Journal of Neurology

, Volume 262, Issue 11, pp 2411–2419 | Cite as

Cerebral small vessel disease, cognitive reserve and cognitive dysfunction

  • Daniela Pinter
  • Christian Enzinger
  • Franz FazekasEmail author


The concept of cognitive reserve describes differences between individuals in the ability to compensate age-related brain changes or pathology as a result of greater intellectual enrichment. Cerebral small vessel disease (CSVD) is a common age-related vascular disease of the brain associated with slowly accumulating tissue damage and represents a leading cause of functional loss, disability and cognitive decline in the elderly. The promotion of cognitive reserve might be a valuable possibility to moderate the negative impact of accumulating brain changes associated with CSVD on cognitive function and thus limit the functional consequences of CSVD. We here review existing studies investigating this topic in CSVD and provide conceptual considerations why future research is needed. Relevant studies were identified using the electronic databases PubMed and MEDLINE. Six studies including 7893 subjects were found that all focused on a single feature of CSVD only, i.e., white matter hyperintensities (WMH). We also included one study investigating 247 CADASIL patients. In general, they confirm that higher cognitive reserve (i.e., educational attainment) attenuates the negative impact of WMH on cognition. Further studies should attempt to replicate this association for all features of CSVD and to expand the concept to other areas of functional loss like disordered gait. Finally intervention studies will be needed to define when and how we can still increase our cognitive reserve and what kind and magnitude of protective effects this may offer.


Cerebral small vessel disease (CSVD) Cognitive reserve WMH Successful aging Aging of the brain White matter changes 


Conflicts of interest

D. Pinter has received funding from Genzyme/Sanofi-Aventis and speaking honoraria from Merck Serono. F. Fazekas serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, D-Pharm Ltd., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serves on the editorial boards of Cerebrovascular Diseases, Multiple Sclerosis, the Polish Journal of Neurology and Neurosurgery, Stroke, and the Swiss Archives of Neurology and Psychiatry; and has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, and sanofi-aventis. C. Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Genzyme a sanofi company, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme a sanofi company, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serves on the editorial board of PloS One, and received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./sanofi-aventis.


