Cerebral small vessel disease: from a focal to a global perspective

Abstract

Cerebral small vessel disease (SVD) is commonly observed on neuroimaging among elderly individuals and is recognized as a major vascular contributor to dementia, cognitive decline, gait impairment, mood disturbance and stroke. However, clinical symptoms are often highly inconsistent in nature and severity among patients with similar degrees of SVD on brain imaging. Here, we provide a new framework based on new advances in structural and functional neuroimaging that aims to explain the remarkable clinical variation in SVD. First, we discuss the heterogeneous pathology present in SVD lesions despite an identical appearance on imaging and the perilesional and remote effects of these lesions. We review effects of SVD on structural and functional connectivity in the brain, and we discuss how network disruption by SVD can lead to clinical deficits. We address reserve and compensatory mechanisms in SVD and discuss the part played by other age-related pathologies. Finally, we conclude that SVD should be considered a global rather than a focal disease, as the classically recognized focal lesions affect remote brain structures and structural and functional network connections. The large variability in clinical symptoms among patients with SVD can probably be understood by taking into account the heterogeneity of SVD lesions, the effects of SVD beyond the focal lesions, the contribution of neurodegenerative pathologies other than SVD, and the interaction with reserve mechanisms and compensatory mechanisms.

Key points

  • Cerebral small vessel disease (SVD) is associated with a remarkable degree of variation in clinical symptoms — both in nature and in severity — that cannot be explained fully by conventional markers of SVD.

  • Conventional MRI does not capture the heterogeneity present in SVD lesions with a similar appearance and reveals only the tip of the iceberg of the total SVD-related brain damage.

  • SVD affects brain tissue beyond the commonly recognized focal lesions by inducing a cascade of events that spread from the initial lesion to remote brain areas, which probably contributes to clinical outcome.

  • SVD disturbs structural and functional network connectivity and thereby disrupts efficient communication in brain networks, which is necessary for functional performance.

  • Brain resilience protects against clinical deterioration caused by SVD via reserve and compensatory mechanisms, which explains the clinical variation observed in patients with apparently equal SVD lesion burden.

  • The clinical notion that SVD mostly constitutes a subcortical disease of focal lesions requires reconsideration.

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Fig. 1: Features of cerebral SVD on MRI.
Fig. 2: What you see is not what you get.

References

  1. 1.

    Kontis, V. et al. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 389, 1323–1335 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Prince, M. et al. World Alzheimer Report 2015: The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends (Alzheimer’s Disease International, 2015).

  3. 3.

    METACOHORTS Consortium. METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: an initiative of the Joint Programme for Neurodegenerative Disease Research. Alzheimers Dement. 12, 1235–1249 (2016).

    Article  Google Scholar 

  4. 4.

    de Laat, K. F. et al. Gait in elderly with cerebral small vessel disease. Stroke 41, 1652–1658 (2010).

    PubMed  Article  Google Scholar 

  5. 5.

    Wardlaw, J. M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Debette, S. & Markus, H. S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341, c3666 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    van Agtmaal, M. J. M., Houben, A., Pouwer, F., Stehouwer, C. D. A. & Schram, M. T. Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis. JAMA Psychiatry 74, 729–739 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    de Leeuw, F. E. et al. 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, 9–14 (2001).

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Pantoni, L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689–701 (2010).

    PubMed  Article  Google Scholar 

  10. 10.

    Cummings, J. L. Frontal-subcortical circuits and human behavior. Arch. Neurol. 50, 873–880 (1993).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Jokinen, H. et al. Longitudinal cognitive decline in subcortical ischemic vascular disease — the LADIS Study. Cerebrovasc. Dis. 27, 384–391 (2009).

    PubMed  Article  Google Scholar 

  12. 12.

    Baezner, H. et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 70, 935–942 (2008).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Smith, E. E. et al. Early cerebral small vessel disease and brain volume, cognition, and gait. Ann. Neurol. 77, 251–261 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    van der Holst, H. M. et al. Cerebral small vessel disease and incident parkinsonism: the RUN DMC study. Neurology 85, 1569–1577 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Marin, R. S., Biedrzycki, R. C. & Firinciogullari, S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 38, 143–162 (1991).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Stanton, B. R. & Carson, A. Apathy: a practical guide for neurologists. Pract. Neurol. 16, 42–47 (2016).

