Cerebral small vessel disease (CSVD) is a collective term encompassing the pathological processes affecting the small perforating arteries, arterioles, capillaries, and venules that supply the deep white matter, basal ganglia, thalamus, brainstem, and cerebellum. These diminutive vessels, typically measuring between 50 and 400 micrometers in diameter, are uniquely vulnerable to hemodynamic stress, metabolic injury, and inflammatory insults by virtue of their anatomical characteristics: they branch directly from larger conducting arteries at near-right angles, possess limited collateral supply, and must maintain blood-brain barrier (BBB) integrity across an exceptionally large cumulative surface area. The clinical significance of CSVD is substantial and multifaceted. It is responsible for approximately 25% of ischemic strokes, predominantly manifesting as lacunar infarctions, and constitutes the leading cause of spontaneous intracerebral hemorrhage in populations over 65 years of age. Beyond these acute cerebrovascular events, CSVD is the principal substrate of vascular cognitive impairment (VCI), the second most prevalent form of dementia globally, and contributes substantially to the cognitive decline observed in mixed dementia pathology. Furthermore, CSVD is independently associated with gait and balance disturbances, urinary incontinence, mood disorders, and increased mortality, collectively constituting an enormous and rising burden on healthcare systems worldwide. Despite its pervasive clinical impact, CSVD has historically occupied a peripheral position in cerebrovascular research and clinical practice. The silent, progressive nature of the disease, the absence of dramatic acute presentations in many patients, and the previous limitations of neuroimaging technology conspired to create a perception of CSVD as an inevitable and untreatable consequence of aging and hypertension. This nihilistic perspective has undergone a fundamental revision over the past decade. Advances in magnetic resonance imaging (MRI) have established a standardized framework for identifying and quantifying CSVD markers in vivo. Simultaneously, molecular and genetic studies have revealed a complex pathobiology that extends far beyond the traditional arteriosclerotic-lipohyalinotic model to encompass endothelial dysfunction, BBB permeability changes, neuroinflammation, impaired perivascular clearance, and oligodendrocyte vulnerability. This review synthesizes the contemporary understanding of CSVD pathogenesis, appraises the evolving neuroimaging landscape for disease characterization, and critically evaluates established and emerging therapeutic strategies. By integrating mechanistic insights with clinical and radiological perspectives, we aim to provide a coherent framework for understanding this heterogeneous disorder and to identify the most promising avenues for future translational research.

Pathological Classification

The classification of CSVD encompasses several distinct pathological entities that differ in their underlying etiology, predilection sites, and clinical manifestations. The most prevalent form, arteriosclerotic or age-related CSVD, is characterized by lipohyalinosis, fibrinoid necrosis, and microatheroma formation in the walls of small penetrating arteries. This subtype is strongly associated with hypertension, diabetes mellitus, and advancing age, and preferentially affects the basal ganglia, thalamus, pons, and deep cerebral white matter. Cerebral amyloid angiopathy (CAA), the second most common form, results from the progressive accumulation of beta-amyloid peptide within the walls of cortical and leptomeningeal arterioles and capillaries. CAA demonstrates a predilection for the posterior cortical regions and is the predominant cause of lobar intracerebral hemorrhage and cortical superficial siderosis in the elderly. Less common subtypes include hereditary CSVD (exemplified by CADASIL, CARASIL, Fabry disease, and collagen IV-related arteriopathies), inflammatory and immunologically mediated forms (central nervous system vasculitis, neurolupus), venous collagenosis, and post-radiation angiopathy.

Epidemiology and Risk Factors

CSVD is an extraordinarily prevalent condition, with neuroimaging evidence detectable in the majority of individuals over 60 years of age. Population-based MRI studies have reported white matter hyperintensities (WMH) in 50 to 98% of elderly cohorts, with prevalence and severity increasing markedly with age. Lacunes are identified in 8 to 28% of the general elderly population, while cerebral microbleeds (CMBs) are present in approximately 15 to 35% of individuals over 80 years. Hypertension is the single most potent modifiable risk factor for arteriosclerotic CSVD, with a dose-response relationship between blood pressure exposure and WMH burden that begins well below traditional hypertension thresholds. Additional established risk factors include diabetes mellitus, smoking, hyperlipidemia, chronic kidney disease, obstructive sleep apnea, and physical inactivity. Genetic susceptibility plays a substantial role: genome-wide association studies have identified over 30 susceptibility loci for WMH burden, implicating pathways related to vascular development, extracellular matrix composition, astrocyte function, and myelination.

