Skip to main content Accessibility help
×
Home

Microbleeds in Alzheimer’s Disease: A Neuropsychological Overview and Meta-Analysis

  • Amir A. Sepehry (a1), Alexander Rauscher (a2), Ging-Yuek Hsiung (a1) and Donna J. Lang (a3)

Abstract

The current literature on the role of brain microbleeds (MB) on the neuropsychological outcomes of Alzheimer’s disease (AD) is heterogeneous. We therefore meta-analytically examined the neuropsychological literature pertaining to MBs in AD. Using a priori selected criteria, studies with cross-sectional neuropsychological assessment on MBs and AD were reviewed. Six of 122 studies met selection criteria and provided neuropsychological data on either AD with MB and without MB, or in contrast to healthy controls. The global neuropsychological difference between AD with MB and AD without MB based on random effect model was nonsignificant, heterogeneous, and small (Effect Size =−0.155; 95% confidence interval =−0.465 to 0.155; p value =0.326; Heterogenity: Q-value =12.744; degrees of freedom =5; p =0.026; I2 =61%). The contribution of MBs to cognitive deficits in AD remains unclear. Future studies of MB in AD should strive to use standardized neuroimaging techniques with high sensitivity for MB, a common standard for MB definition, and neuropsychological tests sensitive for detecting subtle cognitive impairment.

Microsaignements dans la maladie d’Alzheimer : aperçu neuropsychologique et méta-analyse. La littérature actuelle sur le rôle des microsaignements (MS) dans la maladie d’Alzheimer (MA) est hétérogène. Nous avons donc utilisé une méta-analyse pour examiner la littérature neuropsychologique sur les MS dans la MA. Nous avons revu les études sur les MS et la MA, choisies selon des critères de sélection déterminés a priori et rapportant une évaluation neuropsychologique transversale. Six études sur 122 rencontraient nos critères de sélection et présentaient des données neuropsychologiques soit sur des sujets atteints de MA avec MS et sans MS ou comparés à des volontaires sains. La différence neuropsychologique globale entre la MA avec et sans MS selon un modèle à effet aléatoire était non significative, hétérogène et faible (taille d’effet d=-0,155 ; intervalle de confiance à 95%=-0,465 à 0.155 ; p=0,326 ; q=12,744 ; degrés de liberté=5 ; p=0,026 ; I2=61%). La contribution des MS aux déficits cognitifs dans la MA demeure indéterminée. Des études sur les MS dans la MA devraient utiliser des techniques standardisées de neuroimagerie ayant une sensibilité élevée pour les MS, une définition standard commune des MS et des tests neuropsychologiques sensibles pour détecter un déficit cognitif subtil.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Microbleeds in Alzheimer’s Disease: A Neuropsychological Overview and Meta-Analysis
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Microbleeds in Alzheimer’s Disease: A Neuropsychological Overview and Meta-Analysis
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Microbleeds in Alzheimer’s Disease: A Neuropsychological Overview and Meta-Analysis
      Available formats
      ×

Copyright

Corresponding author

Correspondence to: Amir A. Sepehry, Division of Neurology, The University of British Columbia (UBC), UBC Hospital, Koerner Pavilion, S130 - 2211 Wesbrook Mall, Vancouver, Canada V6T 2B5. E-mail: sepehryaa@alumni.ubc.ca. Twitter: @asmetaanalysis.

