Chinese Medical Journal

: 2018  |  Volume : 131  |  Issue : 2  |  Page : 130--136

White Matter Lesions Predict Recurrent Vascular Events in Patients with Transient Ischemic Attacks

Xiao-Mei Ren1, Shu-Wei Qiu2, Ren-Yuan Liu3, Wen-Bo Wu3, Yun Xu4, Hong Zhou5,  
1 Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008; Department of Neurology, Yizheng People's Hospital, Yangzhou, Jiangsu 211400, China
2 Jiangsu Key Laboratory for Molecular Medicine, Nanjing, Jiangsu 210008, China
3 Department of Radiology, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China
4 Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University; Jiangsu Key Laboratory for Molecular Medicine; Department of Neurology, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China
5 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, China

Correspondence Address:
Dr. Hong Zhou
Department of Immunology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166


Background: White matter lesions (WMLs) are common findings in brain magnetic resonance imaging (MRI) and are strongly associated with stroke incidence, recurrence, and prognosis. However, the relationship between WMLs and transient ischemic attacks (TIAs) is not well established. This study aimed to determine the clinical significance of WMLs in patients with TIA. Methods: A total of 181 consecutive inpatients with first-ever TIA were enrolled. Brain MRIs within 2 days of symptom onset were used to measure WML volumes. Recurrent vascular events within 1 year of TIA onset were assessed. The relationship between WMLs and recurrent risk of vascular events was determined by a multivariate logistic regression. Results: WMLs were identified in 104 patients (57.5%). Age and ratio of hypertension were significantly different between patients with and without WMLs. The incidence of vascular events in patients with WMLs significantly increased in comparison to those without WMLs (21.15% vs. 5.19%, 95% confidence interval [CI]: 1.18–15.20, P = 0.027) after controlling for confounders. Furthermore, distributions of WML loads were found to be different between patients who developed vascular events and those who did not. WML volumes were demonstrated to be correlated with recurrent risks, and the fourth quartile of WML volumes led to an 8.5-fold elevation of recurrent risk of vascular events compared with the first quartile (95% CI: 1.52–47.65, P = 0.015) after adjusting for hyperlipidemia. Conclusion: WMLs occur frequently in patients with TIA and are associated with the high risk of recurrent vascular events, suggesting a predictive neuroimaging marker for TIA outcomes.

How to cite this article:
Ren XM, Qiu SW, Liu RY, Wu WB, Xu Y, Zhou H. White Matter Lesions Predict Recurrent Vascular Events in Patients with Transient Ischemic Attacks.Chin Med J 2018;131:130-136

How to cite this URL:
Ren XM, Qiu SW, Liu RY, Wu WB, Xu Y, Zhou H. White Matter Lesions Predict Recurrent Vascular Events in Patients with Transient Ischemic Attacks. Chin Med J [serial online] 2018 [cited 2018 Jan 22 ];131:130-136
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White matter lesions (WMLs) are characterized mainly by white matter hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain, and they are usually categorized into periventricular and subcortical lesions. As the availability and quality of imaging techniques improve, WMLs are common neuroimaging findings in the general population, especially in the elderly. The reported prevalence varies from 25% to 92% in healthy elderly people, depending on different study designs.[1],[2],[3]

The clinical manifestation of WMLs is asymptomatic, mild, or unrecognized in the early stages, but their progression in the advanced stages may result in critical neurological dysfunctions.[4] The volume of WMLs tends to increase over time, and the WML load at the baseline is found to be a significant predictor of lesion progression.[5],[6] WMLs are associated with not only structural lesions but also functional changes.[7] Recent longitudinal studies described WML as a predictor of incident stroke, disability, cognitive decline, depression, and mortality in the general population.[8],[9],[10],[11]

Increasing evidence supports the fact that WMLs are more prevalent and severe in patients with stroke than in healthy controls and is strongly associated with high risks of infarct growth, stroke severity, stroke recurrence, and bad prognosis.[12],[13],[14],[15],[16] A transient ischemic attack (TIA) is a medical emergency associated with a high risk of recurrence, subsequent stroke, and cardiovascular events.[17],[18] However, the relationship between WMLs and TIA is still unclear. Consequently, this study attempted to determine the association of the incidence and volume of WMLs at admission with the prognosis of patients with TIA.


Ethical approval

This study was approved by the Ethics Committee of Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University.

Study population

First-ever patients with TIA who were admitted consecutively to Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University between August 2010 and April 2016 within 48 h of symptom onset were recruited. TIA was defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting <24 h, without acute infarction on imaging.[19] A total of 181 eligible patients were present after excluding 40 patients with prior history of TIA or stroke, 23 with brain injury on diffusion-weighted MRI, 5 with other medical diagnoses that could confound or interfere with the analysis of WMLs, such as multiple sclerosis, neuromyelitis optica, and leukodystrophy, three who underwent endovascular therapy, and three without complete follow-up.

Baseline data collection and definition of covariates

Patient demographics (age and sex), vascular risk factors, TIA symptom details, and ABCD2 score were collected by reviewing medical records. The definitions of vascular risk factors are as follows: hypertension was defined as systolic blood pressure ≥140 mmHg (1 mmHg = 0.133 kPa), diastolic blood pressure ≥90 mmHg, or the use of blood pressure-lowering medication. Hyperlipidemia was defined as total cholesterol ≥5.72 mmol/L, triglycerides ≥1.70 mmol/L, low-density lipoprotein cholesterol ≥3.10 mmol/L, or the use of lipid-lowering medication. Diabetes mellitus was defined as fasting glucose level ≥7.0 mmol/L, 2-h plasma glucose level after a 75 g oral glucose tolerance test, or nonfasting glucose level ≥11.1 mmol/L at least 3 days after TIA, glycated hemoglobin level ≥6.5%, or the use of antidiabetic medication.

A history of coronary heart disease was considered based on a history of angina pectoris, myocardial infarction, a revascularization procedure, and so on. Atrial fibrillation was considered according to the electrocardiogram and Holter monitoring manifestation on admission or previously documented diagnosis. Meanwhile, the current smoking status was also recorded. The ABCD2 score combines five clinical variables (age, blood pressure, clinical features, duration of symptoms, and history of diabetes mellitus) into a seven-point scale. In general, patients with TIA were prescribed antithrombotics, statins, and treatment of vascular risk factors during hospitalization and at discharge. Statins were prescribed for 169 patients (93.4%) and antithrombotics for 171 patients (94.5%) including anticoagulant (n = 6) and antiplatelet therapy (n = 165). All patients with hypertension were prescribed antihypertensive medication, and the blood pressure was lowered to below 140/90 mmHg. According to Chinese Guidelines for the Prevention of Stroke in Patients with Ischemic Stroke or TIA, these patients were routinely visited in the department of neurology, and medication was supervised to rigorously control vascular risk factors. The primary end points were recurrent vascular events (recurrent TIA, stroke, myocardial infarction, and vascular death) at 1 year. Acute stroke was defined based on a neurological deficit attributed to an acute focal cerebral injury by a vascular cause.[20] Acute myocardial infarction was defined as the elevation of cardiac troponins either with symptoms of ischemia or with presumed new electrocardiogram changes. Vascular death was defined as death due to stroke (ischemic or hemorrhagic), systemic hemorrhage, myocardial infarction, congestive heart failure, pulmonary embolism, sudden death, or arrhythmia.

Image acquisition and analysis

MRIs within 2 days of TIA onset were available for all participants, which included T1-weighted image, T2-weighted image, diffusion-weighted imaging (DWI), and FLAIR. MRI scans were performed on a 1.5 Tesla scanner (Philips Intera Master Medical Systems, Best, The Netherlands). The acquisition protocols were as follows: T1-weighted (fast field echo, repetition time: 458 ms and echo time: 14 ms); T2-weighted (turbo spin echo, repetition time: 4070 ms and echo time: 110 ms); T2-weighted FLAIR (repetition time: 9002 ms and echo time: 143 ms); DWI (single-shot echo planar imaging, repetition time: 3200 ms and echo time: 95 ms); thickness/gap: 5 mm/0 mm; matrix: 304 × 512; and field of view: 230 mm × 230 mm.

WMLs were defined as hyperintense lesions on both T2 and FLAIR images, without cavitation, and without prominent hypointensities on T1-weighted scans. MRIcron was applied for image analyses.[21],[22],[23] So far, no widely accepted rules are available for defining periventricular and subcortical WML.[24] In the present study, only the total WML volume was segmented and calculated based on a semiautomatic technique: (1) for the first layer, the intensity threshold filter was used to create a layer of regions of interest corresponding to WMLs. (2) For the second layer, experienced neuroradiologists who remained blinded to the patients' clinical details were required to manually outline the gross contouring of all WMLs on every slice. (3) The intersection of the first and second layers was then obtained to serve as a WML map for further volumetric analysis.[22] WML volumes were set as categorical variables using quartiles. Total WML volumes ranging from 0.95 to 3.31 ml, 3.32 to 5.00 ml, 5.00 to 9.05 ml, and 9.06 to 49.13 ml were defined as the first, second, third, and fourth quartiles, respectively.

Experienced neuroradiologists who remained blinded to the patients' clinical details analyzed all the MRI data. Disagreements were resolved by discussion with a third rater.

Statistical analyses

Quantitative values were reported as mean ± standard deviation (SD). Categorical variables are expressed as numbers (percentages). Continuous variables were tested by the independent samples' t-test, while categorical variables were tested by Chi-squared tests or continuity correction. A multivariable logistic regression analysis was used to identify the independent risk factors of WMLs and the clinical outcome. Independent variables for this model were chosen using a conservative threshold of P < 0.10 in the univariable analysis. Values of P < 0.05 were considered statistically significant. All analyses were performed with the SPSS software package (version 23.0, SPSS Inc., USA).


Demographic and clinical characteristics of patients with transient ischemic attack with and without white matter lesions

As shown in [Table 1], demographic and clinical characteristics were analyzed in patients with TIA with and without WMLs. Among the 181 patients, 108 patients (59.7%) were male. The mean age was 61.4 years (range: 29–85 years; SD: 11.1). Hypertension, present in 97 patients (53.6%), was the main vascular risk factor. Anterior circulation TIA accounts for 75.7% of all patients, whereas posterior circulation TIA accounts for 24.3%. In the univariate analysis, age, hypertension, hyperlipidemia, coronary heart disease, sensory disturbance, and ABCD2 score were associated with WMLs. The multivariate analysis showed a significant difference in age (66.1 ± 9.6 vs. 55.1 ± 9.8, odds ratio [OR]: 1.21, 95% confidence interval [CI] 1.08–1.17, P < 0.001) and ratio of hypertension (62.5% vs. 24.6%, OR: 2.11, 95% CI: 1.06–4.21, P = 0.034) between the two groups.{Table 1}

Recurrent vascular events increased in patients with transient ischemic attack with white matter lesions

The risks of recurrent vascular events were evaluated in patients with TIA with and without WMLs. At the 1-year follow-up, 26 (14.4%) recurrent vascular events occurred, including 16 recurrent TIAs, 7 strokes, 2 myocardial infarctions, and one vascular death. All strokes were ischemic. A univariate analysis showed that the recurrent rate of vascular events in TIAs with WMLs was significantly higher than that in TIAs with no WMLs (21.15% vs. 5.19%, P = 0.002). Furthermore, the significant difference was kept well between those two groups by the multivariate analysis after controlling for age, hyperlipidemia, diabetes mellitus, duration of symptoms, and antithrombotics (OR:4.24, 95% CI: 1.18–15.20, P = 0.027).