Endothelial Dysfunction and the Neurovascular Unit

The cerebral endothelium, once considered merely a passive barrier, is now recognized as a metabolically active organ that orchestrates vascular tone, permeability, angiogenesis, and immune surveillance within the neurovascular unit (NVU). Endothelial dysfunction, characterized by reduced nitric oxide bioavailability, increased oxidative stress, and a shift toward a pro-inflammatory and pro-thrombotic endothelial phenotype, is emerging as a central and potentially initiating mechanism in CSVD pathogenesis. Clinical evidence supporting endothelial dysfunction in CSVD includes elevated circulating biomarkers of endothelial activation (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, von Willebrand factor, thrombomodulin, and asymmetric dimethylarginine) in patients with lacunar stroke and progressive WMH. Retinal microvascular studies, which provide a non-invasive window into the cerebral microcirculation, have consistently demonstrated arteriolar narrowing, reduced fractal dimension, and impaired vasodilatory responses in individuals with CSVD, further substantiating a primary endotheliopathy.

Blood-Brain Barrier Breakdown

The BBB, maintained by the coordinated function of endothelial tight junctions, pericytes, and astrocytic end-feet, is a defining feature of the cerebral microcirculation and a critical determinant of neural homeostasis. Disruption of BBB integrity permits the extravasation of plasma proteins, including fibrinogen, immunoglobulins, and albumin, into the perivascular space and brain parenchyma, initiating a cascade of secondary injury. Dynamic contrast-enhanced (DCE) MRI, which quantifies the leakage of gadolinium-based contrast agent across the BBB, has provided compelling in vivo evidence that BBB permeability is increased in CSVD patients, even in normal-appearing white matter remote from visible lesions. Critically, the degree of BBB leakage correlates with WMH volume, predicts future WMH progression, and is associated with cognitive decline, positioning BBB breakdown as both a biomarker and a pathogenic driver of disease evolution. Extravasated fibrinogen activates microglia, promotes oligodendrocyte apoptosis, and inhibits remyelination, providing a direct mechanistic link between BBB failure and the demyelination that characterizes WMH pathologically.

Neuroinflammation and Immune-Mediated Injury

Chronic low-grade neuroinflammation has emerged as a pivotal mechanism amplifying and perpetuating small vessel injury. Neuropathological studies of CSVD demonstrate perivascular inflammatory infiltrates, microglial activation, and reactive astrogliosis in affected white matter regions. Circulating levels of pro-inflammatory mediators, including C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and matrix metalloproteinase-9, are elevated in CSVD patients and independently predict disease progression. The NLRP3 inflammasome pathway has attracted particular attention as a convergence point for multiple CSVD risk factors. Hypertension, hyperglycemia, oxidative stress, and extravasated plasma proteins each independently activate the NLRP3 inflammasome in endothelial cells, pericytes, and microglia, driving interleukin-1 beta and interleukin-18 secretion and establishing a self-reinforcing inflammatory cycle. Targeting this inflammasome pathway represents a mechanistically rational therapeutic strategy, as discussed in subsequent sections.

Impaired Glymphatic Clearance and Perivascular Drainage

The glymphatic system, a brain-wide perivascular transport network dependent on aquaporin-4 (AQP4) water channels polarized to astrocytic end-feet, facilitates the convective clearance of interstitial solutes, metabolic waste products, and neurotoxic proteins from the brain parenchyma. Glymphatic flow is predominantly active during sleep and is driven by arterial pulsatility. CSVD is hypothesized to impair glymphatic function through multiple mechanisms: arterial stiffening reduces the pulsatile driving force, perivascular space dilation disrupts the anatomical conduit architecture, and reactive astrogliosis causes redistribution and depolarization of AQP4 channels. Enlarged perivascular spaces (EPVS), visible on MRI as fluid-filled channels following the course of penetrating vessels, are a recognized CSVD marker that is thought to reflect impaired perivascular drainage. The severity and distribution of EPVS correlate with WMH burden, cerebral amyloid deposition, and cognitive performance. Impaired glymphatic clearance may establish a vicious cycle in which the accumulation of neurotoxic proteins (beta-amyloid, hyperphosphorylated tau) in the vessel wall further damages the microvasculature, promoting additional clearance failure and accelerating the transition from CSVD to neurodegenerative dementia.