References

Hide All
1. Meier, IB, Gu, Y, Guzaman, VA, et al. Lobar microbleeds are associated with a decline in executive functioning in older adults. Cerebrovasc Dis. 2014;38:377-383.
2. Bouchard, CJ. Etude sur quelques points de la pathogénie des hémorrhagies cérébrales; 1866.
3. Fagge, CH. The principles and practice of medicine. London, UK: J. & A. Churchill; 1886.
4. Huijts, M, Duits, A, van Oostenbrugge, RJ, Kroon, AA, de Leeuw, PW, Staals, J. Accumulation of MRI markers of cerebral small vessel disease is associated with decreased cognitive function. A study in first-ever lacunar stroke and hypertensive patients. Front Aging Neurosci. 2013;5:72.
5. van Rooden, S, Goos, JD, van Opstal, AM, et al. Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology. 2014;270:205-311.
6. Goos, JD, van der Flier, WM, Knol, DL, et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke. 2011;42:1894-1900.
7. van der Flier, WM. Clinical aspects of microbleeds in Alzheimer’s disease. J Neurol Sci. 2012;322:56-58.
8. Cordonnier, C, van der Flier, WM. Brain microbleeds and Alzheimer’s disease: innocent observation or key player? Brain. 2011;134:335-344.
9. Hommet, C, Mondon, K, Constans, T, et al. Review of cerebral microangiopathy and Alzheimer’s disease: relation between white matter hyperintensities and microbleeds. Dement Geriatr Cogn Disord. 2011;32:367-378.
10. Vernooij, MW, Haag, MD, van der Lugt, A, et al. Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study. Arch Neurol. 2009;66:714-720.
11. Greenberg, SM, Al-Shahi Salman, R, Biessels, GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol. 2014;13:419-428.
12. 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. 2014;71:878-883.
13. 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. 2011;7:367-385.
14. Henneman, WJP, Sluimer, JD, Cordonnier, C, et al. MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population. Stroke. 2009;40:492-498.
15. Akoudad, S, Portegies, ML, Koudstaal, PJ, et al. Cerebral microbleeds are associated with an increased risk of stroke: the Rotterdam study. Circulation. 2015;132:509-516.
16. Gregg, NM, Kim, AE, Gurol, ME, et al. Incidental cerebral microbleeds and cerebral blood flow in elderly individuals. JAMA Neurol. 2015;72:1021-1028.
17. Pettersen, JA, Sathiyamoorthy, G, Gao, FQ, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008;65:790-795.
18. Clark, CM, Sheppard, L, Fillenbaum, GG, et al. Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer’s Disease. Arch Neurol. 1999;56:857-862.
19. Feher, EP, Mahurin, RK, Doody, RS, Cooke, N, Sims, J, Pirozzolo, FJ. Establishing the limits of the Mini-Mental State. Examination of ‘subtests’. Arch Neurol. 1992;49:87-92.
20. Martinez-Ramirez, S, Greenberg, SM, Viswanathan, A. Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology. 2013;80:1266.
21. Poels, MMF, Ikram, MA, van der Lugt, A, et al. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012;78:326-333.
22. van Norden, AG, van den Berg, HA, de Laat, KF, Gons, RA, van Dijk, EJ, de Leeuw, FE. Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke. 2011;42:3382-3386.
23. 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. 2009;40:1269-1274.
24. Hilal, S, Saini, M, Tan, CS, et al. Cerebral microbleeds and cognition: the epidemiology of dementia in Singapore study. Alzheimer Dis Assoc Disord. 2014;28:106-112.
25. Kirsch, W, McAuley, G, Holshouser, B, et al. Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J Alzheimers Dis. 2009;17:599-609.
26. Ayaz, M, Boikov, AS, Haacke, EM, Kido, DK, Kirsch, WM. Imaging cerebral microbleeds using susceptibility weighted imaging: one step toward detecting vascular dementia. J Magnet ResonI Imaging. 2010;31:142-148.
27. Martinez-Ramirez, S, Greenberg, SM, Viswanathan, A. Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimer’s Res Ther. 2014;6:33.
28. Sepehry, AA, Lang, D, Hsiung, GY, Rauscher, A. Prevalence of brain microbleeds in Alzheimer Disease: a systematic review and meta-analysis on the influence of neuroimaging techniques. AJNR Am J Neuroradiol. 2016;37:215-222.
29. Reichenbach, JR, Venkatesan, R, Schillinger, DJ, Kido, DK, Haacke, EM. Small vessels in the human brain: MR venography with deoxyhemoglobin as an intrinsic contrast agent. Radiology. 1997;204:272-277.
30. 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. 2014;38:211-221.
31. Begg, CB, Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-1101.
32. Egger, M, Davey Smith, G, Schneider, M, Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.
33. Pettersen, JA, Sathiyamoorthy, G, Gao, FQ, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008;65:790–5.
34. Goos, JDC, Kester, MI, Barkhof, F, et al. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke. 2009;40:3455–60.
35. Benedictus, MR, Goos, JDC, Binnewijzend, MAA, et al. Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer’s disease. Neurobiol Aging. 2013;34:2488-2494.
36. 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. 2006;22:8-14.
37. van Assema, DM, Goos, JD, van der Flier, WM, et al. No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer’s disease patients with microbleeds. J Cere Blood Flow Metab. 2012;32:1468-1471.
38. 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. 2012;79:763-769.
39. Denk, C, Rauscher, A. Susceptibility weighted imaging with multiple echoes. J Magn ResonI Imaging. 2010;31:185-191.
40. Feng, C, Fang, M, Xu, Y, Hua, T, Liu, XY. Microbleeds in late-life depression: comparison of early- and late-onset depression. Biomed Res Int. 2014;2014:682092.
41. van Sloten, TT, Sigurdsson, S, van Buchem, MA, et al. Cerebral small vessel disease and association with higher incidence of depressive symptoms in a general elderly population: the AGES-Reykjavik Study. Am J Psychiatry. 2015;172:570-578.
42. Wu, RH, Feng, C, Xu, Y, Hua, T, Liu, XY, Fang, M. Late-onset depression in the absence of stroke: associated with silent brain infarctions, microbleeds and lesion locations. Int J Med Sci. 2014;11:587-592.
43. 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. 2013;73:584-593.
44. Yakushiji, Y, Noguchi, T, Charidimou, A, et al. Basal ganglia cerebral microbleeds and global cognitive function: the Kashima Scan Study. J Stroke Cerebrovasc Dis. 2015;24:431-439.

Keywords

Type Description Title
WORD
Supplementary materials

Sepehry supplementary material
Supplementary Figure 1

 Word (23 KB)
23 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed