Neuroimaging of White Matter in Aging and Dementia

Clinical neuroscientists have focused increasing attention on white matter connections in the brain and on the effects of aging and disease on these connections. Recent advances in magnetic resonance imaging (MRI) analysis have given researchers new tools for quantifying and visualizing white matter to better relate white matter structure and function. The goals of this article are (a) to acquaint the reader with both established and newer methods for imaging and quantifying white matter anatomy and pathology; and (b) to review recent findings on white matter pathology in aging and dementia. Computer-assisted quantification appears to offer better statistical power than visual rating scales for detecting these relationships. New MR modalities such as diffusion imaging can detect white matter abnormalities not shown with conventional acquisition sequences. These newer techniques hold promise for early detection of disease and for delineating functional connections between brain areas.

[1]  Jean-François Mangin,et al.  Monitoring Disease Progression in CADASIL With Diffusion Magnetic Resonance Imaging: A Study With Whole Brain Histogram Analysis , 2002, Stroke.

[2]  Robert Barber,et al.  A neuropathological study of periventricular white matter hyperintensities in major depression. , 2003, Journal of affective disorders.

[3]  N. Geschwind Disconnexion syndromes in animals and man. II. , 1965, Brain : a journal of neurology.

[4]  V. Hachinski,et al.  Leukoaraiosis: reifying rarefaction. , 2000, Archives of neurology.

[5]  L. Pantoni,et al.  White matter changes: the clinical consequences in the aging population. , 2000, Journal of neural transmission. Supplementum.

[6]  D. DeLong,et al.  The effect of aging on the apparent diffusion coefficient of normal-appearing white matter. , 2000, AJR. American journal of roentgenology.

[7]  N. Schuff,et al.  MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer’s disease , 2001, Neurology.

[8]  A. Auchus,et al.  Single stroke dementia Insights from 12 cases in Singapore , 2002, Journal of the Neurological Sciences.

[9]  Matthias J. Müller,et al.  Ultrastructural Hippocampal and White Matter Alterations in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study , 2004, Dementia and Geriatric Cognitive Disorders.

[10]  M Takasaki,et al.  Increased water diffusion in cerebral white matter in Alzheimer's disease. , 1997, Gerontology.

[11]  E. Martin,et al.  Successful methylphenidate treatment of apathy after subcortical infarcts. , 1995, The Journal of neuropsychiatry and clinical neurosciences.

[12]  M. Witter,et al.  Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions , 2003, Neuropsychologia.

[13]  Oili Salonen,et al.  Leukoaraiosis, Ischemic Stroke, and Normal White Matter on Diffusion-Weighted MRI , 2002, Stroke.

[14]  Domenico Inzitari,et al.  Leukoaraiosis: An Independent Risk Factor for Stroke? , 2003, Stroke.

[15]  T. Heeren,et al.  Is apathy in late-life depressive illness related to age-at-onset, cognitive function or vascular risk? , 2004, International Psychogeriatrics.

[16]  K. Krishnan,et al.  MRI-defined vascular depression. , 1997, The American journal of psychiatry.

[17]  岩本俊彦 Leuko-araiosis と血管性痴呆 , 1996 .

[18]  S. Engelborghs,et al.  Loss of psychic self-activation after paramedian bithalamic infarction. , 2000, Stroke.

[19]  Jeff Victoroff,et al.  White Matter Lesions, Quantitative Magnetic Resonance Imaging, and Dementia , 2002, Alzheimer disease and associated disorders.

[20]  R. Buxton Diffusion and the MR Signal , 2002 .

[21]  M. Weiner,et al.  Executive dysfunction in subcortical ischaemic vascular disease , 2002, Journal of neurology, neurosurgery, and psychiatry.

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

[23]  B L Miller,et al.  Behavioral disorders in the frontal and temporal variants of frontotemporal dementia , 2004, Neurology.

[24]  P. Sachdev,et al.  Reliability and validity of ratings of signal hyperintensities on MRI by visual inspection and computerised measurement , 1999, Psychiatry Research: Neuroimaging.

[25]  S. Rose,et al.  Loss of connectivity in Alzheimer's disease: an evaluation of white matter tract integrity with colour coded MR diffusion tensor imaging , 2000, Journal of neurology, neurosurgery, and psychiatry.