    PubMed  Article  Google Scholar 

  17. 17.

    Hollocks, M. J. et al. Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain 138, 3803–3815 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    van Uden, I. W. et al. White matter integrity and depressive symptoms in cerebral small vessel disease: the RUN DMC study. Am. J. Geriatr. Psychiatry 23, 525–535 (2015).

    PubMed  Article  Google Scholar 

  19. 19.

    Edwards, J. D., Jacova, C., Sepehry, A. A., Pratt, B. & Benavente, O. R. A quantitative systematic review of domain-specific cognitive impairment in lacunar stroke. Neurology 80, 315–322 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Seo, S. W. et al. Clinical significance of microbleeds in subcortical vascular dementia. Stroke 38, 1949–1951 (2007).

    PubMed  Article  Google Scholar 

  21. 21.

    Hillis, A. E. et al. Subcortical aphasia and neglect in acute stroke: the role of cortical hypoperfusion. Brain 125, 1094–1104 (2002).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Hoffmann, M. & Chen, R. The spectrum of aphasia subtypes and etiology in subacute stroke. J. Stroke Cerebrovasc. Dis. 22, 1385–1392 (2013).

    PubMed  Article  Google Scholar 

  23. 23.

    Van Zandvoort, M. J., De Haan, E. H. & Kappelle, L. J. Chronic cognitive disturbances after a single supratentorial lacunar infarct. Neuropsychiatry Neuropsychol. Behav. Neurol. 14, 98–102 (2001).

    PubMed  Google Scholar 

  24. 24.

    Vasquez, B. P. & Zakzanis, K. K. The neuropsychological profile of vascular cognitive impairment not demented: a meta-analysis. J. Neuropsychol. 9, 109–136 (2015).

    PubMed  Article  Google Scholar 

  25. 25.

    Van der Werf, Y. D. et al. Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 41, 1330–1344 (2003).

    PubMed  Article  Google Scholar 

  26. 26.

    Van Der Werf, Y. D. et al. Neuropsychological correlates of a right unilateral lacunar thalamic infarction. J. Neurol. Neurosurg. Psychiatry 66, 36–42 (1999).

    PubMed Central  Article  Google Scholar 

  27. 27.

    Kooistra, C. A. & Heilman, K. M. Memory loss from a subcortical white matter infarct. J. Neurol. Neurosurg. Psychiatry 51, 866–869 (1988).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Tatemichi, T. K. et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 42, 1966–1979 (1992).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    van Uden, I. W. et al. White matter and hippocampal volume predict the risk of dementia in patients with cerebral small vessel disease: the RUN DMC study. J. Alzheimers Dis. 49, 863–873 (2016).

    PubMed  Article  Google Scholar 

  30. 30.

    Gouw, A. A. et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J. Neurol. Neurosurg. Psychiatry 82, 126–135 (2011).

    PubMed  Article  Google Scholar 

  31. 31.

    Lammie, G. A., Brannan, F. & Wardlaw, J. M. Incomplete lacunar infarction (Type Ib lacunes). Acta Neuropathol. 96, 163–171 (1998).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Shoamanesh, A., Kwok, C. S. & Benavente, O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dis. 32, 528–534 (2011).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    van Veluw, S. J., Biessels, G. J., Klijn, C. J. & Rozemuller, A. J. Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy. Neurology 86, 867–871 (2016).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Joutel, A. & Chabriat, H. Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms. Clin. Sci. 131, 635–651 (2017).

    PubMed  Article  Google Scholar 

  36. 36.

    Keith, J. et al. Collagenosis of the deep medullary veins: an underrecognized pathologic correlate of white matter hyperintensities and periventricular infarction? J. Neuropathol. Exp. Neurol. 76, 299–312 (2017).

    PubMed  Article  Google Scholar 

  37. 37.

    Brown, W. R., Moody, D. M., Challa, V. R., Thore, C. R. & Anstrom, J. A. Venous collagenosis and arteriolar tortuosity in leukoaraiosis. J. Neurol. Sci. 203–204, 159–163 (2002).

    PubMed  Article  Google Scholar 

  38. 38.

