White matter lesions in the elderly: Pathophysiological hypothesis on the effect on brain plasticity and reserve

The effect of white matter lesions (WMLs) on the brain of elderly individuals is unclear. Most debate has focused on the clinical effect of WMLs on cognitive impairment. Large cross-sectional and longitudinal clinic- and population-based studies suggest that the effect of WMLs on global cognitive performance is relatively small, only individuals with the most severe degrees of WMLs having clinically relevant effects. Here, we review recent data suggesting that WMLs might affect brain function through impairment of brain plasticity and reserve. The clinical effect consists in inability of the brain to respond to interventions such as psychotropic drug medications or rehabilitative interventions.

[1]  J. O'Brien,et al.  White Matter Lesions in an Unselected Cohort of the Elderly: Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury , 2006, Stroke.

[2]  Jaakko Tuomilehto,et al.  The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. , 2002 .

[3]  A. Tröster,et al.  Risk factors for dementia in Parkinson's disease: effect of education. , 1996, Neuroepidemiology.

[4]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[5]  G. Wilcock,et al.  The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders. , 1997, Age and ageing.

[6]  Massimo Filippi,et al.  The effect of white matter lesions on cognition in the elderly—small but detectable , 2007, Nature Clinical Practice Neurology.

[7]  B. Lu,et al.  Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications , 2005, Trends in Neurosciences.

[8]  G. Frisoni,et al.  Subcortical Vascular Lesions Predict Functional Recovery After Rehabilitation in Patients with L‐Dopa Refractory Parkinsonism , 2004, Journal of the American Geriatrics Society.

[9]  N. Picard-Riéra,et al.  Endogenous adult neural stem cells: Limits and potential to repair the injured central nervous system , 2004, Journal of neuroscience research.

[10]  M. Alberts,et al.  APOE genotype as a risk factor for ischemic cerebrovascular disease , 1999, Neurology.

[11]  J. Cummings,et al.  Cortical Abnormalities Associated With Subcortical Lesions in Vascular Dementia: Clinical and Positron Emission Tomographic Findings , 1995 .

[12]  P. Amouyel,et al.  APOE genotyping and response to drug treatment in Alzheimer's disease , 1997, The Lancet.

[13]  G. Schellenberg,et al.  Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype , 2006, Neurobiology of Aging.

[14]  Jonas Persson,et al.  Reduced functional brain activity response in cognitively intact apolipoprotein E ε4 carriers , 2006 .

[15]  A. Mann,et al.  Risk factors for Alzheimer's disease and dementia , 1994, Neurology.

[16]  P. Sandercock,et al.  Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia? , 2003, Stroke.

[17]  J. Poirier,et al.  Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease , 1998, Neurology.

[18]  A. Malafosse,et al.  Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis , 1996, Journal of the Neurological Sciences.

[19]  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.

[20]  Thomas Arendt,et al.  Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele , 1997, The Journal of Neuroscience.

[21]  A. Hofman,et al.  Regional Variability in the Prevalence of Cerebral White Matter Lesions: An MRI Study in 9 European Countries (CASCADE) , 2005, Neuroepidemiology.

[22]  G. Alexander,et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  N. Henigsberg,et al.  Association of refractory complex partial seizures with a polymorphism of ApoE genotype , 2005, Journal of cellular and molecular medicine.

[24]  H. Imhof,et al.  White matter hyperintensities and chronicity of depression. , 2005, Journal of psychiatric research.

[25]  M. Wasay,et al.  Cerebral White Matter Changes (Leukoaraiosis), Stroke, and Gait Disturbance , 1997, Journal of the American Geriatrics Society.

[26]  Massimo Filippi,et al.  Evidence for Cortical Functional Changes in Patients With Migraine and White Matter Abnormalities on Conventional and Diffusion Tensor Magnetic Resonance Imaging , 2003, Stroke.

[27]  L. Schneider,et al.  Combined Tacrine and Estrogen Replacement Therapy in Patients with Alzheimer's Disease a, b , 1997, Annals of the New York Academy of Sciences.

[28]  S. Golaszewski,et al.  Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. , 2002, Brain : a journal of neurology.

[29]  R. Baloh,et al.  A prospective study of cerebral white matter abnormalities in older people with gait dysfunction , 2001, Neurology.

[30]  Maria Assunta Rocca,et al.  An fMRI study of the motor system in patients with neuropsychiatric systemic lupus erythematosus , 2006, NeuroImage.