Pericyte Loss and Oligodendrocyte Vulnerability

Pericytes, the contractile mural cells embedded within the capillary basement membrane, are essential regulators of BBB integrity, cerebral blood flow at the capillary level, angiogenesis, and neuroinflammatory responses. Pericyte loss and dysfunction have been documented in autopsy studies of CSVD brains and in CADASIL, and are associated with capillary rarefaction, BBB leakage, and impaired neurovascular coupling. The soluble form of platelet-derived growth factor receptor beta (sPDGFRb), released upon pericyte injury, has been proposed as a cerebrospinal fluid biomarker for active small vessel injury. Oligodendrocytes and their precursor cells are among the most metabolically vulnerable cell populations in the central nervous system, with an exceptionally high demand for oxygen and iron and a limited antioxidant capacity. In CSVD, chronic hypoperfusion, oxidative stress, and inflammatory mediators selectively compromise oligodendrocyte survival and impair the capacity for remyelination, driving the progressive demyelination and axonal loss that underlie white matter lesion expansion and cognitive decline.

Table 1: MRI markers of cerebral small vessel disease: definitions, pathological correlates, and clinical significance.

Abbreviations: CAA, cerebral amyloid angiopathy; CMB, cerebral microbleed; CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; EPVS, enlarged perivascular spaces; FLAIR, fluid-attenuated inversion recovery; GRE, gradient-recalled echo; ICH, intracerebral hemorrhage; SVD, small vessel disease; SWI, susceptibility-weighted imaging; WMH, white matter hyperintensities.

The STRIVE Framework and Total SVD Score

The Standards for Reporting Vascular Changes on Neuroimaging (STRIVE) consensus, published in 2013 and updated in version 2 in 2023, established a harmonized terminology and rating framework for MRI-visible CSVD markers, enabling standardized reporting and cross-study comparisons. STRIVE-2 expanded the framework to incorporate emerging markers including cortical cerebral microinfarcts, cortical superficial siderosis, and white matter hyperintensity shape descriptors. The total SVD score, an ordinal composite integrating the presence of WMH, lacunes, CMBs, and EPVS, has been validated as a robust predictor of cognitive decline, dementia, stroke recurrence, and mortality, outperforming individual markers in prognostic accuracy.

Advanced Quantitative MRI Techniques

Conventional MRI markers, while clinically valuable, represent the visible tip of a pathological iceberg. Quantitative MRI techniques are revealing widespread microstructural injury in tissue that appears normal on standard sequences. Diffusion tensor imaging (DTI) demonstrates reduced fractional anisotropy and increased mean diffusivity in normal-appearing white matter (NAWM) of CSVD patients, reflecting incipient demyelination and axonal loss that precedes visible lesion formation. DTI metrics in NAWM are more strongly associated with cognitive performance than WMH volume alone, suggesting that covert microstructural damage is a major contributor to clinical deficits. Arterial spin labeling (ASL) perfusion MRI, which quantifies cerebral blood flow (CBF) non-invasively using magnetically labeled arterial water as an endogenous tracer, has revealed global and regional hypoperfusion in CSVD that extends beyond areas of visible pathology. Cerebrovascular reactivity (CVR) mapping, using blood oxygen level-dependent (BOLD) MRI responses to hypercapnic challenge or acetazolamide, demonstrates impaired vasodilatory reserve in CSVD, reflecting the loss of autoregulatory capacity that renders deep white matter vulnerable to hemodynamic fluctuations. DCE-MRI permeability mapping, as noted earlier, provides a quantitative measure of BBB integrity that is emerging as both a mechanistic biomarker and a potential therapeutic target.

Neuroimaging as a Surrogate Endpoint in Clinical Trials

The slow, progressive nature of CSVD and the absence of validated fluid biomarkers have made neuroimaging surrogate endpoints indispensable for clinical trial design. WMH volume progression, measured by automated segmentation algorithms, has been used as the primary outcome in several landmark trials, including the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and the Prevention of Decline in Cognition after Stroke Trial (PODCAST). However, WMH volume alone has limitations as a trial endpoint, including regression-to-the-mean effects, insensitivity to short-term change, and floor effects in patients with minimal baseline disease. Emerging composite endpoints incorporating DTI metrics, brain volume change, and functional connectivity measures offer enhanced sensitivity to treatment effects and are being incorporated into next-generation trial designs.

Lacunar Stroke and Vascular Parkinsonism

Lacunar stroke, resulting from occlusion of a single penetrating artery, accounts for approximately 25% of ischemic strokes and classically presents with one of five recognized syndromes: pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and dysarthria-clumsy hand syndrome. While traditionally considered benign relative to large-vessel strokes, lacunar events carry a substantial long-term recurrence risk of 25 to 30% over five years, and progressive accumulation of lacunar lesions contributes significantly to the development of vascular parkinsonism, characterized by symmetric lower-body predominant bradykinesia, gait disturbance, postural instability, and limited response to levodopa.