  1. 1.
  2. 2.
    Thompson CS, Hakim AM (2009) Living beyond our physiological means: small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis. Stroke 40:e322–e330CrossRefPubMedGoogle Scholar
  3. 3.
    Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701. doi: 10.1016/S1474-4422(10)70104-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Wardlaw JM, Smith C, Dichgans M (2013) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 12:483–497CrossRefPubMedGoogle Scholar
  5. 5.
    Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838. doi: 10.1016/S1474-4422(13)70124-8 PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Lawrence AJ, Patel B, Morris RG et al (2013) Mechanisms of cognitive impairment in cerebral small vessel disease: multimodal MRI results from the St George’s cognition and neuroimaging in stroke (SCANS) study. PLoS One 8:e61014. doi: 10.1371/journal.pone.0061014 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, Launer LJ, Van Buchem MA, Breteler MM, Microbleed Study Group (2009) Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 8(2):165–174. doi: 10.1016/S1474-4422(09)70013-4 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Schmidt R, Grazer A, Enzinger C et al (2011) MRI-detected white matter lesions: do they really matter? J Neural Transm 118:673–681. doi: 10.1007/s00702-011-0594-9 CrossRefPubMedGoogle Scholar
  9. 9.
    Launer LJ (2003) Epidemiology of white-matter lesions. Int Psychogeriatr 15(Suppl 1):99–103CrossRefPubMedGoogle Scholar
  10. 10.
    Liao D, Cooper L, Cai J (1997) The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology 16:149–162CrossRefPubMedGoogle Scholar
  11. 11.
    De Groot JC, de Leeuw FE, Oudkerk M et al (2000) Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 47:145–151CrossRefPubMedGoogle Scholar
  12. 12.
    De Leeuw FE, de Groot JC, Achten E et al (2001) Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study: the Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 70:9–14PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Chen X, Wen W, Anstey KJ, Sachdev PS (2009) Prevalence, incidence, and risk factors of lacunar infarcts in a community sample. Neurology 73:266–272. doi: 10.1212/WNL.0b013e3181aa52ea CrossRefPubMedGoogle Scholar
  14. 14.
    Vernooij M, van der Lugt A, Ikram M et al (2008) Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 70:1208–1214CrossRefPubMedGoogle Scholar
  15. 15.
    Gouw AA, Van der Flier WM, van Straaten ECW et al (2006) Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study. J Neurol 253:1189–1196. doi: 10.1007/s00415-006-0193-5 CrossRefPubMedGoogle Scholar
  16. 16.
    Poggesi A, Pantoni L, Inzitari D et al (2011) 2001-2011: A Decade of the LADIS (Leukoaraiosis And DISability) Study: What Have We Learned about White Matter Changes and Small-Vessel Disease? Cerebrovasc Dis 32:577–588. doi: 10.1159/000334498 CrossRefPubMedGoogle Scholar
  17. 17.
    Prins ND, Scheltens P (2015) White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol 11:157–165. doi: 10.1038/nrneurol.2015.10 CrossRefPubMedGoogle Scholar
  18. 18.
    Enzinger C, Smith S, Fazekas F et al (2006) Lesion probability maps of white matter hyperintensities in elderly individuals: results of the Austrian stroke prevention study. J Neurol 253:1064–1070. doi: 10.1007/s00415-006-0164-5 CrossRefPubMedGoogle Scholar
  19. 19.
    Inzitari D, Pracucci G, Poggesi A et al (2009) Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ 339:b2477–b2477. doi: 10.1136/bmj.b2477 PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Edwards JD, Jacova C, Sepehry A et al (2013) A quantitative systematic review of domain-specific cognitive impairment in lacunar stroke. Neurology 80:315–322. doi: 10.1212/WNL.0b013e31827deb85 PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Katzman R, Terry R, DeTeresa R et al (1988) Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 23:138–144. doi: 10.1002/ana.410230206 CrossRefPubMedGoogle Scholar
  22. 22.
    Valenzuela MJ (2008) Brain reserve and the prevention of dementia. Curr Opin Psychiatry 21:296–302CrossRefPubMedGoogle Scholar
  23. 23.
    Guo LH, Alexopoulos P, Wagenpfeil S, Kurz A, Perneczky R, Alzheimer’s disease neuroimaging initiative (2013) Brain size and the compensation of Alzheimer's disease symptoms: a longitudinal cohort study. Alzheimers Dement 9(5):580–586. doi: 10.1016/j.jalz.2012.10.002 CrossRefPubMedGoogle Scholar
  24. 24.
    Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11:1006–1012. doi: 10.1016/S1474-4422(12)70191-6 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Sumowski JF, Rocca MA, Leavitt VM et al (2013) Brain reserve and cognitive reserve in multiple sclerosis: what you’ve got and how you use it. Neurology 80:2186–2193. doi: 10.1212/WNL.0b013e318296e98b PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Ghaffar O, Fiati M, Feinstein A (2012) Occupational attainment as a marker of cognitive reserve in multiple sclerosis. PLoS One 7:e47206. doi: 10.1371/journal.pone.0047206 PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Levi Y, Rassovsky Y, Agranov E et al (2013) Cognitive reserve components as expressed in traumatic brain injury. J Int Neuropsychol Soc 19:664–671CrossRefPubMedGoogle Scholar
  28. 28.
    Pinter D, Sumowski J, Deluca J et al (2014) Higher education moderates the effect of t2 lesion load and third ventricle width on cognition in multiple sclerosis. PLoS One 9:e87567. doi: 10.1371/journal.pone.0087567 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Nunnari D, Bramanti P, Marino S (2014) Cognitive reserve in stroke and traumatic brain injury patients. Neurol Sci 35:1513–1518. doi: 10.1007/s10072-014-1897-z CrossRefPubMedGoogle Scholar
  30. 30.
    Elkins JS, Longstreth WT, Manolio TA et al (2006) Education and the cognitive decline associated with MRI-defined brain infarct. Neurology 67:435–440. doi: 10.1212/01.wnl.0000228246.89109.98 CrossRefPubMedGoogle Scholar
  31. 31.
