Cerebral microbleeds as a biomarker in Alzheimer's disease? A review in the field

Biomarkers in Medicine

Volumn 10, Issue 1, 2016, Pages 9-18

  Shams, Sara ^a   Wahlund, Lars Olof ^a,b  

^a KAROLINSKA INSTITUTE   (Sweden)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Alzheimer's disease; amyloid; apolipoprotein allele; biomarkers; cerebral microbleeds; cerebrospinal fluid; MRI; small vessel disease

Indexed keywords

ACETYLSALICYLIC ACID; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; APOLIPOPROTEIN E4; BAPINEUZUMAB; BIOLOGICAL MARKER; DIPEPTIDYL CARBOXYPEPTIDASE; FLORBETAPIR F 18; MULTIDRUG RESISTANCE PROTEIN; TAU PROTEIN; APOLIPOPROTEIN E;

ALLELE; ALZHEIMER DISEASE; BRAIN HEMORRHAGE; CARDIOVASCULAR RISK; DEMENTIA; DISEASE ASSOCIATION; DISEASE COURSE; EDEMA; GENOTYPE; HUMAN; NEUROIMAGING; NUCLEAR MAGNETIC RESONANCE IMAGING; PHASE 2 CLINICAL TRIAL (TOPIC); POSITRON EMISSION TOMOGRAPHY; PREVALENCE; PROTEIN CEREBROSPINAL FLUID LEVEL; REVIEW; RISK FACTOR; SYSTEMATIC REVIEW; VASCULAR AMYLOIDOSIS; VASOGENIC EDEMA; CEREBRAL HEMORRHAGE; COMPLICATION; GENETICS;

ALZHEIMER DISEASE; APOLIPOPROTEINS E; BIOMARKERS; CEREBRAL HEMORRHAGE; HUMANS; PREVALENCE; RISK FACTORS;

EID: 84951832103     PISSN: 17520363     EISSN: 17520371     Source Type: Journal    
DOI: 10.2217/bmm.15.101     Document Type: Review

References (96)