Severe white matter lesions occurred frequently in patients with transient ischemic attacks who developed recurrent vascular events

An attempt was made to find out the differences in the demographic and clinical characteristics of patients with TIA as well as WML, who did or did not develop recurrent vascular events. In the univariate analysis, diabetes mellitus, hyperlipidemia, and WML severity were associated with recurrent vascular events. After the multivariate analysis, the proportion of hyperlipidemia (OR: 5.21, 95% CI: 1.71–15.90, P = 0.004) was higher in patients with TIA who developed recurrent vascular events in comparison to those who did not. Notably, the distribution of WMLs with varying severities was different between those who had recurrent vascular events and those who did not (P = 0.045), and the more severe the WMLs, the more frequent the recurrence of the vascular events that occurred in patients with TIA [Table 2].{Table 2}

White matter lesions were correlated with the recurrent risks of vascular events in patients with transient ischemic attack

This study also attempted to evaluate whether the extent of WMLs was correlated with the recurrent risk of vascular events in patients with TIA with WMLs. The incidence rates of vascular events according to the quartile of the total WML volume are shown in [Table 3]. The multivariate logistic analysis demonstrated that the fourth quartile of WMLs (>9.05 ml) was correlated with a higher risk of vascular events relative to the first quartile (≤3.31 ml) (OR: 8.51, 95% CI: 1.52–47.65, P = 0.015) after adjusting for hyperlipidemia.{Table 3}


The present study showed that WMLs were present in 57.5% of the patients with first-ever TIA, even reaching 95% of patients aged >70 years on MRI. In one large sample of 1643 healthy people aged ≥65 years, the median volume of WMLs was 4.0 ml (IQR: 2.75–6.20 ml).[25] Patients with TIA had a higher WML volume compared with healthy people. Previous studies showed that the risk of stroke increased significantly as the baseline WML grade increased independently of traditional risk factors for stroke in population-based samples.[25],[26],[27] In agreement with these reports about WMLs in stroke, the present study found that, in patients with TIA, the presence of baseline WMLs increased recurrent vascular incidences by up to 4.2-fold. Moreover, the incidence of vascular events increased with increasing volumes of WML, reaching an 8.5-fold higher rate in the fourth quartile as compared with the first quartile. As a result, severe WML was progressive and even malignant, and WMLs needed to be carefully assessed and quantified. With the promotion of clinical guidelines and early treatment after TIA, a measurable decrease in the risk of stroke and other vascular events has been reported over the past decade.[28],[29],[30],[31] However, the recurrent vascular event rate remains unacceptably high in patients with WMLs. The current finding has shifted the importance of WMLs from an incidental neuroimaging description to a radiological surrogate marker for risk stratification in patients with TIA.

WMLs are commonly considered as an expression of chronic cerebral ischemia although the underlying pathogenesis is probably multifactorial. Along with the previous findings, the results of the present study supported the fact that age and hypertension were the most common risk factors for both the presence and the severity of WMLs.[32],[33],[34],[35],[36] Accumulating studies suggested that WMLs may be associated with arteriosclerotic narrowing, plaque, artery stiffening, small vessel disease, hemodynamic injury, and impaired autoregulation.[37],[38],[39],[40],[41] In addition to vascular changes, WMLs are associated with high levels of mean platelet volumes, platelet hyperaggregability, endothelial dysfunction, and blood-brain barrier dysfunction.[42],[43],[44],[45] All alterations mentioned earlier may further modulate cerebral tissue perfusion, capacity for handling ischemia, and dysfunctional white matter tracts, impairing plasticity in patients with TIA, which can contribute to bad prognosis after a TIA. Meanwhile, diffuse vascular damage involved not only cerebral arteries but also peripheral and coronary arteries.[46] Further studies are needed to clarify the mechanism of the relationship between WMLs and clinical outcome of TIA. Special attention should be given to patients with TIA with WMLs for secondary prevention and long-term prognosis. In the present study, except for WMLs, age, hyperlipidemia, diabetes mellitus, and duration of symptoms were independent predictors of recurrent vascular events. Furthermore, antithrombotics significantly reduced the risk, exerting protective effects against vascular events. To date, no definitive effective treatment is available for WMLs. Several pieces of evidence show that good blood pressure control, antiplatelet therapy, and endothelium stability may be feasible.[36],[47],[48] Treating the underlying causes may delay WML progression and improve prognosis.

The unique aspect of the present study is that it focuses on WMLs in patients with TIA rather than on stroke. Consequently, this study was able to provide more detailed information about the relationship between WMLs and TIA outcomes. Another advantage of this study was that volumetric measurements of WMLs were used, which could offer a more reliable, reproducible, and objective result relative to visual rating scales such as the Fazekas score.[49] This study had several limitations. First, it was a single-center study, and the sample size was low, which may lower data reliability and robustness. Second, sampling bias was a potential limitation. Only hospitalized patients were evaluated. Third, the progression of longitudinal WML volumes was not assessed.