Vascular Cognitive Impairment and Dementia

CSVD is the dominant pathological substrate of VCI, which encompasses a clinical spectrum from mild vascular cognitive impairment (without meeting dementia criteria) to established vascular dementia. The cognitive profile of CSVD-associated VCI is characterized by prominent executive dysfunction, processing speed reduction, and attentional deficits, with relative preservation of episodic memory in the early stages, distinguishing it from the amnestic profile of typical Alzheimer disease. However, this distinction is increasingly blurred by the recognition that mixed pathology (concurrent CSVD and Alzheimer disease) is the most common substrate of dementia in the oldest-old, with synergistic effects on cognitive decline that exceed the additive contributions of either pathology alone.

Gait Disturbance, Mood Disorders, and Autonomic Dysfunction

CSVD disrupts the complex distributed neural networks subserving gait initiation, balance, and postural control. The characteristic gait of advanced CSVD, variably termed magnetic gait, marche a petits pas, or lower-body parkinsonism, is characterized by short shuffling steps, broad base, difficulty with initiation and turning, and preserved arm swing. WMH burden in specific white matter tracts connecting prefrontal cortex, supplementary motor area, and basal ganglia is more strongly predictive of gait impairment than total WMH volume, reflecting the importance of strategic lesion location. Depression occurs in 30 to 50% of patients with significant CSVD and is independently associated with WMH in frontal white matter and disruption of fronto-subcortical circuits subserving mood regulation. The concept of vascular depression posits that microvascular injury to these circuits constitutes a distinct etiological pathway, which may explain the relative treatment resistance of late-life depression to conventional antidepressant therapy in some patients. Autonomic dysfunction, including orthostatic hypotension, impaired heart rate variability, and urinary urgency, further compounds the clinical burden and may itself accelerate CSVD progression through hemodynamic mechanisms.

Table 2: Established and investigational therapeutic strategies for cerebral small vessel disease.

Abbreviations: BBB, blood-brain barrier; BP, blood pressure; CBF, cerebral blood flow; CSVD, cerebral small vessel disease; CVD, cardiovascular disease; DAPT, dual antiplatelet therapy; IL-1b, interleukin-1 beta; NO, nitric oxide; PDE3, phosphodiesterase 3; RCT, randomized controlled trial; SAPT, single antiplatelet therapy.

Blood Pressure Management: The Cornerstone

Intensive blood pressure lowering constitutes the only therapeutic intervention for which robust randomized trial evidence demonstrates attenuation of CSVD progression. The SPS3 trial, enrolling 3,020 patients with recent lacunar stroke, demonstrated that a systolic blood pressure target below 130 mmHg reduced the rate of recurrent stroke by 19% compared with the standard target of 130 to 149 mmHg, although this did not reach statistical significance for the primary outcome. More compellingly, the SPRINT-MIND substudy of the landmark SPRINT trial demonstrated that intensive systolic blood pressure targeting (below 120 mmHg) significantly reduced the risk of mild cognitive impairment and the composite of mild cognitive impairment or probable dementia, with accompanying reductions in WMH volume progression compared with standard treatment. The PROGRESS trial had earlier established that perindopril-based blood pressure lowering reduced the risk of cognitive decline and dementia in patients with prior cerebrovascular events, with benefits proportional to the magnitude of blood pressure reduction. Collectively, these trials support a blood pressure target below 130/80 mmHg for patients with established CSVD, while acknowledging that excessive lowering in the setting of impaired cerebral autoregulation may paradoxically exacerbate hypoperfusion and white matter injury, particularly in the elderly and those with advanced disease.

Antiplatelet and Lipid-Lowering Therapy

The SPS3 trial conclusively demonstrated that dual antiplatelet therapy (aspirin plus clopidogrel) did not reduce recurrent stroke compared with aspirin alone in lacunar stroke patients, while significantly increasing the risk of major hemorrhage and all-cause mortality. This finding has important implications for clinical practice, as it discourages dual antiplatelet use in the specific context of pure lacunar stroke attributed to CSVD. Single antiplatelet therapy with aspirin or clopidogrel remains standard, though the optimal agent and duration continue to be debated. Statins, beyond their lipid-lowering effects, exert pleiotropic actions that are particularly relevant to CSVD: improvement of endothelial nitric oxide synthase coupling, reduction of oxidative stress, suppression of matrix metalloproteinase activity, and attenuation of neuroinflammation. Secondary analyses from the SPARCL trial and observational data suggest that statin therapy is associated with slower WMH progression, though dedicated randomized trials specifically evaluating statin efficacy on CSVD outcomes are lacking and urgently needed.