1. Scharf J, Bräuherr E, Forsting M, Sartor K. Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage. Neuroradiology 36(7), 504-508 (1994).
2. Fazekas F, Kleinert R, Roob G et al. Histopathologic analysis of foci of signal loss on gradient-echo T2∗-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am. J. Neuroradiol. 20(4), 637-642 (1999).
3. Shoamanesh A, Kwok CS, Benavente O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc. Dis. Basel Switz. 32(6), 528-534 (2011).
4. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9(7), 689-701 (2010).
5. Cerebral Microbleeds: Pathophysiology to Clinical Practice (1st Editition). Werring DJ (Ed.). Cambridge University Press, UK.
6. Charidimou A. Elderly and forgetful with transient neurological spells: a story of two amyloids? J. Neurol. Sci. 351(1-2), 1-2 (2015).
7. Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J. Neurol. Neurosurg. Psychiatry. 83(2), 124-137 (2012).
8. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann. Neurol. 70(6), 871-880 (2011).
9. Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J. Neural Transm. Vienna Austria 1996. 109(5-6), 813-836 (2002).
10. Ellis RJ, Olichney JM, Thal LJ et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV. Neurology. 46(6), 1592-1596 (1996).
11. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke J. Cereb. Circ. 18(2), 311-324 (1987).
12. Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: a systematic review and metaanalysis. Epidemiol. Camb. Mass. 22(5), 646-659 (2011).
13. Skoog I, Lernfelt B, Landahl S et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 347(9009), 1141-1145 (1996).
14. Manolio TA, Olson J, Longstreth WT. Hypertension and cognitive function: pathophysiologic effects of hypertension on the brain. Curr. Hypertens. Rep. 5(3), 255-261 (2003).
15. Cordonnier C, van der Flier WM. Brain microbleeds and Alzheimer's disease: innocent observation or key player? Brain(2011). http://brain.oxfordjournals.org
16. Cavalieri M, Enzinger C, Petrovic K et al. Vascular dementia and Alzheimer's disease - are we in a dead-end road? Neurodegener. Dis. 7(1-3), 122-126 (2010).
17. Gorelick PB, Scuteri A, Black SE et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke J. Cereb. Circ. 42(9), 2672-2713 (2011).
18. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet. 354(9182), 919-920 (1999).
19. Heyman A, Fillenbaum GG, Welsh-Bohmer KA et al. Cerebral infarcts in patients with autopsy-proven Alzheimer's disease: CERAD, part XVIII. Consortium to establish a registry for Alzheimer's disease. Neurology. 51(1), 159-162 (1998).
20. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA J. Am. Med. Assoc. 277(10), 813-817 (1997).
21. Zekry D, Duyckaerts C, Moulias R et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol. (Berl.) 103(5), 481-487 (2002).
22. Greenberg SM, Vernooij MW, Cordonnier C et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 8(2), 165-174 (2009).
23. Conijn MMA, Geerlings MI, Biessels G-J et al. Cerebral microbleeds on MR imaging: comparison between 1.5 and 7T. AJNR Am. J. Neuroradiol. 32(6), 1043-1049 (2011).
24. Nandigam RNK, Viswanathan A, Delgado P et al. MR imaging detection of cerebral microbleeds: effect of susceptibility-weighted imaging, section thickness, and field strength. AJNR Am. J. Neuroradiol. 30(2), 338-343 (2009).
25. Cheng A-L, Batool S, McCreary CR et al. Susceptibility weighted imaging is more reliable than T2∗-weighted gradient-recalled echo MRI for detecting microbleeds. Stroke J. Cereb. Circ. 44(10), 2782-2786 (2013).
26. Goos JDC, van der Flier WM, Knol DL et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke J. Cereb. Circ. 42(7), 1894-1900 (2011).
27. Shams S, Martola J, Cavallin L et al. SWI or T2∗: Which MRI sequence to use in the detection of cerebral microbleeds? The Karolinska Imaging Dementia Study. Am. J. Neuroradiol. (2015). http://www.ajnr.org/content/early/2015/02/19/ajnr.A4248
28. Kikuta K, Takagi Y, Nozaki K, Okada T, Hashimoto N. Histological analysis of microbleed after surgical resection in a patient with moyamoya disease. Neurol. Med. Chir. (Tokyo) 47(12), 564-567 (2007).
29. 2 ∗-magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates. Cerebrovasc. Dis. Basel Switz. 31(5), 511-517 (2011).
30. Schrag M, McAuley G, Pomakian J et al. Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol. (Berl.) 119(3), 291-302 (2010).
31. Tanaka A, Ueno Y, Nakayama Y, Takano K, Takebayashi S. Small chronic hemorrhages and ischemic lesions in association with spontaneous intracerebral hematomas. Stroke J. Cereb. Circ. 30(8), 1637-1642 (1999).
32. Tatsumi S, Shinohara M, Yamamoto T. Direct comparison of histology of microbleeds with postmortem MR images: a case report. Cerebrovasc. Dis. Basel Switz. 26(2), 142-146 (2008).
33. Cordonnier C, van der Flier WM, Sluimer JD, Leys D, Barkhof F, Scheltens P. Prevalence and severity of microbleeds in a memory clinic setting. Neurology 66(9), 1356-1360 (2006).
34. Hanyu H, Tanaka Y, Shimizu S, Takasaki M, Abe K. Cerebral microbleeds in Alzheimer's disease. J. Neurol. 250(12), 1496-1497 (2003).
