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Contemplating Alzheimer’s Disease and the Contribution of White Matter Hyperintensities

  • Adam M. Brickman
Dementia (KS Marder, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dementia

Abstract

As the older adult segment of the population increases, Alzheimer’s disease (AD) has emerged as a significant public health epidemic. Over the past 3 decades, advances in the understanding of the biology of AD have led to a somewhat unified hypothesis of disease pathogenesis that emphasizes the precipitating role of beta amyloid protein. However, several lines of evidence suggest that multiple pathologies are necessary for clinical manifestation of the disease. Our focus over the past several years has been on the contribution of small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on magnetic resonance imaging, to AD. White matter hyperintensity volume, particularly in parietal regions, is elevated among individuals with and at risk for AD, predicts future diagnosis of AD, predicts the rate of progression of cognitive symptoms among individuals with AD, and increases over time among individuals destined to develop AD. White matter hyperintensities may represent an independent source of impairment and/or may interact more fundamentally with “primary” AD pathology. Future work should focus on more inclusive models of that better define “normal” vs “pathological” aging.

Keywords

Alzheimer’s disease White matter hyperintensities Cerebrovascular disease 

Notes

Acknowledgment

Work presented here was supported in part by grants from the National Institutes of Health (AG034189, AG037212, AG028786, AG029949, AG024708), Alzheimer’s Association, Mary E. Groff Surgical Medical Research and Education Charitable Trust, and Columbia University.

Compliance with Ethics Guidelines

Conflict of Interest

Adam M. Brickman has received travel/accommodations expenses covered or reimbursed from the International Neuropsychological Society (as a board member) and the Alzheimer's Association.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Jack Jr CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119–28. This paper presents a comprehensive hypothesis regarding the cascade of biological events that contribute to the pathogensis of AD.PubMedCrossRefGoogle Scholar
  2. 2.
    • Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–16. This paper is an updated version of a pathogenic model for Alzheimer’s disease.PubMedCrossRefGoogle Scholar
  3. 3.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2010;7:280–92.CrossRefGoogle Scholar
  4. 4.
    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2010;7:270–9.CrossRefGoogle Scholar
  5. 5.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.PubMedCrossRefGoogle Scholar
  6. 6.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2010;7:263–9.CrossRefGoogle Scholar
  7. 7.
    Sperling R, Donohue M, Aisen P. The A4 trial: anti-amyloid treatment of asymptomatic Alzheimer’s disease. Alzheimers Dement. 2012;8(Suppl):425–6.CrossRefGoogle Scholar
  8. 8.
    Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509–17.PubMedCrossRefGoogle Scholar
  9. 9.
    Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006;67:446–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009;106:6820–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, et al. PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. Brain. 2007;130(Pt 10):2607–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Vellas B, Carrillo MC, Sampaio C, Brashear HR, Siemers E, Hampel H, et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement. 2013;9:438–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Rodrigue KM, Kennedy KM, Devous Sr MD, Rieck JR, Hebrank AC, Diaz-Arrastia R, et al. beta-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology. 2012;78:387–95.PubMedCrossRefGoogle Scholar
  14. 14.
    Bourgeat P, Chetelat G, Villemagne VL, Fripp J, Raniga P, Pike K, et al. Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology. 2010;74:121–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, et al. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci. 2009;29:12686–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, et al. Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain. 2009;132(Pt 5):1310–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain. 2007;130(Pt 11):2837–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010;31:1275–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121:171–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. 2008;60:534–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Pavlopoulos E, Jones S, Kosmidis S, Close M, Kim C, Kovalerchik O, et al. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med. 2013;5:200ra115.PubMedCrossRefGoogle Scholar
  23. 23.
    Brickman AM, Stern Y, Small SA. Hippocampal subregions differentially associate with standardized memory tests. Hippocampus. 2011;21:923–8.PubMedGoogle Scholar
  24. 24.
    Castellani RJ, Perry G. Pathogenesis and disease-modifying therapy in Alzheimer’s disease: the flat line of progress. Arch Med Res. 2012;43:694–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(Pt 9):2697–706.PubMedCrossRefGoogle Scholar
  26. 26.
    Elkins JS, O’Meara ES, Longstreth Jr WT, Carlson MC, Manolio TA, Johnston SC. Stroke risk factors and loss of high cognitive function. Neurology. 2004;63:793–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31:780–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology. 2001;56:1683–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ (Clinical research ed). 2001;322:1447–51.CrossRefGoogle Scholar
  30. 30.
    Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001;56:42–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R. Measures of adiposity and dementia risk in elderly persons. Arch Neurol. 2007;64:392–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65:545–51.PubMedCrossRefGoogle Scholar
  33. 33.
    Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004;63:1187–92.PubMedCrossRefGoogle Scholar
  34. 34.
    Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol. 2001;154:635–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, et al. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998;51:986–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Helzner EP, Luchsinger JA, Scarmeas N, Cosentino S, Brickman AM, Glymour MM, et al. Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol. 2009;66:343–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10:819–28.PubMedCrossRefGoogle Scholar
  38. 38.
    Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia. Stroke. 2011;42:2672–713.PubMedCrossRefGoogle Scholar
  39. 39.
    Kertesz A, Black SE, Tokar G, Benke T, Carr T, Nicholson L. Periventricular and subcortical hyperintensities on magnetic resonance imaging. Rims, caps, and unidentified bright objects. Arch Neurol. 1988;45:404–8. Arch Neurol. 1988;45:404–8.Google Scholar
  40. 40.
    Román GC. Senile dementia of the binswanger type: a vascular form of dementia in the elderly. JAMA. 1987;258:1782–8.PubMedCrossRefGoogle Scholar
  41. 41.
    DeCarli C, Murphy DG, Tranh M, Grady CL, Haxby JV, Gillette JA, et al. The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology. 1995;45:2077–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Bronge L, Wahlund LO. White matter changes in dementia: does radiology matter? Br J Radiol. 2007;80:S115–20.PubMedCrossRefGoogle Scholar
  43. 43.
    Erten-Lyons D, Woltjer R, Kaye J, Mattek N, Dodge HH, Green S, et al. Neuropathologic basis of white matter hyperintensity accumulation with advanced age. Neurology. 2013;81:977–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Jagust WJ, Zheng L, Harvey DJ, Mack WJ, Vinters HV, Weiner MW, et al. Neuropathological basis of magnetic resonance images in aging and dementia. Ann Neurol. 2008;63:72–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43:1683–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Launer LJ. Epidemiology of white matter lesions. Top Magn Reson Imaging. 2004;15:365–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Gunning-Dixon FM, Brickman AM, Cheng JC, Alexopoulos GS. Aging of cerebral white matter: a review of MRI findings. Int J Geriat Psychiatry. 2009;24:109–17.CrossRefGoogle Scholar
  48. 48.
    Gunning-Dixon FM, Raz N. The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology. 2000;14:224–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Brickman AM, Muraskin J, Zimmerman ME. Structural neuroimaging in Alzheimer’s disease: do white matter hyperintensities matter? Dialog Clin Neurosci. 2009;11:181–90.Google Scholar
  50. 50.
    Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci. 1993;114:7–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR. 1987;149:351–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Brickman AM, Sneed JR, Provenzano FA, Garcon E, Johnert L, Muraskin J, et al. Quantitative approaches for assessment of white matter hyperintensities in elderly populations. Psychiatry Res. 2011;193:101–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Admiraal-Behloul F, Olofesen H, Van den Heuvel DM, Schmitz N, Reiber JH, Van Buchem MA. Fully automated lobe delineation for regional white matter lesion load quantification in a large scale study. Proc Int Soc Magnet Reson Med. 2004:138.Google Scholar
  54. 54.
    • Provenzano FA, Muraskin J, Tosto G, Narkhede A, Wasserman BT, Griffith EY, et al. White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease? JAMA Neurol. 2013;18:1–7. In this paper we showed that both WMH and amyloid are associated with Alzheimer’s disease and that among individuals with evidence of cerebral amyloidosis, those with higher WMH burden were more likely to manifest clinical symptoms.Google Scholar
  55. 55.
    Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, Rosand J, Growdon JH, Greenberg SM. Plasma beta-amyloid an white matter lesions in AD, CI, and cerebral amyloid angiopathy. Neurology. 2006;66:23–9.Google Scholar
  56. 56.
    Tang MX, Cross P, Andrews H, Jacobs DM, Small S, Bell K, et al. Incidence of Alzheimer’s disease in African-Americans, Caribbean Hispanics and Caucasians in northern Manhattan. Neurology. 2001;56:49–56.PubMedCrossRefGoogle Scholar
  57. 57.
    Brickman AM, Schupf N, Manly JJ, Luchsinger JA, Andrews H, Tang MX, et al. Brain morphology in older African Americans, Caribbean Hispanics, and Whites from northern Manhattan. Arch Neurol. 2008;65:1053–61.PubMedCrossRefGoogle Scholar
  58. 58.
    Scheltens P, Barkhof F, Valk J, Algra PR, van der Hoop RG, Nauta J, et al. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Evidence for heterogeneity. Brain. 1992;115(Pt 3):735–48.PubMedCrossRefGoogle Scholar
  59. 59.
    Kalaria RN. The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging. 2000;21:321–30.PubMedCrossRefGoogle Scholar
  60. 60.
    Rezek DL, Morris JC, Fulling KH, Gado MH. Periventricular white matter lucencies in senile dementia of the Alzheimer type and in normal aging. Neurology. 1987;37:1365–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Luchsinger JA, Brickman AM, Reitz C, Cho SJ, Schupf N, Manly JJ, et al. Subclinical cerebrovascular disease in mild cognitive impairment. Neurology. 2009;73:450–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Brickman AM, Provenzano FA, Muraskin J, Guzman VA, Manly JJ, Schupf N, et al. Distribution of MRI-defined white matter hyperintensities in mild cognitive impairment [abstract]. J Int Neuropsychol Soc. 2011;17(S1).Google Scholar
  63. 63.
    Gootjes L, Teipel SJ, Zebuhr Y, Schwarz R, Leinsinger G, Scheltens P, et al. Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer’s disease and healthy aging. Demen Geriat Cognit Dis. 2004;18:180–8.CrossRefGoogle Scholar
  64. 64.
    Meier IB, Manly JJ, Provenzano FA, Hector J, Wasserman BT, Louie K, et al. White matter predictors of cogntiive functioning in older adults. Annual meeting of the International Neuropsychological Society; February, 2011; Boston, MA 2011.Google Scholar
  65. 65.
    Yoshita M, Fletcher E, Harvey D, Ortega M, Martinez O, Mungas DM, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology. 2006;67:2192–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Leys D, Pruvo JP, Parent M, Vermersch P, Soetaert G, Steinling M, et al. Could Wallerian degeneration contribute to “leuko-araiosis” in subjects free of any vascular disorder? J Neurol Neurosurg Psychiatry. 1991;54:46–50.PubMedCrossRefGoogle Scholar
  67. 67.
    Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ, Oudkerk M, et al. Cerebral white matter lesions and the risk of dementia. Arch Neurol. 2004;61:1531–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215–22.PubMedCrossRefGoogle Scholar
  69. 69.
    Wolf H, Ecke GM, Bettin S, Dietrich J, Gertz HJ. Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study. Int J Geriat Psychiat. 2000;15:803–12.CrossRefGoogle Scholar
  70. 70.
    Smith EE, Egorova S, Blacker D, Killiany RJ, Muzikansky A, Dickerson BC, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol. 2008;65:94–100.PubMedCrossRefGoogle Scholar
