Hippocampal volumes are important predictors for memory function in elderly women

BackgroundNormal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).MethodsBrain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.ResultsAPOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.ConclusionGender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

[1]  F. Lalonde,et al.  Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women , 2001, Neurology.

[2]  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.

[3]  K. Hornik,et al.  Unbiased Recursive Partitioning: A Conditional Inference Framework , 2006 .

[4]  Chuan-fu Li,et al.  [Quantitative analysis of brain volume by in vivo magnetic resonance imaging in normal adults]. , 2006, Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae.

[5]  James R. MacFall,et al.  Predicting memory decline in normal elderly: Genetics, MRI, and cognitive reserve , 2007, Neurobiology of Aging.

[6]  Carole Dufouil,et al.  No ɛ4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects , 2005, NeuroImage.

[7]  M. Weiner,et al.  Patterns of Verbal Memory Performance in Mild Cognitive Impairment, Alzheimer Disease, and Normal Aging , 2006, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology.

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

[9]  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.

[10]  M. Torrens Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[11]  E. Wehling,et al.  APOE status and its association to learning and memory performance in middle aged and older Norwegians seeking assessment for memory deficits. , 2007, Behavioral and brain functions : BBF.

[12]  Arvid Lundervold,et al.  Evaluation of automated brain MR image segmentation and volumetry methods , 2009, Human brain mapping.

[13]  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.

[14]  Klaus Nordhausen,et al.  The Elements of Statistical Learning: Data Mining, Inference, and Prediction, Second Edition by Trevor Hastie, Robert Tibshirani, Jerome Friedman , 2009 .

[15]  N Butters,et al.  Episodic memory changes are associated with the APOE- epsilon 4 allele in nondemented older adults , 1995, Neurology.

[16]  Daniel Bandy,et al.  Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease , 1998, Annals of neurology.

[17]  K. Welsh-Bohmer,et al.  Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition. , 1997, Neurology.

[18]  J. Kaye,et al.  Predicting the rate of cognitive decline in aging and early Alzheimer disease , 2004, Neurology.

[19]  Maria C. Norton,et al.  Neuropsychological performance in advanced age: Influences of Demographic factors and Apolipoprotein E: Findings from the Cache County Memory Study , 2009, The Clinical neuropsychologist.

[20]  N. Makris,et al.  Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. , 2001, Cerebral cortex.

[21]  A Hofman,et al.  Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes , 2002, Neurology.

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

[23]  R. Mahley,et al.  Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology , 2006, Acta neurologica Scandinavica. Supplementum.

[24]  Marianna D. Eddy,et al.  Regionally localized thinning of the cerebral cortex in schizophrenia , 2003, Schizophrenia Research.

[25]  A. Dale,et al.  Regional and progressive thinning of the cortical ribbon in Huntington’s disease , 2002, Neurology.

[26]  Anders M. Fjell,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E ɛ4 , 2008, Neurobiology of Aging.

[27]  Kaarin J Anstey,et al.  Total and regional gray matter volume is not related to APOE*E4 status in a community sample of middle-aged individuals. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[28]  Anders M. Dale,et al.  A hybrid approach to the Skull Stripping problem in MRI , 2001, NeuroImage.

[29]  A. Dekaban,et al.  Changes in brain weights during the span of human life: Relation of brain weights to body heights and body weights , 1978, Annals of neurology.

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

[31]  Nick C Fox,et al.  Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment , 2007, Neurology.

[32]  Tom den Heijer,et al.  Hippocampal Head Size Associated with Verbal Memory Performance in Nondemented Elderly , 2002, NeuroImage.

[33]  Amy J. Jak,et al.  Differential Cross-Sectional and Longitudinal Impact of APOE Genotype on Hippocampal Volumes in Nondemented Older Adults , 2007, Dementia and Geriatric Cognitive Disorders.

[34]  D. Kennedy,et al.  Anatomic segmentation and volumetric calculations in nuclear magnetic resonance imaging. , 1989, IEEE transactions on medical imaging.

[35]  S. Resnick,et al.  Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype , 2000, Neurology.

[36]  M. Greicius Resting-state functional connectivity in neuropsychiatric disorders , 2008, Current opinion in neurology.

[37]  Wiro J. Niessen,et al.  White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging , 2008, NeuroImage.