    Matsusue, E. et al. White matter changes in elderly people: MR-pathologic correlations. Magn. Reson. Med. Sci. 5, 99–104 (2006).

    PubMed  Article  Google Scholar 

  39. 39.

    Auriel, E. et al. Microinfarct disruption of white matter structure: a longitudinal diffusion tensor analysis. Neurology 83, 182–188 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Maillard, P. et al. White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. Stroke 45, 1721–1726 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Spilt, A. et al. Not all age-related white matter hyperintensities are the same: a magnetization transfer imaging study. AJNR Am. J. Neuroradiol. 27, 1964–1968 (2006).

    PubMed  CAS  Google Scholar 

  42. 42.

    Tanabe, J. L. et al. Magnetization transfer ratio of white matter hyperintensities in subcortical ischemic vascular dementia. AJNR Am. J. Neuroradiol. 20, 839–844 (1999).

    PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Haller, S. et al. Do brain T2/FLAIR white matter hyperintensities correspond to myelin loss in normal aging? A radiologic-neuropathologic correlation study. Acta Neuropathol. Commun. 1, 14 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Wardlaw, J. M., Valdes Hernandez, M. C. & Munoz-Maniega, S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc. 4, 001140 (2015).

    PubMed  Article  Google Scholar 

  45. 45.

    Soares, J. M., Marques, P., Alves, V. & Sousa, N. A hitchhiker’s guide to diffusion tensor imaging. Front. Neurosci. 7, 31 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Bouvy, W. H. et al. Abnormalities of cerebral deep medullary veins on 7 Tesla MRI in amnestic mild cognitive impairment and early Alzheimer’s disease: a pilot study. J. Alzheimers Dis. 57, 705–710 (2017).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    van Dalen, J. W. et al. White matter hyperintensity volume and cerebral perfusion in older individuals with hypertension using arterial spin-labeling. AJNR Am. J. Neuroradiol. 37, 1824–1830 (2016).

    Article  Google Scholar 

  48. 48.

    van Nieuwenhuizen, K. M., Hendrikse, J. & Klijn, C. J. M. New microbleed after blood-brain barrier leakage in intracerebral haemorrhage. BMJ Case Rep. https://doi.org/10.1136/bcr-2016-218794 (2017).

    PubMed  Article  Google Scholar 

  49. 49.

    Koch, S., McClendon, M. S. & Bhatia, R. Imaging evolution of acute lacunar infarction: leukoariosis or lacune? Neurology 77, 1091–1095 (2011).

    PubMed  Article  Google Scholar 

  50. 50.

    van Veluw, S. J. et al. Evolution of DWI lesions in cerebral amyloid angiopathy: evidence for ischemia. Neurology 89, 2136–2142 (2017).

    PubMed  Article  Google Scholar 

  51. 51.

    Maillard, P. et al. White matter hyperintensity penumbra. Stroke 42, 1917–1922 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Maniega, S. M. et al. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol. Aging 36, 909–918 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Reijmer, Y. D., Freeze, W. M., Leemans, A. & Biessels, G. J. The effect of lacunar infarcts on white matter tract integrity. Stroke 44, 2019–2021 (2013).

    PubMed  Article  Google Scholar 

  54. 54.

    Hinman, J. D., Lee, M. D., Tung, S., Vinters, H. V. & Carmichael, S. T. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain 138, 736–745 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Lee, W. J., Lee, J. Y., Lim, J. S., Kwon, H. M. & Lee, Y. S. Transient isolated ocular motor abnormality related to perilesional edema of an acute medullary microbleed: A case report and review of the literatures. Clin. Neurol. Neurosurg. 138, 174–176 (2015).

    PubMed  Article  Google Scholar 

  56. 56.

    Lawrence, A. J. et al. 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 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Pasi, M., van Uden, I. W., Tuladhar, A. M., de Leeuw, F. E. & Pantoni, L. White matter microstructural damage on diffusion tensor imaging in cerebral small vessel disease: clinical consequences. Stroke 47, 1679–1684 (2016).

    PubMed  Article  Google Scholar 

  58. 58.

    Tuladhar, A. M. et al. White matter integrity in small vessel disease is related to cognition. Neuroimage Clin. 7, 518–524 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Baykara, E. et al. A novel imaging marker for small vessel disease based on skeletonization of white matter tracts and diffusion histograms. Ann. Neurol. 80, 581–592 (2016).

    PubMed  Article  Google Scholar 

  60. 60.

    Williams, O. A. et al. Diffusion tensor image segmentation of the cerebrum provides a single measure of cerebral small vessel disease severity related to cognitive change. Neuroimage Clin. 16, 330–342 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Coban, H., Tung, S., Yoo, B., Vinters, H. V. & Hinman, J. D. Molecular disorganization of axons adjacent to human cortical microinfarcts. Front. Neurol. 8, 405 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Shih, A. Y. et al. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat. Neurosci. 16, 55–63 (2013).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Summers, P. M. et al. Functional deficits induced by cortical microinfarcts. J. Cereb. Blood Flow Metab. 37, 3599–3614 (2017).

    PubMed  Article  Google Scholar 

  64. 64.

    Arvanitakis, Z., Leurgans, S. E., Barnes, L. L., Bennett, D. A. & Schneider, J. A. Microinfarct pathology, dementia, and cognitive systems. Stroke 42, 722–727 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    van Veluw, S. J. et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol. 16, 730–740 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Tullberg, M. et al. White matter lesions impair frontal lobe function regardless of their location. Neurology 63, 246–253 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

    Dickie, D. A. et al. Progression of white matter disease and cortical thinning are not related in older community-dwelling subjects. Stroke 47, 410–416 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Lambert, C. et al. Characterising the grey matter correlates of leukoaraiosis in cerebral small vessel disease. Neuroimage Clin. 9, 194–205 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Tuladhar, A. M. et al. Relationship between white matter hyperintensities, cortical thickness, and cognition. Stroke 46, 425–432 (2015).

    PubMed  Article  Google Scholar 

  70. 70.

    Lambert, C. et al. Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease. Brain 139, 1136–1151 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Duering, M. et al. Incident subcortical infarcts induce focal thinning in connected cortical regions. Neurology 79, 2025–2028 (2012).

    PubMed  Article  Google Scholar 

  72. 72.

    Duering, M. et al. Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. Neurology 84, 1685–1692 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Jokinen, H. et al. Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study. Neurology 78, 1785–1792 (2012).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Schmidt, R. et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study. Ann. Neurol. 58, 610–616 (2005).

    PubMed  Article  Google Scholar 

  75. 75.

    Righart, R. et al. Impact of regional cortical and subcortical changes on processing speed in cerebral small vessel disease. Neuroimage Clin. 2, 854–861 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Kim, Y. J. et al. Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86, 1199–1207 (2016).

    PubMed  Article  Google Scholar 

  77. 77.

    Lawrence, A. J., Chung, A. W., Morris, R. G., Markus, H. S. & Barrick, T. R. Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology 83, 304–311 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Tuladhar, A. M. et al. Disruption of rich club organisation in cerebral small vessel disease. Hum. Brain Mapp. 38, 1751–1766 (2017).

    PubMed  Article  Google Scholar 

  79. 79.

    Tuladhar, A. M. et al. Structural network connectivity and cognition in cerebral small vessel disease. Hum. Brain Mapp. 37, 300–310 (2016).

    PubMed  Article  Google Scholar 

  80. 80.

    Tang, J. et al. Aberrant white matter networks mediate cognitive impairment in patients with silent lacunar infarcts in basal ganglia territory. J. Cereb. Blood Flow Metab. 35, 1426–1434 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    van den Heuvel, M. P. & Sporns, O. Rich-club organization of the human connectome. J. Neurosci. 31, 15775–15786 (2011).

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    van den Heuvel, M. P., Kahn, R. S., Goni, J. & Sporns, O. High-cost, high-capacity backbone for global brain communication. Proc. Natl Acad. Sci. USA 109, 11372–11377 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Reijmer, Y. D. et al. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy. Brain 138, 179–188 (2015).

    PubMed  Article  Google Scholar 

  84. 84.

    Xie, X., Shi, Y. & Zhang, J. Structural network connectivity impairment and depressive symptoms in cerebral small vessel disease. J. Affect. Disord. 220, 8–14 (2017).

    PubMed  Article  Google Scholar 

  85. 85.

