.

[143]  C. Van Petten,et al.  Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis. , 2004, Neuropsychologia.

[144]  Adolf Pfefferbaum,et al.  Diffusion tensor imaging in normal aging and neuropsychiatric disorders. , 2003, European journal of radiology.

[145]  D. Head,et al.  Differential aging of the medial temporal lobe , 2004, Neurology.

[146]  Faith M. Gunning-Dixon,et al.  Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study , 2003, Neuropsychologia.