Cerebral microbleeds in early Alzheimer’s disease

Abstract

We hypothesize that cerebral microbleeds (CMB) in patients with different neuropsychological profiles (amnestic or non-amnestic) and MRI features of vascular damage could provide important information on the underlying pathological process in early Alzheimer’s disease. The study was performed at two trial sites. We studied 136 outpatients with cognitive decline. MRI was performed using a magnetic field of 1.5 and 3 T. Neuropsychological assessment included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment scale (MoCA), Addenbrooke’s Cognitive Examination (ACE-R), Cambridge Cognitive Examination battery (CAMCOG) (Part 3), Clock Drawing Test, fluency test and the visual memory test (SCT). CSF was examined for standard parameters such as tau, phosphorylated tau, amyloid-β 1–40 and 42 and Qalbumin, in accordance with established protocols and genotype. In 61 patients (45 %), at least 1 CMB was found. Most of the CMBs were described in the amnestic profile (67 %). In 86 % of the cases, multiple CMB were observed. The ratio of Aβ1-40/42 in non-amnestic patients with CMB was significantly lower (mean 0.6) than in patients without CMB (mean 1.2). A notable difference in the albumin ratio as an indicator of the BBB was observed between groups with and without CMB. In the CMP-positive group, the E2 genotype was observed more frequently, and the E4 genotype less frequently, than in the CMB-negative group. Based on the cerebrospinal fluid–serum albumin ratio, we were able to show that patients with CMB present several features of BBB dysfunction. According to logistic regression, the predictive factors for CMB in patients with cognitive decline were age, WMHs score and albumin ratio. We found a significant reduction in the Aβ-amyloid ratio in the non-amnestic profile group with CMB (particularly in the cortical region) in comparison to those without CMB. While this is an interesting finding, its significance needs to be assessed in a prospective follow-up.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256:183–194

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Cui Y, Liu B, Luo S, Zhen X, Fan M, Liu T, Zhu W, Park M, Jiang T, Jin JS (2011) Identification of conversion from mild cognitive impairment to Alzheimer’s disease using multivariate predictors. PLoS One 6:e21896

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Haldenwanger A, Eling P, Kastrup A, Hildebrandt H (2010) Correlation between cognitive impairment and CSF biomarkers in amnesic MCI, non-amnesic MCI, and Alzheimer’s disease. J Alzheimers Dis 22:971–980

    PubMed  Google Scholar 

  4. 4.

    Hu WT, Chen-Plotkin A, Arnod SE, Grossman M, Shaw L, McCluskey L, Elman L, Hurtig H, Siderowf A, Lee VM, Soares H, Trojanowski JQ (2010) Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment. Acta Neuropathol 119:669–678

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Mitchell AJ, Monge-Argilés JA, Sánchez-Paya J (2010) Do CSF biomarkers help clinicians predict the progression of mild cognitive impairment to dementia? Pract Neurol 10:202–207

    Article  PubMed  Google Scholar 

  6. 6.

    Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, Breteler MM (2009) Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 8:165–174

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Cheng AL, Batool S, McCreary CR, Lauzon ML, Frayne R, Goyal M, Smith EE (2013) Susceptibility-weighted imaging is more reliable than T2*-weighted gradient-recalled echo MRI for detecting microbleeds. Stroke 44:2782–2786

    Article  PubMed  Google Scholar 

  8. 8.

    Schrag M, Greer DM (2014) Clinical associations of cerebral microbleeds on magnetic resonance neuroimaging. J Stroke Cerebrovasc Dis 23:2489–2497

    Article  PubMed  Google Scholar 

  9. 9.

    Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC (2014) Cerebral microbleeds: a review of clinical, genetic, and neuroimaging associations. Front Neurol 4:205

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Fang M, Feng C, Xu Y, Hua T, Jin AP, Liu XY (2013) Microbleeds and silent brain infarctions are differently associated with cognitive dysfunction in patients with advanced periventricular leukoaraiosis. Int J Med Sci 10:1307–1313

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Van der Flier WM, Cordonnier C (2012) Microbleeds in vascular dementia: clinical aspects. Exp Gerontol 47:853–857

    Article  PubMed  Google Scholar 

  12. 12.

    Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, De Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, van Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M, v1) SfRVconS, (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lanc Neurol 12:822–838

    Article  Google Scholar 

  13. 13.

    Zhang M, Chen M, Wang Q, Yun W, Zhang Z, Yin Q, Huang Q, Zhu W (2013) Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Int Med Res 41:347–355

    Article  PubMed  Google Scholar 

  14. 14.

    Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5:228–234

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR (2006) The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 21:1078–1085

    Article  PubMed  Google Scholar 

  16. 16.

    Gregoire SM, Chaudhary UJ, Brown M, Yousry TA, Kallis C, Jäger HR, Werring D (2009) The Microbleed Anatomocal Rating Scale (MARS):reliability of a tool to map brain microbleeds. Neurology 73:1759–1766

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjögren M, Wallin A, Ader H, Leys D, Pantoni L, Changes ETFoA-RWM (2001) A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32:1318–1322

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Scheltens P, Launer LJ, Barkhof F, Weinstein HC, Van Gool WA (1995) Visual assessment of medial temporal lobe atrophy on magnetic resonance imaging: interobserver reliability. J Neurol 242:557–560

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Schmidt C, Becker H, Zerr I (2014) Cerebrospinal fluid apolipoprotein E concentration and severity of cognitive impairment in patients with newly diagnosed Alzheimer’s disease. Am J Alzheimers Dis Other Demen 29:54–60

    Article  PubMed  Google Scholar 

  20. 20.

    Karch A, Manthey H, Ponto C, Hermann P, Heinemann U, Schmidt C, Zerr I (2013) Investigating the association of ApoE genotypes with blood-brain barrier dysfunction measured by cerebrospinal fluid-serum albumin ratio in a cohort of patients with different types of dementia. PLoS One 8:e84405

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, Van der Flier W (2009) Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke 40:3455–3460

    Article  PubMed  Google Scholar 

  22. 22.

    Lei C, Lin S, Tao W, Hao Z, Liu M, Wu B (2013) Association between cerebral microbleeds and cognitive function: a systematic review. J Neurol Neurosurg Psychiatry 84:693–697

    Article  PubMed  Google Scholar 

  23. 23.

    Wu R, Feng C, Zhao Y, Jin AP, Fang M, Liu X (2014) A meta-analysis of association between cerebral microbleeds and cognitive impairment. Med Sci Monit 20:2189–2198

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Samtani M, Raghavan N, Shi Y, Novak G, Farnum M, Lobanov V, Schultz T, Yang E, DiBernardo A, Narayan VA, AsDN Initiative (2013) Disease progression model in subjects with mild cognitive impairment from the Alzheimer’s disease neuroimaging initiative: CSF biomarkers predict population subtypes. Br J Clin Pharmacol 75:146–161

    Article  PubMed  Google Scholar 

  25. 25.

    Waragai M, Yoshida M, Mizoi M, Saiki R, Kashiwagi K, Takagi K, Arai H, Tashiro J, Hashimoto M, Iwai N, Uemura K, Igarashi K (2012) Increased protein-conjugated acrolein and amyloid -β40/42 ratio in plasma of patients with mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 32:33–41

    CAS  PubMed  Google Scholar 

  26. 26.

    Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O (2012) Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5–10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69:98–106

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, Minthon L, Wallin AK, Hampel H, Burger K, Pirttila T, Soininen H, Rikkert MO, Verbeek MM, Spiru L, Blennow K (2009) Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 8:619–627

    Article  PubMed  Google Scholar 

  28. 28.