[26]  K. Krishnan Biological risk factors in late life depression , 2002, Biological Psychiatry.

[27]  J. Frank,et al.  The role of nonconventional magnetic resonance imaging techniques in demyelinating disorders , 2003, Current neurology and neuroscience reports.

[28]  C. Marsden,et al.  The behavioural and motor consequences of focal lesions of the basal ganglia in man. , 1994, Brain : a journal of neurology.

[29]  M. Filippi,et al.  White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging , 2002, Journal of neurology, neurosurgery, and psychiatry.

[30]  David Shera,et al.  Age-related, regional, hemispheric, and medial-lateral differences in myelin integrity in vivo in the normal adult brain. , 2004, AJNR. American journal of neuroradiology.

[31]  David H. Miller,et al.  Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain , 2004, Annals of neurology.

[32]  James A. Mortimer,et al.  Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply , 1997 .

[33]  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.

[34]  M. Kaste,et al.  Diffusion-weighted MR imaging in normal human brains in various age groups. , 2002, AJNR. American journal of neuroradiology.

[35]  H. Hanyu,et al.  Magnetization transfer measurements of the hippocampus in the early diagnosis of Alzheimer's disease , 2001, Journal of the Neurological Sciences.

[36]  John Breitner,et al.  Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. , 2003, Archives of neurology.

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

[38]  José M Ferro,et al.  Age-related white matter changes and cognitive impairment , 2002, Journal of the Neurological Sciences.

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

[40]  E. Mori,et al.  Impact of White Matter Changes on Clinical Manifestation of Alzheimer’s Disease: A Quantitative Study , 2000, Stroke.

[41]  R. Leiguarda,et al.  Neuropsychological, psychiatric, and cerebral perfusion correlates of leukoaraiosis in Alzheimer’s disease , 1997, Journal of neurology, neurosurgery, and psychiatry.

[42]  Hugh S Markus,et al.  Frequency of subclinical lacunar infarcts in ischemic leukoaraiosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. , 2003, AJNR. American journal of neuroradiology.

[43]  A Capdevila,et al.  Leuko-araiosis on magnetic resonance imaging and speed of mental processing. , 1990, Archives of neurology.

[44]  K. Krishnan,et al.  MRI subcortical hyperintensities in old and very old depressed outpatients The important role of age in late-life depression , 2002, Journal of the Neurological Sciences.

[45]  若菜 勢津 Fiber tract-based atlas of human white matter anatomy , 2006 .

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

[47]  M. Hennerici,et al.  Are gait disturbances and white matter degeneration early indicators of vascular dementia? , 1994, Dementia.

[48]  D. Laidlaw,et al.  MR microscopy of transgenic mice that spontaneously acquire experimental allergic encephalomyelitis , 1998, Magnetic resonance in medicine.

[49]  F. Fazekas,et al.  Pathologic correlates of incidental MRI white matter signal hyperintensities , 1993, Neurology.

[50]  David H. Laidlaw,et al.  Visualizing Diffusion Tensor MR Images Using Streamtubes and Streamsurfaces , 2003, IEEE Trans. Vis. Comput. Graph..

[51]  N. De Stefano,et al.  Age-related changes in conventional, magnetization transfer, and diffusion-tensor MR imaging findings: study with whole-brain tissue histogram analysis. , 2003, Radiology.

[52]  R. Bammer Basic principles of diffusion-weighted imaging. , 2003, European journal of radiology.

[53]  N. Schuff,et al.  Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer's disease , 2001, Journal of neurology, neurosurgery, and psychiatry.

[54]  Werner Hacke,et al.  Imaging-Based Decision Making in Thrombolytic Therapy for Ischemic Stroke: Present Status , 2003, Stroke.

[55]  L. Vlahos,et al.  Brain MR post-gadolinium contrast in multiple sclerosis: the role of magnetization transfer and image subtraction in detecting more enhancing lesions , 2004, Neuroradiology.

[56]  R. Barber,et al.  The Association between White Matter Lesions on Magnetic Resonance Imaging and Noncognitive Symptoms , 2000, Annals of the New York Academy of Sciences.

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

[58]  T. Brannelly Negotiating ethics in dementia care , 2006 .

[59]  I. Deary,et al.  Brain white matter lesions detected by magnetic resonance [correction of resosnance] imaging are associated with balance and gait speed. , 2003, Journal of neurology, neurosurgery, and psychiatry.