35. Nakata-Kudo Y, Mizuno T, Yamada K et al. Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease. Dement. Geriatr. Cogn. Disord. 22(1), 8-14 (2006).
36. Pettersen JA, Sathiyamoorthy G, Gao F-Q et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch. Neurol. 65(6), 790-795 (2008).
37. van der Flier WM. Clinical aspects of microbleeds in Alzheimer's disease. J. Neurol. Sci. 322(1-2), 56-58 (2012).
38. Brundel M, Heringa SM, de Bresser J et al. High prevalence of cerebral microbleeds at 7Tesla MRI in patients with early Alzheimer's disease. J. Alzheimers Dis. 31(2), 259-263 (2012).
39. van Veluw SJ, Heringa SM, Kuijf HJ et al. Cerebral cortical microinfarcts at 7Tesla MRI in patients with early Alzheimer's disease. J. Alzheimers Dis. 39(1), 163-167 (2014).
40. Olazarán J, Ramos A, Boyano I et al. Pattern of and risk factors for brain microbleeds in neurodegenerative dementia. Am. J. Alzheimers Dis. Other Demen. 29(3), 263-269 (2014).
41. Benedictus MR, Goos JDC, Binnewijzend MAA et al. Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease. Neurobiol. Aging. 34(11), 2488-2494 (2013).
42. Heringa SM, Reijmer YD, Leemans A et al. Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer's disease. J. Alzheimers Dis. JAD. 38(1), 211-221 (2014).
43. Wollenweber FA, Buerger K, Mueller C et al. Prevalence of cortical superficial siderosis in patients with cognitive impairment. J. Neurol. 261(2), 277-282 (2014).
44. Zonneveld HI, Goos JDC, Wattjes MP et al. Prevalence of cortical superficial siderosis in a memory clinic population. Neurology doi:10.1212/WNL.0000000000000150 (2014) (Epub ahead of print).
45. Yates PA, Desmond PM, Phal PM et al. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology. 82(14), 1266-1273 (2014).
46. Uetani H, Hirai T, Hashimoto M et al. Prevalence and topography of small hypointense foci suggesting microbleeds on 3T susceptibility-weighted imaging in various types of dementia. AJNR Am. J. Neuroradiol. 34(5), 984-989 (2013).
47. Shams S, Martola J, Granberg T et al. Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis - the Karolinska Imaging Dementia Study. Am. J. Neuroradiol. (2014). http://www.ajnr.org/content/early/2014/12/18/ajnr.A4176
48. Kester MI, Goos JDC, Teunissen CE et al. Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol. 71(7), 855-862 (2014).
49. Fukui T, Oowan Y, Yamazaki T, Kinno R. Prevalence and clinical implication of microbleeds in dementia with lewy bodies in comparison with microbleeds in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. Extra. 3(1), 148-160 (2013).
50. Nakata Y, Shiga K, Yoshikawa K et al. Subclinical brain hemorrhages in Alzheimer's disease: evaluation by magnetic resonance T2∗-weighted images. Ann. N. Y. Acad. Sci. 977, 169-172 (2002).
51. Nagasawa J, Kiyozaka T, Ikeda K. Prevalence and clinicoradiological analyses of patients with Alzheimer disease coexisting multiple microbleeds. J. Stroke Cerebrovasc. Dis. Off. J. Natl. Stroke Assoc. 23(9), 2444-2449 (2014).
52. Nagata K, Takano D, Yamazaki T et al. Cerebrovascular lesions in elderly Japanese patients with Alzheimer's disease. J. Neurol. Sci. 322(1-2), 87-91 (2012).
53. Doi H, Inamizu S, Saito B-Y, Murai H, Araki T, Kira J-I. Analysis of cerebral lobar microbleeds and a decreased cerebral blood flow in a memory clinic setting. Intern. Med. 54(9), 1027-1033 (2015).
54. van der Vlies AE, Goos JDC, Barkhof F, Scheltens P, van der Flier WM. Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology 79(8), 763-769 (2012).
55. Atri A, Locascio JJ, Lin JM et al. Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodegener. Dis. 2(6), 305-312 (2005).
56. Cordonnier C. Brain microbleeds: more evidence, but still a clinical dilemma. Curr. Opin. Neurol. 24(1), 69-74 (2011).
57. Kantarci K, Gunter JL, Tosakulwong N et al. Focal hemosiderin deposits and β-amyloid load in the ADNI cohort. Alzheimers Dement. 9(5), S116-S123 (2013).
58. Attems J, Jellinger KA, Lintner F. Alzheimer's disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol. (Berl.) 110(3), 222-231 (2005).
59. Rosand J, Muzikansky A, Kumar A et al. Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann. Neurol. 58(3), 459-462 (2005).
60. Vinters HV, Gilbert JJ. Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke J. Cereb. Circ. 14(6), 924-928 (1983).
61. Whitwell JL, Kantarci K, Weigand SD et al. Microbleeds in atypical presentations of Alzheimer's disease: a comparison to dementia of the Alzheimer's type. J. Alzheimers Dis. http://dx.doi.org/10.3233/JAD-142628
62. De Reuck JL, Deramecourt V, Auger F et al. The significance of cortical cerebellar microbleeds and microinfarcts in neurodegenerative and cerebrovascular diseases. A post-mortem 7.0-Tesla magnetic resonance study with neuropathological correlates. Cerebrovasc. Dis. Basel Switz. 39(2), 138-143 (2015).
63. Goos JDC, Henneman WJP, Sluimer JD et al. Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology 74(24), 1954-1960 (2010).
64. Henneman WJP, Sluimer JD, Cordonnier C et al. MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population. Stroke J. Cereb. Circ. 40(2), 492-498 (2009).