In conclusion, WMLs occur frequently in patients with first-ever TIA and are associated with high risks of recurrent vascular events. Consequently, this could serve as a predictive neuroimaging marker for the unfavorable prognosis of patients with TIA in clinical practice.

Financial support and sponsorship

This study was supported by grants from the National Key Research and Development Program of China (No. 2016YFC1300500-504), the National Natural Science Foundation of China (No. 81230026 and No. 81630028), the Natural Science Foundation (No. BE2016610), the Jiangsu Province Commission of Health and Family Planning (No. LJ201101) of China, the Jiangsu Provincial Key Medical Discipline (Laboratory) (No.ZDXKA2016020), and the Nanjing Medical Science and Technique Development Foundation (No. QRX17118).

Conflicts of interest

There are no conflicts of interest.


1Launer LJ. Epidemiology of white matter lesions. Top Magn Reson Imaging 2004;15:365-7. doi: 10.1017/S1041610203009037.
2Szolnoki Z. Pathomechanism of leukoaraiosis: A molecular bridge between the genetic, biochemical, and clinical processes (a mitochondrial hypothesis). Neuromolecular Med 2007;9:21-33. doi: 10.1385/NMM:9:1:21.
3de Leeuw FE, de Groot JC, Achten E, Oudkerk M, Ramos LM, 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. doi: 10.1136/jnnp.70.1.9.
4Schmidt R, Berghold A, Jokinen H, Gouw AA, van der Flier WM, Barkhof F, et al. White matter lesion progression in LADIS: Frequency, clinical effects, and sample size calculations. Stroke 2012;43:2643-7. doi: 10.1161/STROKEAHA.112.662593.
5Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F; Austrian Stroke Prevention Study, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian stroke prevention study. Lancet 2003;361:2046-8. doi: 10.1016/S0140-6736(03)13616-1.
6Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. MRI white matter hyperintensities: Three-year follow-up of the Austrian stroke prevention study. Neurology 1999;53:132-9. doi: 10.1212/WNL.53.1.132.
7Etherton MR, Wu O, Rost NS. Recent advances in leukoaraiosis: White matter structural integrity and functional outcomes after acute ischemic stroke. Curr Cardiol Rep 2016;18:123. doi: 10.1007/s11886-016-0803-0.
8Debette S, Beiser A, DeCarli C, Au R, Himali JJ, Kelly-Hayes M, et al. Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: The Framingham Offspring Study. Stroke 2010;41:600-6. doi: 10.1161/STROKEAHA.109.570044.
9Firbank MJ, Teodorczuk A, van der Flier WM, Gouw AA, Wallin A, Erkinjuntti T, et al. Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study. Br J Psychiatry 2012;201:40-5. doi: 10.1192/bjp.bp.111.098897.
10Inaba M, White L, Bell C, Chen R, Petrovitch H, Launer L, et al. White matter lesions on brain magnetic resonance imaging scan and 5-year cognitive decline: The Honolulu-Asia aging study. J Am Geriatr Soc 2011;59:1484-9. doi: 10.1111/j.1532-5415.2011.03490.x.
11Sabayan B, van der Grond J, Westendorp RG, van Buchem MA, de Craen AJ. Accelerated progression of white matter hyperintensities and subsequent risk of mortality: A 12-year follow-up study. Neurobiol Aging 2015;36:2130-5. doi: 10.1016/j.neurobiolaging.2015.03.003.
12Henninger N, Lin E, Baker SP, Wakhloo AK, Takhtani D, Moonis M, et al. Leukoaraiosis predicts poor 90-day outcome after acute large cerebral artery occlusion. Cerebrovasc Dis 2012;33:525-31. doi: 10.1159/000337335.
13Henninger N, Khan MA, Zhang J, Moonis M, Goddeau RP Jr. Leukoaraiosis predicts cortical infarct volume after distal middle cerebral artery occlusion. Stroke 2014;45:689-95. doi: 10.1161/STROKEAHA.113.002855/-/DC1.