    Forlenza OV, Diniz BS, Stella F, Teixeira AL, Gattaz WF (2013) Mild cognitive impairment. Part 1: clinical characteristics and predictors of dementia. Rev Bras Psiquitar 35:178–185

    Article  Google Scholar 

  29. 29.

    Parnetti L, Chiasserini D, Eusebi P, Giannandrea D, Bellomo G, De Carlo C, Padiglioni C, Mastrocola S, Lisetti V, Calabresi P (2012) Performance of Aβ1-40, Aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment. J Alzheimers Dis 29:229–238

    CAS  PubMed  Google Scholar 

  30. 30.

    Lim YY, Ellis KA, Harrington K, Pietrzak RH, Gale J, Ames D, Bush AI, Darby D, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Villemagne VL, Maruff P (2013) Cognitive decline in adults with amnestic mild cognitive impairment and high amyloid-β: prodromal Alzheimer’s disease? J Alzheimers Dis 33:1167–1176

    CAS  PubMed  Google Scholar 

  31. 31.

    Vieira RT, Caixeta L, Machado S, Silva AC, Nardi AE, Arias-Carrión O, Carta MG (2013) Epidemiology of early-onset dementia: a review of the literature. Clin Pract Epidemiol Ment Health 9:88–95

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Charidimou A, Werring D (2014) A raging fire in acute lacunar stroke: inflammation, blood-brain barrier dysfunction and the origin of cerebral microbleeds. J Neurol Sci 34:1–2

    Article  Google Scholar 

  33. 33.

    Taheri S, Gasparovic C, Huisa BN, Adair JC, Edmonds E, Prestopnik J, Grossetete M, Shah NJ, Wills J, Qualls C, Rosenberg GA (2011) Blood-brain barrier permeability abnormalities in vascular cognitive impairment. Stroke 42:2158–2163

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Van Assema DM, Lubberrink M, Bauer M, van der Flier W, Schuit RC, Windhorst AD, Comans EF, Hoetjes NJ, Tolboom N, Langer O, Müller M, Scheltens P, Lammertsma AA, van Berckel BN (2012) No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer’s disease patients with microbleeds. J Cereb Blood Flow Metab 32:1468–1471

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Wallin A, Blennow K, Fredman F (1990) Blood brain barrier function in vascular dementia. Acta Neurol Scand 81:318–322

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Loehrer E, Ikram MA, Akoudad S, Vrooman HA, van der Lugt A, Niessen WJ, Hofman A, Vernooij MW (2014) Apolipoprotein E genotype influences spatial distribution of cerebral microbleeds. Neurobiol Aging 35:899–905

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Maxwell SS, Jackson CA, Paternoster L, Cordonnier C, Thijs V, Al-Shahi Salman R, Sudlow CL (2011) Genetic associations with brain microbleeds: systematic review and meta-analyses. Neurology 77:158–167

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Spampinato MV, Rumboldt Z, Hosker RJ, Mintzer JE, AsDN Initiative (2011) Apolipoprotein E and gray matter volume loss in patients with mild cognitive impairment and Alzheimer disease. Radiology 258:843–852

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The research was supported by the Russian–German grant from the Federal Ministry of Education and Research (BMBF) of Germany, “Stage-dependent biochemical, clinical and imaging features of the Alzheimer type of dementia and vascular dementia” No. RUS 12/018.

Author information

Affiliations

Authors

Corresponding author

Correspondence to I. Zerr.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

Ethics approval by ethical committee, University Medical Center, University of Göttingen, 34/9/07 http://www.intechopen.com/books/understanding-alzheimer-s-disease.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Poliakova, T., Levin, O., Arablinskiy, A. et al. Cerebral microbleeds in early Alzheimer’s disease. J Neurol 263, 1961–1968 (2016). https://doi.org/10.1007/s00415-016-8220-2

Download citation

Keywords

  • Cerebral microbleeds
  • Mild cognitive impairment
  • Alzheimer disease
  • White matter lesions
  • Magnetic resonance imaging
  • Blood–brain barrier damage