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.
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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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.
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.
Nature Reviews Neurology thanks A. Charidimou, S. Black and the other anonymous reviewer for their contribution to the peer review of this work.
The authors declare no competing interests.
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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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