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

[32]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[33]  M. Filippi,et al.  Correlations between Structural CNS Damage and Functional MRI Changes in Primary Progressive MS , 2002, NeuroImage.

[34]  M. Albert,et al.  Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD , 2005, Neurology.

[35]  Charles D. Smith,et al.  Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. , 1999, Neurology.

[36]  R B D'Agostino,et al.  The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study , 1995, Neurology.

[37]  A. Hofman,et al.  Plasma amyloid β, apolipoprotein E, lacunar infarcts, and white matter lesions , 2004, Annals of neurology.

[38]  P. Piccini,et al.  White matter hyperintensities in Parkinson's disease. Clinical correlations. , 1995, Archives of neurology.

[39]  Paul M Matthews,et al.  Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis. , 2006, Brain : a journal of neurology.

[40]  Y. Stern.  What is cognitive reserve? Theory and research application of the reserve concept , 2002, Journal of the International Neuropsychological Society.

[41]  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.

[42]  Gerd Kempermann,et al.  Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus , 2006, Neurobiology of Aging.

[43]  Lisa T. Eyler,et al.  Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response , 2007, Neurobiology of Aging.

[44]  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.

[45]  D. Michaelson,et al.  APOE genotype is a major predictor of long-term progression of disability in MS , 2001, Neurology.

[46]  L. Traykov,et al.  Presence or absence of at least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer's disease. , 2002, Pharmacogenetics.

[47]  Sterling C. Johnson,et al.  Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study , 2006, BMC medicine.

[48]  P. Satz.  Brain reserve capacity on symptom onset after brain injury: A formulation and review of evidence for threshold theory. , 1993 .

[49]  Yaakov Stern,et al.  Cognitive reserve and Alzheimer disease. , 2006, Alzheimer disease and associated disorders.

[50]  Evan Fletcher,et al.  White Matter Changes Compromise Prefrontal Cortex Function in Healthy Elderly Individuals , 2006 .

[51]  G. Small,et al.  Specificity of brain activation patterns in people at genetic risk for Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[52]  Gregory G. Brown,et al.  fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease , 2005, Neurology.

[53]  M. Filippi,et al.  Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage , 2002, Annals of neurology.

[54]  W. White,et al.  Preliminary report of a genetic basis for cognitive decline after cardiac operations. The Neurologic Outcome Research Group of the Duke Heart Center. , 1997, The Annals of thoracic surgery.

[55]  Giuseppe Scotti,et al.  A functional magnetic resonance imaging study of patients with secondary progressive multiple sclerosis , 2003, NeuroImage.

[56]  B. Gulanski,et al.  Metrifonate treatment of AD , 1999, Neurology.

[57]  Patrice Boyer,et al.  Neuroplasticity: from MRI to depressive symptoms , 2004, European Neuropsychopharmacology.

[58]  C. Caltagirone,et al.  Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis , 2004, Journal of Neurology.

[59]  T J Sejnowski,et al.  Running enhances neurogenesis, learning, and long-term potentiation in mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[60]  P. Connelly,et al.  Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease , 2005, International journal of geriatric psychiatry.

[61]  R. Martins,et al.  Oestrogen replacement therapy may improve memory functioning in the absence of APOE e4 , 2004 .

[62]  J. Toole,et al.  The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. , 1997, Neuroepidemiology.

[63]  G. Frisoni,et al.  Topographic correspondence between white matter hyperintensities and brain atrophy , 2006, Journal of Neurology.

[64]  W. Greenough,et al.  Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Stephen Smith,et al.  Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. , 2003, Brain : a journal of neurology.

[66]  L. Kuller,et al.  Estrogen use, APOE, and cognitive decline , 2000, Neurology.

[67]  Y. Stern,et al.  APOE related alterations in cerebral activation even at college age , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[68]  G. Alexander,et al.  Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease , 1992, Annals of neurology.

[69]  I. Hickie,et al.  Subcortical hyperintensities on magnetic resonance imaging: Clinical correlates and prognostic significance in patients with severe depression , 1995, Biological Psychiatry.

[70]  Diederick E Grobbee,et al.  Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study , 1995, BMJ.

[71]  C. Fisher.  The arterial lesions underlying lacunes , 1969, Acta Neuropathologica.

[72]  Charles D. Smith,et al.  Women at risk for AD show increased parietal activation during a fluency task , 2002, Neurology.