    Tuladhar, A. M. et al. Structural network efficiency predicts conversion to dementia. Neurology 86, 1112–1119 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Reijmer, Y. D. et al. Small vessel disease and cognitive impairment: the relevance of central network connections. Hum. Brain Mapp. 37, 2446–2454 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Fornito, A., Zalesky, A. & Breakspear, M. The connectomics of brain disorders. Nat. Rev. Neurosci. 16, 159–172 (2015).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    van den Heuvel, M. P. & Hulshoff Pol, H. E. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur. Neuropsychopharmacol 20, 519–534 (2010).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Spreng, R. N., Sepulcre, J., Turner, G. R., Stevens, W. D. & Schacter, D. L. Intrinsic architecture underlying the relations among the default, dorsal attention, and frontoparietal control networks of the human brain. J. Cogn. Neurosci. 25, 74–86 (2013).

    PubMed  Article  Google Scholar 

  90. 90.

    Dey, A. K., Stamenova, V., Turner, G., Black, S. E. & Levine, B. Pathoconnectomics of cognitive impairment in small vessel disease: a systematic review. Alzheimers Dement. 12, 831–845 (2016).

    PubMed  Article  Google Scholar 

  91. 91.

    Cheng, H. L. et al. Impairments in cognitive function and brain connectivity in severe asymptomatic carotid stenosis. Stroke 43, 2567–2573 (2012).

    PubMed  Article  Google Scholar 

  92. 92.

    Schaefer, A. et al. Early small vessel disease affects frontoparietal and cerebellar hubs in close correlation with clinical symptoms — a resting-state fMRI study. J. Cereb. Blood Flow Metab. 34, 1091–1095 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Sun, Y. W. et al. Abnormal functional connectivity in patients with vascular cognitive impairment, no dementia: a resting-state functional magnetic resonance imaging study. Behav. Brain Res. 223, 388–394 (2011).

    PubMed  Article  Google Scholar 

  94. 94.

    van Duinkerken, E. et al. Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables. Diabetes 61, 1814–1821 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Yi, L. et al. Structural and functional changes in subcortical vascular mild cognitive impairment: a combined voxel-based morphometry and resting-state fMRI study. PLoS ONE 7, e44758 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Zhou, Y., Yu, F. & Duong, T. Q. Alzheimer’s Disease Neuroimaging Initiative. White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer’s disease patients. J. Magn. Reson. Imag. 41, 102–109 (2015).

    Article  Google Scholar 

  97. 97.

    Nordahl, C. W. et al. White matter changes compromise prefrontal cortex function in healthy elderly individuals. J. Cogn. Neurosci. 18, 418–429 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Venkatraman, V. K. et al. Executive control function, brain activation and white matter hyperintensities in older adults. Neuroimage 49, 3436–3442 (2010).

    PubMed  Article  Google Scholar 

  99. 99.

    Welker, K. M., De Jesus, R. O., Watson, R. E., Machulda, M. M. & Jack, C. R. Altered functional MR imaging language activation in elderly individuals with cerebral leukoaraiosis. Radiology 265, 222–232 (2012).

    PubMed  Article  Google Scholar 

  100. 100.

    Aizenstein, H. J. et al. fMRI correlates of white matter hyperintensities in late-life depression. Am. J. Psychiatry 168, 1075–1082 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Liu, C. et al. Abnormal intrinsic brain activity patterns in patients with subcortical ischemic vascular dementia. PLoS ONE 9, e87880 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Mayda, A. B., Westphal, A., Carter, C. S. & DeCarli, C. Late life cognitive control deficits are accentuated by white matter disease burden. Brain 134, 1673–1683 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Papma, J. M. et al. The influence of cerebral small vessel disease on default mode network deactivation in mild cognitive impairment. Neuroimage Clin. 2, 33–42 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Chen, Y. et al. Aberrant functional networks connectivity and structural atrophy in silent lacunar infarcts: relationship with cognitive impairments. J. Alzheimers Dis. 42, 841–850 (2014).

    PubMed  Article  Google Scholar 

  105. 105.

    Stern, Y. Cognitive reserve. Neuropsychologia 47, 2015–2028 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Brickman, A. M. et al. White matter hyperintensities and cognition: testing the reserve hypothesis. Neurobiol. Aging 32, 1588–1598 (2011).

    PubMed  Article  Google Scholar 

  107. 107.

    Mortimer, J. A., Snowdon, D. A. & Markesbery, W. R. Head circumference, education and risk of dementia: findings from the Nun Study. J. Clin. Exp. Neuropsychol 25, 671–679 (2003).

    PubMed  Article  Google Scholar 

  108. 108.

    Smith, E. E. et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch. Neurol. 65, 94–100 (2008).

    PubMed  Google Scholar 

  109. 109.

    Pinter, D., Enzinger, C. & Fazekas, F. Cerebral small vessel disease, cognitive reserve and cognitive dysfunction. J. Neurol. 262, 2411–2419 (2015).

    PubMed  Article  Google Scholar 

  110. 110.

    Barulli, D. & Stern, Y. Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn. Sci. 17, 502–509 (2013).

    PubMed  Article  Google Scholar 

  111. 111.

    Stern, Y. What is cognitive reserve? Theory and research application of the reserve concept. J. Int. Neuropsychol Soc. 8, 448–460 (2002).

    PubMed  Article  Google Scholar 

  112. 112.

    Dufouil, C., Alperovitch, A. & Tzourio, C. Influence of education on the relationship between white matter lesions and cognition. Neurology 60, 831–836 (2003).

    PubMed  Article  CAS  Google Scholar 

  113. 113.

    Elbaz, A. et al. Motor function in the elderly: evidence for the reserve hypothesis. Neurology 81, 417–426 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Nebes, R. D. et al. The relation of white matter hyperintensities to cognitive performance in the normal old: education matters. Neuropsychol Dev. Cogn. B Aging Neuropsychol Cogn. 13, 326–340 (2006).

    PubMed  Article  Google Scholar 

  115. 115.

    Saczynski, J. S. et al. White matter lesions and cognitive performance: the role of cognitively complex leisure activity. J. Gerontol. A Biol. Sci. Med. Sci. 63, 848–854 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Vemuri, P. et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761–771 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Murray, A. D. et al. The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer’s diseases. Brain 134, 3687–3696 (2011).

    PubMed  Article  Google Scholar 

  118. 118.

    Jokinen, H. et al. Cognitive reserve moderates long-term cognitive and functional outcome in cerebral small vessel disease. J. Neurol. Neurosurg. Psychiatry 87, 1296–1302 (2016).

    PubMed  Article  Google Scholar 

  119. 119.

    Park, D. C. & Reuter-Lorenz, P. The adaptive brain: aging and neurocognitive scaffolding. Annu. Rev. Psychol. 60, 173–196 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Steffener, J., Brickman, A. M., Rakitin, B. C., Gazes, Y. & Stern, Y. The impact of age-related changes on working memory functional activity. Brain Imag. Behav. 3, 142–153 (2009).

    Article  Google Scholar 

  121. 121.

    Daselaar, S. M. et al. Less wiring, more firing: low-performing older adults compensate for impaired white matter with greater neural activity. Cereb. Cortex 25, 983–990 (2015).

    PubMed  Article  Google Scholar 

  122. 122.

    Nestor, S. M. et al. Small vessel disease is linked to disrupted structural network covariance in Alzheimer’s disease. Alzheimers Dement. 13, 749–760 (2017).

    PubMed  Article  Google Scholar 

  123. 123.

    Godin, O. et al. Joint effect of white matter lesions and hippocampal volumes on severity of cognitive decline: the 3C-Dijon MRI study. J. Alzheimers Dis. 20, 453–463 (2010).

    PubMed  Article  Google Scholar 

  124. 124.

    van der Flier, W. M. et al. Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study. J. Neurol. Neurosurg. Psychiatry 76, 1497–1500 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Koncz, R. & Sachdev, P. S. Are the brain’s vascular and Alzheimer pathologies additive or interactive? Curr. Opin. Psychiatry 31, 147–152 (2018).

    PubMed  Google Scholar 

  126. 126.

    Roseborough, A., Ramirez, J., Black, S. E. & Edwards, J. D. Associations between amyloid beta and white matter hyperintensities: a systematic review. Alzheimers Dement 13, 1154–1167 (2017).

    PubMed  Article  Google Scholar 

  127. 127.