Novel Vascular-Targeted Therapies

The Lacunar Intervention (LACI) trials program represents the most significant dedicated therapeutic initiative for CSVD to date. The LACI-1 pilot trial evaluated the safety and tolerability of isosorbide mononitrate (ISMN), a nitric oxide donor that improves endothelial function, and cilostazol, a phosphodiesterase-3 inhibitor with vasodilatory, antiplatelet, and endothelial-protective properties, in patients with lacunar stroke. Both agents were well tolerated, and preliminary analyses suggested favorable effects on blood pressure variability, an established predictor of WMH progression. The ongoing LACI-2 full trial is powered to evaluate the effects of these agents, alone and in combination, on WMH progression and cognitive decline over 12 to 24 months. Cilostazol has accumulated a particularly compelling evidence base in Asian populations. The Cilostazol Stroke Prevention Study 2 (CSPS 2) demonstrated superiority of cilostazol over aspirin in preventing recurrent stroke among patients with prior ischemic stroke, with a significantly lower rate of hemorrhagic complications. Mechanistic studies have demonstrated that cilostazol attenuates BBB permeability, suppresses matrix metalloproteinase-9 activity, enhances pericyte survival, and promotes oligodendrocyte precursor cell proliferation, making it a particularly promising agent for CSVD-specific neuroprotection.

Anti-Inflammatory and Immunomodulatory Approaches

The success of the CANTOS trial, which demonstrated that interleukin-1 beta inhibition with canakinumab reduced recurrent cardiovascular events independently of lipid lowering, has catalyzed interest in anti-inflammatory strategies for vascular disease. While no CSVD-specific anti-inflammatory trial has been completed, the strong mechanistic rationale implicating NLRP3 inflammasome activation and persistent neuroinflammation in small vessel injury supports the evaluation of targeted anti-inflammatory agents. Colchicine, which suppresses NLRP3 inflammasome activation and has demonstrated cardiovascular benefit in the COLCOT and LoDoCo2 trials, represents a practical and cost-effective candidate for CSVD trials.

Lifestyle Interventions and Glymphatic Enhancement

Aerobic exercise has been consistently associated with reduced CSVD burden in observational studies and has demonstrated improvements in cerebral perfusion, endothelial function, and cognitive performance in pilot interventional trials. The mechanisms underlying exercise-mediated neuroprotection in CSVD include enhanced endothelial nitric oxide production, upregulation of brain-derived neurotrophic factor, improved cerebrovascular reactivity, and potentially enhanced glymphatic clearance. Sleep optimization represents another frontier, given the dependence of glymphatic clearance on sleep quality and duration. Obstructive sleep apnea, independently associated with WMH burden and CSVD progression, constitutes a modifiable risk factor whose treatment may attenuate small vessel injury through both hemodynamic and clearance-mediated mechanisms.

Several critical knowledge gaps must be addressed to advance the management of CSVD from reactive to proactive, mechanism-targeted, and individualized strategies. First, the development and validation of fluid biomarkers (blood-based or cerebrospinal fluid) that reflect active small vessel injury, BBB breakdown, or neuroinflammation would complement neuroimaging in enabling earlier diagnosis, risk stratification, and treatment monitoring. Promising candidates include neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), sPDGFRb, and circulating microRNAs, though multicenter validation studies in diverse populations remain necessary. Second, the genetic architecture of CSVD, while increasingly characterized through genome-wide association studies, requires functional genomic investigation to translate statistical associations into mechanistic understanding and druggable targets. Mendelian randomization studies leveraging these genetic insights can identify causal risk factors amenable to intervention. Third, artificial intelligence-driven analysis of neuroimaging data, including automated WMH segmentation, lesion progression prediction, and multimodal integration of structural, diffusion, and perfusion data, promises to enhance both clinical practice and trial methodology. Fourth, clinical trial design for CSVD requires innovation, including the adoption of adaptive trial platforms, basket and umbrella designs that stratify patients by mechanistic phenotype rather than clinical syndrome, and the validation of digital endpoints (wearable-derived gait and activity metrics, smartphone-based cognitive assessments) that capture clinically meaningful change with greater sensitivity and ecological validity than traditional outcome measures. Finally, given the strong interplay between CSVD and Alzheimer disease pathology, therapeutic strategies that address both vascular and neurodegenerative mechanisms simultaneously may offer synergistic benefits for the large population of patients with mixed dementia.