  71. 71.
    Brickman AM, Provenzano FA, Muraskin J, Manly JJ, Blum S, Apa Z, et al. Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community. Arch Neurol. 2012;69:1621–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Brickman AM, Honig LS, Scarmeas N, Tatarina O, Sanders L, Albert MS, et al. Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease. Arch Neurol. 2008;65:1202–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Wiegman AF, Meier IB, Provenzano FA, Schupf N, Manly JJ, Stern Y, et al. Regional white matter hyperintensity volume and cognition predict death in a multi-ethnic, community cohoort of older adults. J Am Geriatr Soc. 2013.Google Scholar
  74. 74.
    Brickman AM, Zarhodne LB, Guzman VA, Narkhede A, Provenzano FA, Schupf N, et al. Reconsidering harbingers of Alzheimer’s disease: regionally distributed progression of white matter hyperintensities in the community. [In preparation].Google Scholar
  75. 75.
    Brickman AM, Reitz C, Luchsinger JA, Manly JJ, Schupf N, Muraskin J, et al. Long-term blood pressure fluctuation and cerebrovascular disease in an elderly cohort. Arch Neurol. 2010;67:564–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Alosco ML, Brickman AM, Spitznagel MB, Garcia SL, Narkhede A, Griffith EY, et al. Cerebral perfusion is associated with white matter hyperintensities in older adults with heart failure. Congest Heart Fail. 2013;19:E29–34.PubMedCrossRefGoogle Scholar
  77. 77.
    Alosco ML, Brickman AM, Spitznagel MB, Griffith EY, Narkhede A, Raz N, et al. Independent and interactive effects of blood pressure and cardiac function on brain volume and white matter hyperintensities in heart failure. J Am Soc Hypertens. 2013;7:336–43.PubMedCrossRefGoogle Scholar
  78. 78.
    Jefferson AL, Tate DF, Poppas A, Brickman AM, Paul RH, Gunstad J, et al. Lower cardiac output is associated with greater white matter hyperintensities in older adults with cardiovascular disease. J Am Geriatr Soc. 2007;55:1044–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Portet F, Brickman AM, Stern Y, Scarmeas N, Muraskin J, Provenzano FA, et al. Metabolic syndrome and localization of white matter hyperintensities in the elderly population. Alzheimers Dement. 2012;8(5 Suppl):S88–95 e1.PubMedCrossRefGoogle Scholar
  80. 80.
    Brickman AM, Zahra A, Muraskin J, Steffener J, Holland CM, Habeck C, et al. Reduction in cerebral blood flow in areas appearing as white matter hyperintensities on magnetic resonance imaging. Psychiatry Res. 2009;172:117–20.PubMedCrossRefGoogle Scholar
  81. 81.
    Holland CM, Smith EE, Csapo I, Gurol ME, Brylka DA, Killiany RJ, et al. Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke. 2008;39:1127–33.Google Scholar
  82. 82.
    Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C. Cerebral auotregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol. 2002;283:H315–23.Google Scholar
  83. 83.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.PubMedCrossRefGoogle Scholar
  84. 84.
    Schupf N, Tang MX, Fukuyama H, Manly J, Andrews H, Mehta P, et al. Peripheral Abeta subspecies as risk biomarkers of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2008;105:14052–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med. 2003;9:112–22.PubMedGoogle Scholar
  86. 86.
    Weller RO, Cohen NR, Nicoll JA. Cerebrovascular disease and the pathophysiology of Alzheimer’s disease. Implications for therapy. Panminerva Med. 2004;46:239–51.PubMedGoogle Scholar
  87. 87.
    Niwa K, Carlson GA, Iadecola C. Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab. 2000;20:1659–68.PubMedCrossRefGoogle Scholar
  88. 88.
    Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO. Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol. 2003;29:106–17.PubMedCrossRefGoogle Scholar
  89. 89.
    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. Beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–71.PubMedCrossRefGoogle Scholar
  90. 90.
    Maia LF, Vasconcelos C, Seixas S, Magalhaes R, Correia M. Lobar brain hemorrhages and white matter changes: clinical, radiological and laboratorial profiles. Cerebrovasc Dis. 2006;22:155–61.PubMedCrossRefGoogle Scholar
  91. 91.
    Chen YW, Gurol ME, Rosand J, Viswanathan A, Rakich SM, Groover TR, et al. Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy. Neurology. 2006;67:83–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008;65:790–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Meier IB, Narkhede A, Provenzano FA, Luchsinger JA, Manly JJ, Willey JZ, et al. Lobar microbleeds are associated with white matter hyperintensities and memory in older adults [abstract]. J Int Neuropsychol Soc. 2012;18:224–5.Google Scholar
  94. 94.
    Guzman VA, Carmichael OT, Schwarz C, Tosto G, Zimmerman ME, Brickman AM, et al. White matter hyperintensities and amyloid are independently associated with entorhinal cortex volume. Alzheimer’s and Dementia. 2013;9:S124–31.Google Scholar
  95. 95.
    van der Flier WM, Barkhof F, Scheltens P. Shifting paradigms in dementia: toward stratification of diagnosis and treatment using MRI. Ann NY Acad Sci. 2007;1097:215–24.PubMedCrossRefGoogle Scholar
  96. 96.
    Provenzano FA, Cortes ER, Dashnaw S, Brickman AM. Neuroimaging-guided pathological examination of white matter hyperintensities in aging. Annual Meeting of the International Neuropsychological Society; February, 2011; Boston, MA. 2011.Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of NeurologyCollege of Physicians and Surgeons, Columbia UniversityNew YorkUSA

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