14Hénon H, Vroylandt P, Durieu I, Pasquier F, Leys D. Leukoaraiosis more than dementia is a predictor of stroke recurrence. Stroke 2003;34:2935-40. doi: 10.1161/01.STR.0000103747.58719.59.
15Lin Q, Li Z, Wei R, Lei Q, Liu Y, Cai X, et al. Increased risk of post-thrombolysis intracranial hemorrhage in acute ischemic stroke patients with leukoaraiosis: A Meta-analysis. PLoS One 2016;11:e0153486. doi: 10.1371/journal.pone.0153486.
16Wen W, Sachdev PS. Extent and distribution of white matter hyperintensities in stroke patients: The Sydney Stroke Study. Stroke 2004;35:2813-9. doi: 10.1161/01.STR.0000147034.25760.3d.
17Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284:2901-6. doi: 10.1001/jama.284.22.2901.
18Ranta A, Barber PA. Transient ischemic attack service provision: A review of available service models. Neurology 2016;86:947-53. doi: 10.1212/WNL.0000000000002339.
19Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009;40:2276-93. doi: 10.1161/STROKEAHA.108.192218.
20Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064-89. doi: 10.1161/STR.0b013e318296aeca.
21Arsava EM, Rahman R, Rosand J, Lu J, Smith EE, Rost NS, et al. Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology 2009;72:1403-10. doi: 10.1212/WNL.0b013e3181a18823.
22Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, et al. Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 2006;66:23-9. doi: 10.1212/01.wnl.0000191403.95453.6a.
23Schwichtenberg J, Al-Zghloul M, Kerl HU, Wenz H, Hausner L, Frölich L, et al. Late-onset major depression is associated with age-related white matter lesions in the brainstem. Int J Geriatr Psychiatry 2017;32:446-54. doi: 10.1002/gps.4487.
24DeCarli C, Fletcher E, Ramey V, Harvey D, Jagust WJ. Anatomical mapping of white matter hyperintensities (WMH): Exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 2005;36:50-5. doi: 10.1161/01.STR.0000150668.58689.f2.
25Buyck JF, Dufouil C, Mazoyer B, Maillard P, Ducimetière P, Alpérovitch A, et al. Cerebral white matter lesions are associated with the risk of stroke but not with other vascular events: The 3-city Dijon study. Stroke 2009;40:2327-31. doi: 10.1161/STROKEAHA.109.548222.
26Kuller LH, Longstreth WT Jr., Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr., et al. White matter hyperintensity on cranial magnetic resonance imaging: A predictor of stroke. Stroke 2004;35:1821-5. doi: 10.1161/01.STR.0000132193.35955.69.
27Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: The Rotterdam Scan Study. Stroke 2003;34:1126-9. doi: 10.1161/01.STR.0000068408.82115.D2.
28Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave JN, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): A prospective population-based sequential comparison. Lancet 2007;370:1432-42. doi: 10.1016/S0140-6736(07)61448-2.
29Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z, et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: Time-course analysis of randomised trials. Lancet 2016;388:365-75. doi: 10.1016/S0140-6736(16)30468-8.
30Sundararajan V, Thrift AG, Phan TG, Choi PM, Clissold B, Srikanth VK, et al. Trends over time in the risk of stroke after an incident transient ischemic attack. Stroke 2014;45:3214-8. doi: 10.1161/STROKEAHA.114.006575.
31Wasserman J, Perry J, Dowlatshahi D, Stotts G, Stiell I, Sutherland J, et al. Stratified, urgent care for transient ischemic attack results in low stroke rates. Stroke 2010;41:2601-5. doi: 10.1161/STROKEAHA.110.586842.
32Arntz RM, van den Broek SM, van Uden IW, Ghafoorian M, Platel B, Rutten-Jacobs LC, et al. Accelerated development of cerebral small vessel disease in young stroke patients. Neurology 2016;87:1212-9. doi: 10.1212/WNL.0000000000003123.