Cerebral small vessel disease, once dismissed as an inevitable and inconsequential accompaniment of aging, has emerged as a dynamic and heterogeneous disorder with profound implications for brain health across the lifespan. Contemporary research has revealed a pathobiology that extends far beyond arteriosclerosis to encompass endothelial dysfunction, blood-brain barrier breakdown, chronic neuroinflammation, impaired glymphatic clearance, and pericyte degeneration, each offering potential therapeutic targets. Advances in quantitative neuroimaging are enabling the detection of subclinical disease, mechanistic phenotyping, and the monitoring of treatment response with unprecedented precision. While intensive blood pressure management remains the bedrock of CSVD prevention and treatment, the therapeutic landscape is expanding with the evaluation of agents targeting endothelial function, phosphodiesterase inhibition, neuroinflammation, and perivascular clearance. The convergence of mechanistic understanding, advanced imaging, fluid biomarker development, and innovative trial design holds the promise of transforming CSVD management from a reactive, one-size-fits-all approach to a proactive, precision medicine strategy. Realizing this promise will require sustained multidisciplinary collaboration, dedicated investment in CSVD-specific clinical trials, and an expanded recognition of small vessel disease as one of the most pressing and tractable challenges in contemporary neuroscience.

The authors declare no conflicts of interest relevant to this article.

Funding

This review article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgments

The authors acknowledge the contributions of all researchers whose work has been cited in this review and thank the editorial team of the International Journal of Neurobiology for the opportunity to contribute to this field of inquiry.

Author Contributions

AD conceptualized the review, performed the literature search, and drafted the manuscript. VK and AS contributed to critical appraisal of the literature, manuscript revision, and intellectual content. All authors reviewed and approved the final version of the manuscript.