[38]  Robert Tibshirani,et al.  The Elements of Statistical Learning: Data Mining, Inference, and Prediction, 2nd Edition , 2001, Springer Series in Statistics.

[39]  H. Fillit,et al.  Strategies for drug discovery for cognitive aging and alzheimer’s disease , 2002, Journal of Molecular Neuroscience.

[40]  Carole Dufouil,et al.  No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. , 2005, NeuroImage.

[41]  Daniel L. Rubin,et al.  Network Analysis of Intrinsic Functional Brain Connectivity in Alzheimer's Disease , 2008, PLoS Comput. Biol..

[42]  C. Masters,et al.  Decline in verbal memory in non-demented older adults , 2007, Journal of clinical and experimental neuropsychology.

[43]  A. M. Saunders,et al.  Apolipoprotein E ϵ4 allele and hippocampal volume in twins with normal cognition , 1997, Neurology.

[44]  J. Babb,et al.  Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis. , 2002, AJNR. American journal of neuroradiology.

[45]  A. Convit,et al.  Specific Hippocampal Volume Reductions in Individuals at Risk for Alzheimer’s Disease , 1997, Neurobiology of Aging.

[46]  R. Mayeux,et al.  Hippocampal and entorhinal atrophy in mild cognitive impairment , 2007, Neurology.

[47]  S. Resnick,et al.  Longitudinal changes in verbal memory in older adults , 2003, Neurology.

[48]  L. Thal,et al.  Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease. , 1999, Psychology and aging.

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

[50]  A. Dale,et al.  Whole Brain Segmentation Automated Labeling of Neuroanatomical Structures in the Human Brain , 2002, Neuron.

[51]  H C Charles,et al.  Impact of APOE in mild cognitive impairment , 2004, Neurology.

[52]  A Pfefferbaum,et al.  Heritability of hippocampal size in elderly twin men: Equivalent influence from genes and environment , 2001, Hippocampus.

[53]  A M Dale,et al.  Size does matter in the long run , 2004, Neurology.

[54]  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.

[55]  E G Tangalos,et al.  Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer's disease but not in healthy control subjects , 1998, Neurology.

[56]  F. Fazekas,et al.  Apolipoprotein E4allele in the normal elderly: neuropsychologic and brain MRI correlates , 1996, Clinical genetics.

[57]  R. Parasuraman,et al.  Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults , 2006, Cognitive, affective & behavioral neuroscience.

[58]  J. Wesson Ashford,et al.  ApoE genotype accounts for the vast majority of AD risk and AD pathology , 2004, Neurobiology of Aging.

[59]  D. Kennedy,et al.  Magnetic resonance technology in human brain science: Blueprint for a program based upon morphometry , 1989, Brain and Development.

[60]  Lars T Westlye,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. , 2008, Neurobiology of aging.

[61]  Jonas Persson,et al.  Reduced hippocampal volume in non-demented carriers of the apolipoprotein E ɛ4: Relation to chronological age and recognition memory , 2006, Neuroscience Letters.

[62]  Adolf Pfefferbaum,et al.  Brain structure in men remains highly heritable in the seventh and eighth decades of life☆ , 2000, Neurobiology of Aging.

[63]  Nikos Makris,et al.  Thalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis , 1999, Biological Psychiatry.

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

[65]  J. Franklin,et al.  The elements of statistical learning: data mining, inference and prediction , 2005 .

[66]  J. Jolles,et al.  Cognitive Functioning in Healthy Older Adults Aged 64–81: A Cohort Study into the Effects of Age, Sex, and Education , 2007, Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition.

[67]  M. Borga,et al.  Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: The Göteborg MCI study , 2008, Journal of the Neurological Sciences.

[68]  D A Bennett,et al.  Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer's disease , 2000, Hippocampus.

[69]  K. Hornik,et al.  party : A Laboratory for Recursive Partytioning , 2009 .

[70]  D A Grayson,et al.  Hippocampal size and memory function in the ninth and tenth decades of life: the Sydney Older Persons Study , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[71]  Richard Camicioli,et al.  Independent predictors of cognitive decline in healthy elderly persons. , 2002, Archives of neurology.

[72]  C. Jack,et al.  Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial , 2002, Journal of Molecular Neuroscience.