33Gebeily S, Fares Y, Kordahi M, Khodeir P, Labaki G, Fazekas F, et al. Cerebral white matter hyperintensities (WMH): An analysis of cerebrovascular risk factors in Lebanon. Int J Neurosci 2014;124:799-805. doi: 10.3109/00207454.2014.884087.
34Gottesman RF, Fornage M, Knopman DS, Mosley TH. Brain aging in African-Americans: The atherosclerosis risk in communities (ARIC) experience. Curr Alzheimer Res 2015;12:607-13. doi: 10.2174/1567205012666150701102445.
35Ryu WS, Woo SH, Schellingerhout D, Chung MK, Kim CK, Jang MU, et al. Grading and interpretation of white matter hyperintensities using statistical maps. Stroke 2014;45:3567-75. doi: 10.1161/STROKEAHA.114.006662.
36Verhaaren BF, Vernooij MW, de Boer R, Hofman A, Niessen WJ, van der Lugt A, et al. High blood pressure and cerebral white matter lesion progression in the general population. Hypertension 2013;61:1354-9. doi: 10.1161/HYPERTENSIONAHA.111.00430.
37Bakker SL, de Leeuw FE, de Groot JC, Hofman A, Koudstaal PJ, Breteler MM, et al. Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly. Neurology 1999;52:578-83. doi: 10.1212/WNL.52.3.578.
38Ben-Assayag E, Mijajlovic M, Shenhar-Tsarfaty S, Bova I, Shopin L, Bornstein NM, et al. Leukoaraiosis is a chronic atherosclerotic disease. ScientificWorldJournal 2012;2012:532141. doi: 10.1100/2012/532141.
39Moody DM, Thore CR, Anstrom JA, Challa VR, Langefeld CD, Brown WR, et al. Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis. Radiology 2004;233:883-90. doi: 10.1148/radiol.2333020981.
40O'Sullivan M, Lythgoe DJ, Pereira AC, Summers PE, Jarosz JM, Williams SC, et al. Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 2002;59:321-6. doi: 10.1212/WNL.59.3.321.
41Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM, et al. Increased cerebral arterial pulsatility in patients with leukoaraiosis: Arterial stiffness enhances transmission of aortic pulsatility. Stroke 2012;43:2631-6. doi: 10.1161/STROKEAHA.112.655837.
42Fujita S, Kawaguchi T. Association of platelet hyper-aggregability with leukoaraiosis. Acta Neurol Scand 2002;105:445-9. doi: 10.1034/j.1600-0404.2002.01208.x.
43Hassan A, Hunt BJ, O'Sullivan M, Parmar K, Bamford JM, Briley D, et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 2003;126:424-32. doi: 10.1093/brain/awg040.
44Huisa 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;46:2413-8. doi: 10.1161/STROKEAHA.115.009589.
45Kang SJ, Park BJ, Shim JY, Lee HR, Hong JM, Lee YJ, et al. Mean platelet volume (MPV) is associated with leukoaraiosis in the apparently healthy elderly. Arch Gerontol Geriatr 2012;54:e118-21. doi: 10.1016/j.archger.2011.10.010.
46Putaala J, Haapaniemi E, Kurkinen M, Salonen O, Kaste M, Tatlisumak T, et al. Silent brain infarcts, leukoaraiosis, and long-term prognosis in young ischemic stroke patients. Neurology 2011;76:1742-9. doi: 10.1212/WNL.0b013e31821a44ad.
47Basile AM, Pantoni L, Pracucci G, Asplund K, Chabriat H, Erkinjuntti T, et al. Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and disability in the elderly) study. Cerebrovasc Dis 2006;21:315-22. doi: 10.1159/000091536.
48Fujita S, Kawaguchi T, Uehara T, Fukushima K. Progress of leukoaraiosis is inhibited by correction of platelet hyper-aggregability. Int Psychogeriatr 2005;17:689-98. doi: 10.1017/S104161020500164X.
49van den Heuvel DM, ten Dam VH, de Craen AJ, Admiraal-Behloul F, van Es AC, Palm WM, et al. Measuring longitudinal white matter changes: Comparison of a visual rating scale with a volumetric measurement. AJNR Am J Neuroradiol 2006;27:875-8. doi: 10.1300/J016v07n03_17.