1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010; 9: 689-701.
2. Wardlaw J M, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019; 18: 684-696.
3. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 2017; 96: 17-42.
4. Norrving B. Lacunar infarcts: no black holes in the brain are benign. Pract Neurol. 2008; 8: 222-228.
5. Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry. 2012; 83: 124-137.
6. Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg CM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011; 42: 2672-2713.
7. Van der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, et al. Vascular cognitive impairment. Nat Rev Dis Primers. 2018; 4: 18003.
8. Smith EE, Saposnik G, Bhatt DK. Cerebral small vessel disease, cognitive impairment, and other sequelae: a statement for healthcare professionals. Stroke. 2023; 54: 251-271.
9. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010; 341: 3666.
10. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration (STRIVE). Lancet Neurol. 2013; 12: 822-838.
11. Joutel A, Chabriat H. Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms. Clin Sci. 2017; 131: 635-651.
12. Shi Y, Wardlaw JM. Update on cerebral small vessel disease: a dynamic whole-brain disease. Stroke Vasc Neurol. 2016; 1: 83-92.
13. Fisher CM. Lacunar strokes and infarcts: a review. Neurology. 1982; 32: 871-876.
14. Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, Veluw SJV. Cerebral amyloid angiopathy and Alzheimer disease: one peptide, two pathways. Nat Rev Neurol. 2020; 16: 30-42.
15. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. CADASIL. Lancet Neurol. 2009; 8: 643-653.
16. Stam AH, Kothari PH, Shaber A, Gschwendter A, Jen JC, Hodgkinson S, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016; 139: 2909-2922.
17. De Leeuw FE, De Groot JC, Achten E, Oudkerk M, Ramos LMP, Heijboer R, 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. 2001; 70: 9-14.
18. Vernooij MW, Lugt VDA, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: The Rotterdam Scan Study. Neurology. 2008; 70: 1208-1214.
19. Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, Lugt AV, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam Scan Study. Stroke. 2010; 41: 103-106.
20. Rost N S, Rahman R M, Guedera S, Smith EE, Kanakis A, Fitzpatrick K, et al. White matter hyperintensity volume is increased in small vessel stroke subtypes. Neurology. 2010; 75: 1670-1677.
21. Fornage M, Debette S, Bis JC, Schmidt H, Ikram MA, Dufouil C, et al. Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. Ann Neurol. 2011; 69: 928-939.
22. Traylor M, Persyn E, Tomppo L, Klasson S, Abedi V, Bakker MK, et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021; 20: 351-361.
23. Muoio V, Persson PB, Sendeski MM. The neurovascular unit: concept review. Acta Physiol. 2014; 210: 790-798.
24. Rajani RM, Quick S, Engert JC, Graham D, Harris S, Verhaaren BJ, et al. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med. 2018; 10: 9507.
25. Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J Cereb Blood Flow Metab. 2016; 36: 72-94.
26. Hassan A, Hunt B J, OSullivan M, Parmar K, Bamford JM, Briley D, et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain. 2003; 126: 424-432.
27. Ikram MK, De Jong FJ, Bos MJ, Vingerling JR, Hofman A, Koudstaal PJ, et al. Retinal vessel diameters and risk of stroke: the Rotterdam Study. Neurology. 2006; 66: 1339-1343.
28. Wardlaw JM, Makin SJ, Valdes Hernandez MC, Armitage PA, Heye AK, Chappell FM, et al. Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement. 2017; 13: 634-643.
29. Zhang CE, Wong SM, Van de Haar HJ, Staals J, Jansen JFA, Jeukens CR, et al. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. Neurology. 2017; 88: 426-432.
30. Huisa BN, Caprihan A, Thompson J, Prestopnik J, Qualls CR, Rosenberg GA, et al. Long-term blood-brain barrier permeability changes in Binswanger disease. Stroke. 2015; 46: 2413-2418.
31. Petersen MA, Ryu JK, Akassoglou K. Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat Rev Neurosci. 2018; 19: 283-301.
32. Ryu JK, Rafalski VA, Meyer-Franke A, Adams RA, Poda SB, Coronado PER, et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol. 2018; 19: 1212-1223.
33. Simpson JE, Ince PG, Haynes LJ, Theaker R, Gelsthorpe C, Baxter L, et al. Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol. 2010; 36: 25-40.
34. Low A, Mak E, Rowe J B, Markus HS, OBrien JT. Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev. 2019; 53: 100916.
35. Shoamanesh A, Preis SR, Beiser AS, Vasan RS, Benjamin EJ, Kase CS, et al. Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology. 2015; 84: 825-832.
36. Iadecola C, Bhatt DK. NLRP3 inflammasome activation in vascular disease. Trends Cardiovasc Med. 2020; 30: 401-408.
37. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012; 4: 147ra111.
38. Mestre H, Tithof J, Du T, Song W, Peng W, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018; 9: 48-78.
39. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018; 17: 1016-1024.
40. Doubal FN, MacLullich AM, Ferguson KJ. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke. 2010; 41: 450-454.
41. Charidimou A, Boulouis G, Gurol ME. Emerging concepts in sporadic cerebral amyloid angiopathy. Brain. 2017; 140: 1829-1850.
42. Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016; 19: 771-783.
43. Nation DA, Sweeney MD, Montagne A, Sagare AP, DOrazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019; 25: 270-276.
44. Back SA, Kroenke CD, Sherman LS. White matter lesions defined by diffusion tensor imaging in older adults. Ann Neurol. 2011; 70: 465-476.
45. Hainsworth AH, Minett T, Sherrell A. Neuropathology of white matter lesions, blood-brain barrier dysfunction, and dementia. Stroke. 2017; 48: 2799-2804.
46. Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease: advances since 2013. Lancet Neurol. 2023; 22: 602-618.
47. Staals J, Makin SDJ, Doubal FN, et al. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. 2014; 83: 1228-1234.
