Cerebral Small Vessel Disease: A Review Focusing on Pathophysiology, Biomarkers, and Machine Learning Strategies

Cuadrado-Godia, Elisa; Dwivedi, Pratistha; Sharma, Sanjiv; Santiago, Ángel Ois; González, Jaume Roquer; Balcells, Mercedes; Laird, John R.; Turk, Monika; Suri, Harman S.; Nicolaides, Andrew; Saba, Luca; Khanna, Narendra N.; Suri, Jasjit S.

doi:10.5853/jos.2017.02922

Cited by 227 publications

(173 citation statements)

References 160 publications

(155 reference statements)

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“…A possible mechanism for this relationship is that coffee has been found to be inversely associated with endothelia dysfunction, which is a major cause of the development of cerebral SV disease. 29 Coffee contains many antioxidant and anti-inflammatory components such as caffeine, chlorogenic acid, and diterpenes. 30 In addition, chlorogenic acid protects neurons from glutamate neurotoxicity by regulating Ca 2+ entry into neurons.…”

Section: Discussionmentioning

confidence: 99%

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Huang

et al. 2020

Annals of Neurology

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Objective Observational epidemiological studies have reported a relationship between coffee intake and risk of stroke. However, evidence for this association is inconsistent, and it remains uncertain whether the association is causal or due to confounding or reverse causality. To clarify this relationship, we adopted a Mendelian randomization (MR) approach to evaluate the effects of coffee consumption on the risk of stroke and its subtypes. Methods A meta‐analysis of genome‐wide association studies (GWASs) including 91,462 coffee consumers was used to identify instruments for coffee consumption. Summary‐level data for stroke, intracerebral hemorrhage, ischemic stroke (IS), and IS subtypes were obtained from GWAS meta‐analyses conducted by the MEGASTROKE consortium. MR analyses were performed using the inverse‐variance‐weighted, weighted‐median, MR‐PRESSO (Pleiotropy RESidual Sum and Outlier) test and MR‐Egger regression. Sensitivity analyses were further performed using alternative instruments to test the robustness of our findings. Results Genetically predicted coffee consumption (high vs infrequent/no) was not associated with risk of stroke. Similarly, among coffee consumers, MR analysis did not indicate causal associations between coffee consumption (cups/day) and risk of stroke. However, in the subgroup analysis, we found weak suggestive evidence for a potential protective effect of coffee consumption on risk of small vessel (SV)‐IS, although the association did not reach statistical significance after correction for multiple comparisons. Interpretation This study suggests that coffee consumption is not causally associated with risk of stroke or its subtypes. Further studies are warranted to elucidate the possible association between coffee intake and risk of SV‐IS, as well as its potential underlying mechanisms. ANN NEUROL 2020;87:525–532

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Section: Discussionmentioning

confidence: 99%

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Huang

et al. 2020

Annals of Neurology

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“…Increasing data have implicated endothelial damage as a key process in the pathogenesis of small vessel disease . Experimental studies have shown that elevated tHcy levels can lead to alterations within the blood vessel wall .…”

Section: Discussionmentioning

confidence: 99%

Homocysteine and small vessel stroke: A mendelian randomization analysis

Larsson

Traylor

Markus

2019

Annals of Neurology

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Objective Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. Methods We used summary statistics data for single‐nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B 6 (n = 1), and vitamin B 12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). Results Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13–1.58; p = 6.7 × 10 –4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B 6 levels were 0.49 (95% CI, 0.34–0.71; p = 1.3 × 10 –4 ) and 0.70 (95% CI, 0.52–0.94; p = 0.02), respectively. Genetically higher vitamin B 12 levels were not associated with any stroke subtype. Interpretation These findings suggest that any effect of homocysteine‐lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495–501

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“…1 The disease has multifarious etiology and pathogenesis, the most common form being arteriolosclerotic CSVD (A-CSVD), which is also known as age-and vascular risk-factor-related CSVD. 2 Recurrent minor strokes, blood-brain barrier (BBB) impairment, inflammatory responses and leukocyte infiltration are classical pathological features of CSVD. 3 The inflammatory reaction is triggered both at the onset of ischemic and hemorrhagic stroke (attack phase) 4 and chronic stages (remitting phase) of "silent CSVD".…”

Section: Introductionmentioning

confidence: 99%

<p>Chronic Insomnia Is Associated with Higher Circulating Interleukin-8 in Patients with Atherosclerotic Cerebral Small Vessel Disease</p>

Wang

Chen

Men

et al. 2020

NSS

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Objective: Chronic inflammatory responses and leukocyte infiltration are classical pathological features of cerebral small vessel disease (CSVD). To date, limited evidence of a relationship between chronic insomnia and inflammatory responses in patients with CSVD has been uncovered. The purpose of the present study was to investigate the potential relationship between chronic insomnia and pro-inflammatory cytokine levels in patients with atherosclerotic CSVD (A-CSVD). Methods: In total, 76 A-CSVD patients with or without chronic insomnia (CI) confirmed using magnetic resonance (MR) were prospectively recruited. Overnight polysomnography (PSG) was performed and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-8, and IL-12 assessed. Cytokine levels were compared between CSVD+CI (study group) and CSVD without CI (control group) patients, and the correlations between PSG parameters and cytokine levels were explored in all patients via multiple linear regression analyses. Results: The serum IL-8 level of the study group (12.3±4.4 pg/mL) was significantly higher than that of the control group (7.5±2.2 pg/mL; P<0.05). PSG measurements showed that patients in the study group had significantly higher sleep onset latency (SOL), arousal index (ArI) and wake after sleep onset (WASO) as well as lower total sleep time (TST), sleep efficiency (SE) and stage 3 NREM sleep (N-3) ratio, compared with the control group (P<0.05). Multiple linear regression analyses led to the identification of ArI (β=0.026, P<0.05) and TST (β=−0.054, P<0.05) as significant positive and negative predictors of the IL-8 level, respectively. Conclusion: Chronic insomnia, in particular, sleep fragmentation and short sleep duration, may be involved in promotion of serum IL-8 expression in patients with atherosclerotic CSVD.

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Cerebral Small Vessel Disease: A Review Focusing on Pathophysiology, Biomarkers, and Machine Learning Strategies

Cited by 227 publications

References 160 publications

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Homocysteine and small vessel stroke: A mendelian randomization analysis

<p>Chronic Insomnia Is Associated with Higher Circulating Interleukin-8 in Patients with Atherosclerotic Cerebral Small Vessel Disease</p>

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