    Glymour MM, Weuve J, Fay ME et al (2008) Social ties and cognitive recovery after stroke: does social integration promote cognitive resilience? Neuroepidemiology 31:10–20. doi: 10.1159/000136646 PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Ojala-Oksala J, Jokinen H, Kopsi V et al (2012) Educational history is an independent predictor of cognitive deficits and long-term survival in postacute patients with mild to moderate ischemic stroke. Stroke 43:2931–2935. doi: 10.1161/STROKEAHA.112.667618 CrossRefPubMedGoogle Scholar
  33. 33.
    Farfel JM, Nitrini R, Suemoto CK et al (2013) Very low levels of education and cognitive reserve: a clinicopathologic study. Neurology 81:650–657. doi: 10.1212/WNL.0b013e3182a08f1b PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Dufouil C, Alpérovitch A, Tzourio C (2003) Influence of education on the relationship between white matter lesions and cognition. Neurology 60:831–836CrossRefPubMedGoogle Scholar
  35. 35.
    Nebes RD, Meltzer CC, Whyte EM, Scanlon JM, Halligan EM, Saxton JA, Houck PR, Boada FE, Dekosky ST (2006) The relation of white matter hyperintensities to cognitive performance in the normal old: education matters. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 13(3–4):326–340CrossRefPubMedGoogle Scholar
  36. 36.
    Saczynski J, Jonsdottir M, Sigurdsson S et al (2008) White matter lesions and cognitive performance: the role of cognitively complex leisure activity. J Gerontol 63:848–854CrossRefGoogle Scholar
  37. 37.
    Brickman AM, Siedlecki KL, Muraskin J et al (2011) White matter hyperintensities and cognition: testing the reserve hypothesis. Neurobiol Aging 32:1588–1598. doi: 10.1016/j.neurobiolaging.2009.10.013 PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Vemuri P, Lesnick TG, Przybelski SA et al (2015) Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138:761–771. doi: 10.1093/brain/awu393 PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Duering M, Zieren N, Hervé D et al (2011) Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL. Brain 134:2366–2375. doi: 10.1093/brain/awr169 CrossRefPubMedGoogle Scholar
  40. 40.
    Ringelstein EB, Kleffner I, Dittrich R et al (2010) Hereditary and non-hereditary microangiopathies in the young. An up-date. J Neurol Sci 299:81–85. doi: 10.1016/j.jns.2010.08.037 CrossRefPubMedGoogle Scholar
  41. 41.
    Stern Y, Habeck C, Moeller J et al (2005) Brain networks associated with cognitive reserve in healthy young and old adults. Cereb Cortex 15:394–402. doi: 10.1093/cercor/bhh142 PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Sumowski JF, Wylie GR, Deluca J, Chiaravalloti N (2010) Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve. Brain 133:362–374. doi: 10.1093/brain/awp307 PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    López ME, Aurtenetxe S, Pereda E et al (2014) Cognitive reserve is associated with the functional organization of the brain in healthy aging: a MEG study. Front Aging Neurosci 6:1–9. doi: 10.3389/fnagi.2014.00125 Google Scholar
  44. 44.
    Bosch B, Bartrés-Faz D, Rami L et al (2010) Cognitive reserve modulates task-induced activations and deactivations in healthy elders, amnestic mild cognitive impairment and mild Alzheimer’s disease. Cortex 46:451–461. doi: 10.1016/j.cortex.2009.05.006 CrossRefPubMedGoogle Scholar
  45. 45.
    Barulli D, Stern Y (2013) Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn Sci 17:1–17. doi: 10.1016/j.tics.2013.08.012.Efficiency CrossRefGoogle Scholar
  46. 46.
    Nordahl C, Ranganath C, Yonelinas A et al (2006) White matter changes compromise prefrontal cortex function in healthy elderly individuals. J Cogn Neurosci 18:418–429. doi: 10.1162/089892906775990552.White PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Venkatraman V, Aizenstein H, Guralnik J et al (2010) Executive control function, brain activation and white matter hyperintensities in older adults. Neuroimage 49:1–18. doi: 10.1016/j.neuroimage.2009.11.019.Executive CrossRefGoogle Scholar
  48. 48.
    Linortner P, Fazekas F, Schmidt R et al (2012) White matter hyperintensities alter functional organization of the motor system. Neurobiol Aging 33:1–8CrossRefGoogle Scholar
  49. 49.
    Elbaz A, Vicente-Vytopilova P, Tavernier B et al (2013) Motor function in the elderly: evidence for the reserve hypothesis. Neurology 81:417–426PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Sajjad A, Mirza SS, Portegies MLP et al (2015) Subjective memory complaints and the risk of stroke. Stroke 46:170–175. doi: 10.1161/STROKEAHA.114.006616 CrossRefPubMedGoogle Scholar
  51. 51.
    Ihara M, Okamoto Y, Hase Y, Takahashi R (2013) Association of physical activity with the visuospatial/executive functions of the montreal cognitive assessment in patients with vascular cognitive impairment. J Stroke Cerebrovasc Dis 22:146–151. doi: 10.1016/j.jstrokecerebrovasdis.2012.10.007 CrossRefGoogle Scholar
  52. 52.
    Verdelho A, Madureira S, Ferro JM et al (2012) Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study. Stroke 43:3331–3335. doi: 10.1161/STROKEAHA.112.661793 CrossRefPubMedGoogle Scholar
  53. 53.
    Zieren N, Duering M, Peters N et al (2013) Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy. Neurobiol Aging 34:400–407CrossRefPubMedGoogle Scholar
  54. 54.
    Amato MP, Razzolini L, Goretti B et al (2013) Cognitive reserve and cortical atrophy in multiple sclerosis: a longitudinal study. Neurology. doi: 10.1212/WNL.0b013e3182918c6f Google Scholar
  55. 55.
    Cavalieri M, Enzinger C, Petrovic K et al (2010) Vascular dementia and Alzheimer’s disease—are we in a dead-end road? Neurodegener Dis 7:122–126. doi: 10.1159/000285521 CrossRefPubMedGoogle Scholar
  56. 56.
    Brehmer Y, Kalpouzos G, Wenger E, Lövdén M (2014) Plasticity of brain and cognition in older adults. Psychol Res. doi: 10.1007/s00426-014-0587-z PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Daniela Pinter
    • 1
  • Christian Enzinger
    • 1
    • 2
  • Franz Fazekas
    • 1
    Email author
  1. 1.Department of NeurologyMedical University of GrazGrazAustria
  2. 2.Division of Neuroradiology, Department of RadiologyMedical University of GrazGrazAustria

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