    Oosterman, J. M., Oosterveld, S., Rikkert, M. G., Claassen, J. A. & Kessels, R. P. Medial temporal lobe atrophy relates to executive dysfunction in Alzheimer’s disease. Int. Psychogeriatr. 24, 1474–1482 (2012).

    PubMed  Article  Google Scholar 

  128. 128.

    De Guio, F. et al. Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease. J. Cereb. Blood Flow Metab. 36, 1319–1337 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Goos, J. D. et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke 42, 1894–1900 (2011).

    PubMed  Article  Google Scholar 

  130. 130.

    Tryambake, D. et al. Intensive blood pressure lowering increases cerebral blood flow in older subjects with hypertension. Hypertension 61, 1309–1315 (2013).

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Fleischer, V. et al. Graph theoretical framework of brain networks in multiple sclerosis: a review of concepts. Neuroscience https://doi.org/10.1016/j.neuroscience.2017.10.033 (2017).

    Article  Google Scholar 

  132. 132.

    Charidimou, A., Pantoni, L. & Love, S. The concept of sporadic cerebral small vessel disease: a road map on key definitions and current concepts. Int. J. Stroke 11, 6–18 (2016).

    PubMed  Article  Google Scholar 

  133. 133.

    Wardlaw, J. M., Smith, C. & Dichgans, M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483–497 (2013).

    PubMed  Article  Google Scholar 

  134. 134.

    Hill, M. A. & Meininger, G. A. Arteriolar vascular smooth muscle cells: mechanotransducers in a complex environment. Int. J. Biochem. Cell Biol. 44, 1505–1510 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    Charidimou, A. et al. Emerging concepts in sporadic cerebral amyloid angiopathy. Brain 140, 1829–1850 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Damoiseaux, J. S. et al. Consistent resting-state networks across healthy subjects. Proc. Natl Acad. Sci. USA 103, 13848–13853 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Bullmore, E. & Sporns, O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 10, 186–198 (2009).

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    Sporns, O. Contributions and challenges for network models in cognitive neuroscience. Nat. Neurosci. 17, 652–660 (2014).

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Brundel, M., de Bresser, J., van Dillen, J. J., Kappelle, L. J. & Biessels, G. J. Cerebral microinfarcts: a systematic review of neuropathological studies. J. Cereb. Blood Flow Metab. 32, 425–436 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

C.J.M.K. was supported by a clinical established investigator grant of the Dutch Heart Foundation (grant number 2012 T077) and an Aspasia grant from the Netherlands Organisation for Health Research and Development (ZonMw grant 015.008.048). A.M.T. was supported by the Dutch Heart Foundation (grant number 2016T044). F.-E.d.L. was supported by a clinical established investigator grant of the Dutch Heart Foundation (grant number 2014 T060) and a VIDI innovational grant from the Netherlands Organisation for Health Research and Development (ZonMw grant 016.126.351). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Review criteria

Articles were selected from PubMed. To select articles on small vessel disease, we used the following search terms appearing in the title and abstract: “cerebral small vessel disease”, “cerebral microangiopath*”, “white matter hyperintensities”, “leukoaraiosis”, “lacunar stroke”, “lacunar infarct”, “perivascular spaces” or “microbleeds”. We combined these searches with search terms covering the topics in this Review, including “cognition”, “motor”, “cerebral cortex”, “network” or “connect*”. We included only articles in English and focused on articles published within the past decade to discuss the most recent scientific findings. Furthermore, reference lists of cited articles and articles in our personal databases were screened for eligibility.

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Nature Reviews Neurology thanks A. Charidimou, S. Black and the other anonymous reviewer for their contribution to the peer review of this work.

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A.t.T. and E.M.C.v.L. researched the data for the article and wrote the text. A.t.T., K.W. and A.M.T. researched the data and created the boxes and figures. A.t.T., E.M.C.v.L., K.W., C.J.M.K., A.M.T. and F.-E.d.L. provided substantial contributions to discussions of the content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Frank-Erik de Leeuw.

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ter Telgte, A., van Leijsen, E.M.C., Wiegertjes, K. et al. Cerebral small vessel disease: from a focal to a global perspective. Nat Rev Neurol 14, 387–398 (2018). https://doi.org/10.1038/s41582-018-0014-y

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