[60]  L. Fried,et al.  Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. , 1996, Stroke.

[61]  Geoffrey A. Donnan,et al.  Advances in Penumbra Imaging with MR , 2004, Cerebrovascular Diseases.

[62]  A. Bogucki,et al.  Evaluation of dementia in subcortical arteriosclerotic encephalopathy (Binswanger's disease) , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[63]  天野 康雄,et al.  骨髄病変に対する脂肪抑制法併用 magnetization transfer imaging の検討 , 1997 .

[64]  C. Jack,et al.  DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment , 2005, Neurology.

[65]  B L Miller,et al.  Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect. , 1992, Archives of neurology.

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

[67]  G. Alexopoulos,et al.  'Vascular depression' hypothesis. , 1997, Archives of general psychiatry.

[68]  Matthijs Oudkerk,et al.  Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam scan study , 2002, Annals of neurology.

[69]  R Stewart,et al.  Cerebral white matter lesions and subjective cognitive dysfunction: The Rotterdam Scan Study , 2001, Neurology.

[70]  W. M. van der Flier,et al.  Interaction of medial temporal lobe atrophy and white matter hyperintensities in AD , 2004, Neurology.

[71]  T. Tatemichi,et al.  Strategic infarcts in vascular dementia. A clinical and brain imaging experience. , 1995, Arzneimittel-Forschung.

[72]  T. Kurki,et al.  Relationship between vascular factors and white matter low attenuation of the brain , 1993, Acta neurologica Scandinavica.

[73]  P. Thomas,et al.  [Loss of motivation and frontal dysfunction. Role of the white matter change]. , 2004, L'Encephale.

[74]  Ronald A Cohen,et al.  Computer-Mediated Measurement and Subjective Ratings of White Matter Hyperintensities in Vascular Dementia: Relationships to Neuropsychological Performance , 2004, The Clinical neuropsychologist.

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

[76]  R. Schmidt,et al.  Comparison of magnetic resonance imaging in Alzheimer's disease, vascular dementia and normal aging. , 1992, European neurology.

[77]  J. Jolles,et al.  Quantitative analysis of magnetization transfer images of the brain: Effect of closed head injury, age and sex on white matter , 1999, Magnetic Resonance in Medicine.

[78]  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.

[79]  J. Cummings,et al.  Anatomic and Behavioral Aspects of Frontal‐Subcortical Circuits a , 1995, Annals of the New York Academy of Sciences.

[80]  Wang Min,et al.  Leuko araiosis , 2006 .

[81]  H Merskey,et al.  Leuko-Araiosis: An Ancient Term for a New Problem , 1986, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[82]  S. Wakana,et al.  Fiber tract-based atlas of human white matter anatomy. , 2004, Radiology.

[83]  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.

[84]  Howard Chertkow,et al.  Regional magnetization transfer ratio changes in mild cognitive impairment , 2002, Magnetic resonance in medicine.

[85]  Robert Sawyer,et al.  Core Text of Neuroanatomy, 4th Ed. , 1992, Neurology.

[86]  R. Grossman,et al.  Magnetization transfer effects in MR-detected multiple sclerosis lesions: comparison with gadolinium-enhanced spin-echo images and nonenhanced T1-weighted images. , 1995, AJNR. American journal of neuroradiology.

[87]  C. Hazif-Thomas,et al.  Démotivation et dysfonctionnements frontaux chez le sujet âgé : place de la leucoaraïose , 2002 .

[88]  G J Barker,et al.  Magnetisation transfer ratio of normal brain white matter: a normative database spanning four decades of life. , 1997, Journal of neurology, neurosurgery, and psychiatry.

[89]  R. Luypaert,et al.  Imaging tutorial: differential diagnosis of bright lesions on diffusion-weighted MR images. , 2003, Radiographics : a review publication of the Radiological Society of North America, Inc.

[90]  D. LeBihan,et al.  Diffusion Tensor Imaging Study of Subcortical Gray Matter in CADASIL , 2001, Stroke.

[91]  H. Gertz,et al.  Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study , 2000, International journal of geriatric psychiatry.

[92]  C. Sotak,et al.  The role of diffusion tensor imaging in the evaluation of ischemic brain injury – a review , 2002, NMR in biomedicine.