48. Tuladhar AM, Van Norden AG, De Laat KF, Zwiers MP, Dijk EJ, Norris DG, et al. White matter integrity in small vessel disease is related to cognition. Neuroimage Clin. 2015; 7: 518-524.
49. Lawrence AJ, Chung AW, Morris RG, Markus HS, Barrick TR. Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology. 2014; 83: 304-311.
50. Shi Y, Thrippleton MJ, Makin SD, Marshall I, Geerlings MI, Craen AJM, et al. Cerebral blood flow in small vessel disease: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2016; 36: 1653-1667.
51. Blair GW, Doubal FN, Thrippleton MJ, Marshall I, Wardlaw JM, et al. Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease: a systematic review. J Cereb Blood Flow Metab. 2016; 36: 833-841.
52. SPS3 Investigators. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013; 382: 507-515.
53. Bath PM, Scutt P, Blackburn DJ. Intensive versus guideline blood pressure and lipid lowering in patients with previous stroke: main results from the pilot Prevention of Decline in Cognition after Stroke Trial (PODCAST) randomised controlled trial. PLoS One. 2017; 12: 0164608.
54. Benjamin P, Trippier S, Lawrence AJ, Lambert C, Zeestraten E, Williams OA, et al. Lacunar infarcts, but not perivascular spaces, are predictors of cognitive decline in cerebral small-vessel disease. Stroke. 2018; 49: 586-593.
55. Bamford J, Sandercock P, Dennis M, Warlow C, Burn J. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991; 337: 1521-1526.
56. Rektor I, Rektorova I, Kubova D. Vascular parkinsonism- an update. J Neurol Sci. 2006; 248: 185-191.
57. O'Brien JT, Thomas A. Vascular dementia. Lancet. 2015; 386: 1698-1706.
58. Sachdev P, Kalaria R, OBrien J, Skoog I, Alladi S, Black SE, et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord. 2014; 28: 206-218.
59. Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 2017; 134: 171-186.
60. De Laat KF, Van Norden AG, Gons RA, Oudheusden LJB, Uden IMW, Bloem BR, et al. Gait in elderly with cerebral small vessel disease. Stroke. 2010; 41: 1652-1658.
61. Rosario BL, Rosso AL, Aizenstein HJ, Harris T, Newman AB, Satterfield S, et al. Cerebral white matter and slow gait: contribution of hyperintensities and normal-appearing parenchyma. J Gerontol A Biol Sci Med Sci. 2016; 71: 968-973.
62. Van Agtmaal MJ, Houben AJ, Pouwer F. Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis. JAMA Psychiatry. 2017; 74: 729-739.
63. Alexopoulos GS, Meyers BS, Young RC. Vascular depression' hypothesis. Arch Gen Psychiatry. 1997; 54: 915-922.
64. Emdin CA, Rothwell PM, Salimi-Khorshidi G. Blood pressure, blood pressure lowering treatment, and MRI markers of cerebral small vessel disease: a systematic review and meta-analysis. Stroke. 2017; 48: 3272-3280.
65. SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012; 367: 817-825.
66. SPRINT MIND Investigators. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019; 321: 553-561.
67. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033-1041.
68. Tryambake D, He J, Liddle J, et al. Intensive blood pressure lowering, cerebral blood flow, and white matter hyperintensities in older adults. Neurology. 2020; 95: 1168-1177.
69. SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012; 367: 817-825.
70. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355: 549-559.
71. Ji T, Zhao Y, Wang J, Cui Y, Duan D, Chai Q, et al. Effect of low-dose statins and apolipoprotein E genotype on cerebral small vessel disease in older hypertensive patients: a subgroup analysis of a randomised clinical trial. J Am Heart Assoc. 2018; 11: 995-1002.
72. Blair GW, Appleton JP, Law ZK, Doubal F, Flaherty K. Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination. Int J Stroke. 2017; 13: 750-757.
73. Wardlaw JM, Bath PM, Doubal F, Heye A, Sprigg N, Woodhouse LJ, et al. The Lacunar Intervention Trial-2 (LACI-2). A trial of two repurposed licenced drugs to prevent progression of cerebral small vessel disease. Eur Stroke J. 2020; 5: 297-308.
74. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 2010; 9: 959-968.
75. Omote Y, Deguchi K, Tian F, Kawai H, Kurata T, Yamashita T, et al. Clinical and pathological improvement in stroke-prone spontaneous hypertensive rats related to the pleiotropic effect of cilostazol. Stroke. 2012; 43: 1639-1646.
76. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377: 1119-1131.
77. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019; 381: 2497-2505.
78. Nidorf S M, Fiolet A T L, Mosterd A. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020; 383: 1838-1847.
79. Guadagni V, Drogos LL, Tyndall AV. Aerobic exercise improves cognition and cerebrovascular regulation in older adults. Neurology. 2020; 94: 2245-2257.
80. Trigiani LJ, Bhatt DK. Exercise promotes cerebrovascular plasticity and cognitive benefits in old age. Nat Rev Neurosci. 2017; 18: 252.
81. Kim H, Yun CH, Thomas RJ, Lee SH, Seo HS, Cho ER, et al. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep. 2013; 36: 709-715.
82. Castronovo V, Scifo P, Castellano A, Aloia MS, Iadanza A, Marelli S, et al. White matter integrity in obstructive sleep apnea before and after treatment. Sleep. 2014; 37: 1465-1475.
83. Gattringer T, Pinter D, Enzinger C, Seifert-Held T, Kneihsl M, Fandler S, et al. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology. 2017; 89: 2108-2114.
84. Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol. 2019; 18: 587-599.
85. Traylor M, Malik R, Nalls MA. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol. 2012; 11: 951-962.
86. Sundaresan V, Zamboni G, Rothwell PM, Jenkinson M, Griffanti L. Triplanar ensemble U-Net model for white matter hyperintensities segmentation on MR images. Med Image Anal. 2021; 73: 102184.
87. Wardlaw JM, Debette S, Jokinen H, Leeuw FF, Pantoni L, Chabriat H, et al. ESO Guideline on covert cerebral small vessel disease. Eur Stroke J. 2021; 6: 1-52.
88. Del Brutto OH, Mera RM, Zambrano M. Population-based study of cerebral small vessel disease in community-dwelling older adults. Clin Neurol Neurosurg. 2015; 46: 106036.
89. Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke. 2012; 43: 3137-3146.