[73]  G. Winocur,et al.  The relation between brain activity during memory tasks and years of education in young and older adults. , 2005, Neuropsychology.

[74]  K. Krishnan,et al.  The relationship of MRI subcortical hyperintensities to treatment response in a trial of sertraline in geriatric depressed outpatients. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[75]  Eric E. Smith,et al.  Plasma β-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy , 2006, Neurology.

[76]  Guy M McKhann,et al.  Neurobehavioural sequelae of cardiopulmonary b ypass , 1999, The Lancet.

[77]  C. Barnes,et al.  Neural plasticity in the ageing brain , 2006, Nature Reviews Neuroscience.

[78]  J. Mocco,et al.  APOE-ε4 predisposes to cognitive dysfunction following uncomplicated carotid endarterectomy , 2005, Neurology.

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

[80]  P. Froom,et al.  Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury , 1999, Neurology.

[81]  J. Garcìa,et al.  Pathogenesis of leukoaraiosis: a review. , 1997, Stroke.

[82]  P M Matthews,et al.  Evidence for widespread movement-associated functional MRI changes in patients with PPMS , 2002, Neurology.

[83]  B. Tress,et al.  Severe deep white matter lesions and outcome in elderly patients with major depressive disorder: follow up study , 1998, BMJ.

[84]  P. Matthews,et al.  Functional Reorganization of Motor Cortex Increases With Greater Axonal Injury From CADASIL , 2002, Stroke.

[85]  C. Dufouil,et al.  Influence of education on the relationship between white matter lesions and cognition , 2003, Neurology.

[86]  K. Welsh-Bohmer,et al.  APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease , 1998, Nature Genetics.

[87]  Bertrand Audoin,et al.  Modulation of effective connectivity inside the working memory network in patients at the earliest stage of multiple sclerosis , 2005, NeuroImage.

[88]  Giuseppe Scotti,et al.  Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis , 2003, NeuroImage.

[89]  A Hofman,et al.  C-Reactive Protein and Cerebral Small-Vessel Disease: The Rotterdam Scan Study , 2005, Circulation.

[90]  B. Tycko,et al.  Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele). , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[91]  J. Schneider,et al.  Education modifies the relation of AD pathology to level of cognitive function in older persons , 2003, Neurology.

[92]  L. Lannfelt,et al.  Amyloid Aβ40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia , 2000, Neurobiology of Aging.

[93]  My-Van Au Duong,et al.  Structural and functional surrogates of cognitive impairment at the very early stage of multiple sclerosis , 2006, Journal of the Neurological Sciences.

[94]  C. Fisher.  Lacunar strokes and infarcts , 1982, Neurology.

[95]  A. Hofman,et al.  Cerebral white matter lesions and the risk of dementia. , 2004, Archives of neurology.

[96]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[97]  A. Hofman,et al.  Rates and risk factors for dementia and Alzheimer’s disease , 1999, Neurology.

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

[99]  Warren D Taylor,et al.  White matter hyperintensity progression and late-life depression outcomes. , 2003, Archives of general psychiatry.

[100]  H. Geerts,et al.  APOE Genotype: No Influence on Galantamine Treatment Efficacy Nor on Rate of Decline in Alzheimer’s Disease , 2001, Dementia and Geriatric Cognitive Disorders.

[101]  M. Filippi,et al.  Simple and complex movement‐associated functional MRI changes in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis , 2004, Human brain mapping.

[102]  P. Matthews,et al.  White matter lesion progression, brain atrophy, and cognitive decline: The Austrian stroke prevention study , 2005, Annals of neurology.

[103]  C. Marra,et al.  Apolipoprotein E ε4 Allele Differentiates the Clinical Response to Donepezil in Alzheimer’s Disease , 2005, Dementia and Geriatric Cognitive Disorders.

[104]  C. Lyketsos,et al.  Cognitive decline in adulthood: an 11.5-year follow-up of the Baltimore Epidemiologic Catchment Area study. , 1999, The American journal of psychiatry.

[105]  Yi-Ching Lee,et al.  Amyloid-β at sublethal level impairs BDNF-induced arc expression in cortical neurons , 2006, Neuroscience Letters.

[106]  J. Haines,et al.  Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. , 2002, American journal of human genetics.

[107]  C. Lustig,et al.  Prefrontal activation patterns in subjects at risk for Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[108]  R. D'Agostino,et al.  Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. , 2006, Archives of neurology.