[93]  Derek K. Jones,et al.  Normal-appearing white matter in ischemic leukoaraiosis: A diffusion tensor MRI study , 2001, Neurology.

[94]  P. Scheltens,et al.  A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging , 1993, Journal of the Neurological Sciences.

[95]  C. Filley The Behavioral Neurology of White Matter , 2001 .

[96]  T. Bekinschtein,et al.  White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer’s disease , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[97]  D. Le Bihan,et al.  Clinical severity in CADASIL related to ultrastructural damage in white matter: in vivo study with diffusion tensor MRI. , 1999, Stroke.

[98]  R G Robinson,et al.  Post‐stroke depressive disorders: a follow‐up study of 103 patients. , 1982, Stroke.

[99]  A. Snyder,et al.  Quantitative diffusion-tensor anisotropy brain MR imaging: normative human data and anatomic analysis. , 1999, Radiology.

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

[101]  I. Appollonio,et al.  Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease , 2002, Movement disorders : official journal of the Movement Disorder Society.

[102]  C. Jack,et al.  Mild cognitive impairment and Alzheimer disease: regional diffusivity of water. , 2001, Radiology.

[103]  M. Moseley Diffusion tensor imaging and aging – a review , 2002, NMR in biomedicine.

[104]  F. Fazekas,et al.  The spectrum of age-associated brain abnormalities: their measurement and histopathological correlates. , 1998, Journal of neural transmission. Supplementum.

[105]  D. Mungas Contributions of Subcortical Lacunar Infarcts to Cognitive Impairment in Older Persons , 2005 .

[106]  P. Basser,et al.  Diffusion tensor MR imaging of the human brain. , 1996, Radiology.

[107]  O Salonen,et al.  Variable agreement between visual rating scales for white matter hyperintensities on MRI. Comparison of 13 rating scales in a poststroke cohort. , 1997, Stroke.

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

[109]  E P Steinberg,et al.  Magnetic resonance abnormalities and cardiovascular disease in older adults. The Cardiovascular Health Study. , 1994, Stroke.

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

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

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

[113]  SONG ZHANG,et al.  Diffusion Tensor MRI Visualization , 2005, The Visualization Handbook.

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

[115]  P. Scheltens,et al.  White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging , 1999, Journal of neurology, neurosurgery, and psychiatry.

[116]  P. Scheltens,et al.  Measuring progression of cerebral white matter lesions on MRI , 2004, Neurology.

[117]  M. Bastin,et al.  Visualization and analysis of white matter structural asymmetry in diffusion tensor MRI data , 2004, Magnetic resonance in medicine.

[118]  M. Kameyama,et al.  White Matter Lesions and Dementia MRI‐Pathological Correlation , 2002, Annals of the New York Academy of Sciences.

[119]  Karen J. Ferguson,et al.  White matter hyperintensities and rating scales—observer reliability varies with lesion load , 2004, Journal of Neurology.

[120]  B L Miller,et al.  Cerebral blood flow correlates of apathy in Alzheimer disease. , 1996, Archives of neurology.

[121]  Volker A Coenen,et al.  Imaging of postthalamic visual fiber tracts by anisotropic diffusion weighted MRI and diffusion tensor imaging: principles and applications. , 2004, European journal of radiology.

[122]  M. Carpenter,et al.  The Essentials of Neuroanatomy , 1978 .

[123]  J. Grace,et al.  A Review of Rating Scales for Measuring Behavior Change Due to Frontal Systems Damage , 2005, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology.

[124]  M Takasaki,et al.  Magnetization transfer measurements of the hippocampus in patients with Alzheimer's disease, vascular dementia, and other types of dementia. , 2000, AJNR. American journal of neuroradiology.

[125]  Derek K. Jones,et al.  Diffusion‐tensor MRI: theory, experimental design and data analysis – a technical review , 2002 .

[126]  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.

[127]  M Filippi,et al.  A Magnetization Transfer Imaging Study of Normal-Appearing White Matter in Multiple Sclerosis , 1995, Neurology.

[128]  Scott T. Grafton,et al.  A method to improve interrater reliability of visual inspection of brain MRI scans in dementia , 1994, Neurology.

[129]  A. Alavi,et al.  MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. , 1987, AJR. American journal of roentgenology.