65. Benedictus MR, Prins ND, Goos JDC, Scheltens P, Barkhof F, van der Flier WM. Microbleeds, mortality, and stroke in Alzheimer disease: the MISTRAL study. JAMA Neurol.doi:10.1001/jamaneurol.2015.14 (2015) (Epub ahead of print).
66. Jeerakathil T, Wolf PA, Beiser A et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke J. Cereb. Circ. 35(8), 1831-1835 (2004).
67. Qiu C, Cotch MF, Sigurdsson S et al. Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik study. Neurology. 75(24), 2221-2228 (2010).
68. Staekenborg SS, Koedam ELGE, Henneman WJP et al. Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy. Stroke J. Cereb. Circ. 40(4), 1269-1274 (2009).
69. Miwa K, Tanaka M, Okazaki S et al. Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors. Neurology. 83(7), 646-653 (2014).
70. Haller S, Bartsch A, Nguyen D et al. Cerebral microhemorrhage and iron deposition in mild cognitive impairment: susceptibility-weighted MR imaging assessment. Radiology. 257(3), 764-773 (2010).
71. Martinez-Ramirez S, Romero J-R, Shoamanesh A et al. Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement. J. Alzheimers Assoc. doi:10.1016/j.jalz.2015.04.009 (2015) (Epub ahead of print).
72. Ringman JM, Sachs MC, Zhou Y, Monsell SE, Saver JL, Vinters HV. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. JAMA Neurol. 71(7), 878-883 (2014).
73. Charidimou A, Peeters A, Fox Z et al. Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis. Stroke J. Cereb. Circ. 43(9), 2324-2330 (2012).
74. Schrag M, Crofton A, Zabel M et al. Effect of cerebral amyloid angiopathy on brain iron, copper, and zinc in Alzheimer's disease. J. Alzheimers Dis. JAD. 24(1), 137-149 (2011).
75. Shams S, Granberg T, Martola J et al. Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment. J. Cereb. Blood Flow Metab. doi:271678X15606141 (2015) (Epub ahead of print).
76. Goos JDC, Kester MI, Barkhof F et al. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke J. Cereb. Circ. 40(11), 3455-3460 (2009).
77. Goos JDC, Teunissen CE, Veerhuis R et al. Microbleeds relate to altered amyloid-beta metabolism in Alzheimer's disease. Neurobiol. Aging. 33(5), 1011.e1-1011.e9 (2012).
78. Chiang GC, Cruz Hernandez JC, Kantarci K, Jack CR, Weiner MW, Alzheimer's Disease Neuroimaging Initiative. Cerebral microbleeds, CSF p-Tau, and cognitive decline: significance of anatomic distribution. AJNR Am. J. Neuroradiol. doi:10.3174/ajnr.A4351 (2015) (Epub ahead of print).
79. Maia LF, Mackenzie IRA, Feldman HH. Clinical phenotypes of cerebral amyloid angiopathy. J. Neurol. Sci. 257(1-2), 23-30 (2007).
80. Verbeek MM, Kremer BPH, Rikkert MO, Van Domburg PHMF, Skehan ME, Greenberg SM. Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy. Ann. Neurol. 66(2), 245-249 (2009).
81. Jochemsen HM, van der Flier WM, Ashby EL et al. Angiotensin-converting enzyme in cerebrospinal fluid and risk of brain atrophy. J. Alzheimers Dis. JAD. 44(1), 153-162 (2015).
82. Jellinger KA, Lauda F, Attems J. Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 14(8), 923-928 (2007).
83. Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nat. Rev. Neurol. 9(2), 106-118 (2013).
84. Charidimou A, Martinez-Ramirez S, Shoamanesh A et al. Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes. Neurology 84(12), 1206-1212 (2015).
85. Ii Y, Maeda M, Kida H et al. In vivo detection of cortical microinfarcts on ultrahigh-field MRI. J. Neuroimaging Off. J. Am. Soc. Neuroimaging. 23(1), 28-32 (2013).
86. van Rooden S, Goos JDC, van Opstal AM et al. Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology 270(1), 205-211 (2014).
87. De Reuck JL, Cordonnier C, Deramecourt V et al. Microbleeds in postmortem brains of patients with Alzheimer disease: a T2∗-weighted gradient-echo 7.0 T magnetic resonance imaging study. Alzheimer Dis. Assoc. Disord. 27(2), 162-167 (2013).
88. Chi N-F, Chien L-N, Ku H-L, Hu C-J, Chiou H-Y. Alzheimer disease and risk of stroke: a populationbased cohort study. Neurology. 80(8), 705-711 (2013).
89. Thoonsen H, Richard E, Bentham P et al. Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage: cause for concern? Stroke J. Cereb. Circ. 41(11), 2690-2692 (2010).
90. Sperling RA, Jack CR Jr, Black SE et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimers Dement. J. Alzheimers Assoc. 7(4), 367-385 (2011).
91. Barakos J, Sperling R, Salloway S et al. MR imaging features of amyloid-related imaging abnormalities. AJNR Am. J. Neuroradiol. 34(10), 1958-1965 (2013).
92. Sperling R, Salloway S, Brooks DJ et al. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 11(3), 241-249 (2012).
93. Park J-H, Seo SW, Kim C et al. Pathogenesis of cerebral microbleeds: in vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann. Neurol. 73(5), 584-593 (2013).
94. van Assema DME, Goos JDC, van der Flier WM et al. No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 32(8), 1468-1471 (2012).
95. Vogelgesang S, Jedlitschky G, Brenn A, Walker LC. The role of the ATP-binding cassette transporter P-glycoprotein in the transport of β-amyloid across the blood-brain barrier. Curr. Pharm. Des. 17(26), 2778-2786 (2011).
96. Vogelgesang S, Warzok RW, Cascorbi I et al. The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease. Curr. Alzheimer Res. 1(2), 121-125 (2004).