[130]  A. Hofman,et al.  Cerebral white matter lesions, vascular risk factors, and cognitive function in a population‐based study , 1994, Neurology.

[131]  O Almkvist,et al.  Visual Rating of Age-Related White Matter Changes on Magnetic Resonance Imaging: Scale Comparison, Interrater Agreement, and Correlations With Quantitative Measurements , 2003, Stroke.

[132]  K. Krishnan,et al.  Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression , 2004, Biological Psychiatry.

[133]  George S Alexopoulos,et al.  Frontal white matter microstructure and treatment response of late-life depression: a preliminary study. , 2002, The American journal of psychiatry.

[134]  Haruyasu Yamada,et al.  Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis , 2002, Neurobiology of Aging.

[135]  P. Basser,et al.  In vivo fiber tractography using DT‐MRI data , 2000, Magnetic resonance in medicine.

[136]  D. Moser,et al.  White Matter Hyperintensities and Cognition , 2005 .

[137]  M. Kaste,et al.  MRI correlates of executive dysfunction in patients with ischaemic stroke , 2003, European journal of neurology.

[138]  C. Reynolds,et al.  Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression. , 2001, The American journal of psychiatry.

[139]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. , 1997, JAMA.

[140]  Joseph James Duffy,et al.  Apathy: a treatable syndrome. , 1995, The Journal of neuropsychiatry and clinical neurosciences.

[141]  M. Rafii,et al.  Agrin and microvascular damage in Alzheimer's disease , 2000, Neurobiology of Aging.

[142]  R. Marin,et al.  Apathy: a neuropsychiatric syndrome. , 1991, The Journal of neuropsychiatry and clinical neurosciences.

[143]  P J Elliott,et al.  Interactive region and volume growing for segmenting volumes in MR and CT images. , 1994, Medical informatics = Medecine et informatique.

[144]  W. Longstreth Brain abnormalities in the elderly: frequency and predictors in the United States (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group. , 1998, Journal of neural transmission. Supplementum.

[145]  D. Leys,et al.  Relevance of White Matter Changes to Pre‐ and Poststroke Dementia , 2000, Annals of the New York Academy of Sciences.

[146]  Yasuo Nishihara,et al.  Why do frontal lobe symptoms predominate in vascular dementia with lacunes? , 1986, Neurology.

[147]  G. Press,et al.  Methods for measuring brain morphologic features on magnetic resonance images. Validation and normal aging. , 1990, Archives of neurology.

[148]  E. Gillard,et al.  MRI and neuropsychological differences in early- and late-life-onset geriatric depression , 1996, Neurology.

[149]  P. Boyle,et al.  Treating Apathy in Alzheimer’s Disease , 2003, Dementia and Geriatric Cognitive Disorders.

[150]  P. Basser,et al.  Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. , 1996, Journal of magnetic resonance. Series B.

[151]  B Horwitz,et al.  White matter hyperintensities in dementia of Alzheimer's type and in healthy subjects without cerebrovascular risk factors. A magnetic resonance imaging study. , 1990, Archives of neurology.

[152]  T. Huisman Diffusion-weighted imaging: basic concepts and application in cerebral stroke and head trauma , 2003, European Radiology.

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

[154]  G. Scotti,et al.  Quantification of tissue damage in AD using diffusion tensor and magnetization transfer MRI , 2001, Neurology.

[155]  Takashi Inoue,et al.  Selective reduction of diffusion anisotropy in white matter of Alzheimer disease brains measured by 3.0 Tesla magnetic resonance imaging , 2002, Neuroscience Letters.

[156]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. , 1997, JAMA.

[157]  K. Matsubayashi,et al.  Incidental Brain Lesions on Magnetic Resonance Imaging and Neurobehavioral Functions in the Apparently Healthy Elderly , 1992, Stroke.

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

[159]  K. Krishnan,et al.  Subcortical hyperintensities on brain magnetic resonance imaging: A comparison between late age onset and early onset elderly depressed subjects , 1991, Neurobiology of Aging.

[160]  Wilkins,et al.  European Journal of Neurology , 1998 .

[161]  S. Salloway,et al.  Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease , 2002, Journal of the Neurological Sciences.

[162]  C. Mehringer,et al.  Clinical and neuroradiologic features associated with chronicity in late-life depression. , 1999, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[163]  W. M. van der Flier,et al.  Magnetization transfer imaging in normal aging, mild cognitive impairment, and Alzheimer's disease , 2002, Annals of neurology.

[164]  D. Le Bihan,et al.  Diffusion tensor imaging: Concepts and applications , 2001, Journal of magnetic resonance imaging : JMRI.

[165]  M W Weiner,et al.  A serial study of new MS lesions and the white matter from which they arise , 1998, Neurology.

[166]  K. Haaland,et al.  Clinical significance of MRI white matter lesions in the elderly , 1989, Neurology.

[167]  H S Markus,et al.  Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[168]  David H. Laidlaw,et al.  Visualizing diffusion tensor images of the mouse spinal cord , 1998 .

[169]  S. Kobayashi,et al.  Poststroke apathy and regional cerebral blood flow. , 1997, Stroke.

[170]  Sheng-Kwei Song,et al.  Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition , 2004, Neurobiology of Disease.

[171]  V. Hachinski,et al.  Clinical correlates of white-matter changes on magnetic resonance imaging scans of the brain. , 1991, Archives of neurology.

[172]  Daniel A. Rüfenacht,et al.  ADC mapping of the aging frontal lobes in mild cognitive impairment , 2004, Neuroradiology.

[173]  Carl-Fredrik Westin,et al.  Processing and visualization for diffusion tensor MRI , 2002, Medical Image Anal..

[174]  M. Modic,et al.  Magnetic resonance imaging in vascular dementia , 1987, Neurology.

[175]  R. Grossman,et al.  Magnetization transfer imaging of periventricular hyperintense white matter in the elderly. , 1995, AJNR. American journal of neuroradiology.

[176]  W. Meier-Ruge,et al.  Age‐Related White Matter Atrophy in the Human Brain , 1992, Annals of the New York Academy of Sciences.

[177]  J. E. Tanner,et al.  Spin diffusion measurements : spin echoes in the presence of a time-dependent field gradient , 1965 .

[178]  N. Geschwind Disconnexion syndromes in animals and man. I. , 1965, Brain : a journal of neurology.

[179]  J. Adair,et al.  Diffusion-weighted MRI in vascular dementia , 2000, Neurology.

[180]  D. Leys,et al.  Periventricular and white matter magnetic resonance imaging hyperintensities do not differ between Alzheimer's disease and normal aging. , 1990, Archives of neurology.

[181]  Reinhold Schmidt,et al.  Pathophysiologic Mechanisms in the Development of Age-Related White Matter Changes of the Brain , 1998, Dementia and Geriatric Cognitive Disorders.

[182]  F. Barkhof,et al.  Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging , 1995, Neurology.

[183]  White matter lesions are associated with cortical atrophy more than entorhinal and hippocampal atrophy , 2006 .

[184]  R. Floris,et al.  Diffusion-weighted MR Imaging: clinical applications in neuroradiology. , 2003, La Radiologia medica.

[185]  M S Mega,et al.  Frontal-subcortical circuits and neuropsychiatric disorders. , 1994, The Journal of neuropsychiatry and clinical neurosciences.

[186]  K. Krishnan,et al.  Organic bases of depression in the elderly. , 1991, Annual review of medicine.

[187]  R. Henkelman,et al.  Magnetization transfer in MRI: a review , 2001, NMR in biomedicine.

[188]  I. Appollonio,et al.  Unconventional affective symptoms and executive functions after stroke in the elderly. , 2004, Archives of gerontology and geriatrics. Supplement.

[189]  D. Le Bihan,et al.  Visualizing the Neural Bases of a Disconnection Syndrome with Diffusion Tensor Imaging , 2002, Journal of Cognitive Neuroscience.

[190]  M W Weiner,et al.  Magnetization transfer ratio of white matter hyperintensities in subcortical ischemic vascular dementia. , 1999, AJNR. American journal of neuroradiology.

[191]  Anand R. Kumar,et al.  Neuropsychiatric Correlates of Vascular Injury , 2005 .

[192]  Maria Assunta Rocca,et al.  Evidence of subtle gray-matter pathologic changes in healthy elderly individuals with nonspecific white-matter hyperintensities. , 2003, Archives of neurology.

[193]  P. Murali Doraiswamy,et al.  Magnetic resonance findings in patients with early-onset Alzheimer's disease , 1991, Biological Psychiatry.