Journal List > Dement Neurocogn Disord > v.14(3) > 1120313

Dement Neurocogn Disord. 2015 Sep;14(3):114-119. English.
Published online Sep 30, 2015.  https://doi.org/10.12779/dnd.2015.14.3.114
© 2015 Korean Dementia Association
Is the Severity of Dilated Virchow-Robin Spaces Associated with Cognitive Dysfunction?
Eun Hye Jeong,1 Yong Joo Lee,2 Sang Joon Kim,3 and Jae-Hong Lee2
1Department of Neurology, Bundang Jesaeng General Hospital, Seongnam, Korea.
2Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
3Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Correspondence: Jae-Hong Lee, MD, PhD, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3446, Fax: +82-2-474-4691, Email: jhlee@amc.seoul.kr
Received Sep 07, 2015; Revised Sep 10, 2015; Accepted Sep 10, 2015.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Background and Purpose

Dilated Virchow-Robin spaces (dVRS) are not uncommon findings in the normal brain, particularly in the old people, and have been largely regarded as benign lesions. However, there is accumulating evidence that dVRS may serve as an neuroimaging marker of small vessel disease and are associated with cognitive decline. We investigated whether the severity of dVRS would be associated with cognitive dysfunction by comparing the subjects with subjective memory impairment (SMI), mild cognitive impairment (MCI), and Alzheimer's disease (AD). We also examined whether there were differences in the degree of correlation between dVRS and magnetic resonance imaging (MRI) markers of small vessel disease among the three groups.

Methods

In this retrospective study, a total of 225 subjects were included: those with SMI (n=65), MCI (n=100), and AD (n=60). We rated the severity of dVRS using the axial MRI slice containing the greatest number of dVRS in the basal ganglia (dVRS-BG) and in the deep white matter (dVRS-WM), separately. We also assessed baseline characteristics including vascular risk factors and MRI markers of small vessel disease such as white matter hyperintensities (WMH), lacunar infarcts and microbleeds.

Results

A cumulative logit model revealed that the severity of cognitive dysfunction was associated with age (p<0.001), hypertension (p=0.006), diabetes mellitus (p=0.042), the severity of dVRS-BG (p=0.001), the severity of WMH (p=0.074) and the presence of lacunar infarcts (p<0.001) and microbleeds (p=0.003) in univariate analysis. However, after adjusting for other confounding variables, the severity of dVRS-BG was not a significant discriminating factor among subjects with SMI, MCI, and AD. Spearman's correlation analysis showed a trend that the correlation between the severity of dVRS-BG and the severity of WMH became more prominent in subjects with AD than in those with MCI or SMI (r=0.191 in SMI; r=0.284 in MCI; r=0.312 in AD), and the same is true of the severity of dVRS-BG and the number of lacunar infarcts.

Conclusions

The severity of dVRS was associated with cognitive dysfunction, which appeared to be confounded by other well-known risk factors. The correlation between dVRS-BG and small vessel disease markers tended to be more significant with the advancement of cognitive impairment. These results suggest that severe dVRS may reflect cerebral small vessel disease and contribute to cognitive impairment.

Keywords: dilated Virchow-Robin spaces; cognition; Alzheimer's disease; mild cognitive impairment; white matter hyperintensities; small vessel disease

INTRODUCTION

Virchow-Robin spaces (VRS) are perivascular spaces surrounding the perforating cerebral arteries or arterioles.1, 2 They distribute throughout the subarachnoid space to the brain parenchyma. Solutes from the brain parenchyma and lymphatics are drained into VRS, but VRS themselves do not have direct communication with the subarachnoid space.3 Dilated VRS (dVRS) are easily detectable by magnetic resonance imaging (MRI), usually in the basal ganglia (BG) at the level of the anterior commissure and in the deep white matter (WM), along the penetrating vessels.4 They appear as non-enhancing, high T2 and low T1 signals with iso-signal intensities relative to cerebrospinal fluid (CSF), and sometimes may resemble small lacunar infarct lesions.

dVRS are commonly detected in the normal brain, particularly in the elderly. Because dVRS seldom lead to tissue damage in the surrounding parenchyma, they have been regarded as benign variants.5 However, their exact role and pathogenesis is still controversial. The dilation may be caused by an alteration in the blood brain barrier,6 abnormal interstitial fluid drainage,7 or segmental angiitis.8

Recently, there is accumulating evidence that dVRS are associated with some pathological conditions, such as stroke, small vessel disease,9 dementia,10 and multiple sclerosis.11 dVRS were reported to be associated with deterioration of non-verbal reasoning and visuospatial ability in healthy elderly men.12 A large population-based prospective study showed that a high degree of dVRS was associated with increased risk of dementia and higher rate of cognitive decline.10 The parenchymal amyloid is believed to be drained with interstitial fluid along the perivascular pathway.13 dVRS may somehow affect the clearance mechanism of brain amyloid, contributing to Alzheimer's disease (AD).

However, there have been few studies addressing the implication of dVRS in the development of AD. Therefore, the purpose of our study was to investigate the association of dVRS with various levels of cognitive dysfunction and the relationship of dVRS to cerebral small vessel disease, particularly in AD patients with cerebrovascular lesion.

METHODS

Subjects

In this retrospective study, we reviewed the patients who visited the memory disorder clinic of Asan Medical Center, Seoul, Korea between March, 2009 and August, 2012. A total of 225 subjects were included: those with subjective memory impairment (SMI) (n=65), mild cognitive impairment (MCI) (n=100), and AD (n=60). All subjects underwent detailed history taking, physical and neurologic examinations, neuropsychological assessment and MRI scan. For SMI, we included subjects with sustained subjective memory complaints, but normal age-, gender-, and education-adjusted cognitive performance in Seoul Neuropsychological Screening Battery.14 Patients who fulfilled the Petersen's MCI criteria were enrolled in the MCI group.15 The diagnosis of dementia was based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.16 The diagnosis of AD was made on the basis of criteria for possible and probable AD proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association.17

Clinical parameters

Information on age, sex, the Korean version of Mini-Mental State Examination (K-MMSE) score, and vascular risk factors was collected. Investigation was done on vascular risk factors including hypertension (previously diagnosed and treated, or systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg), diabetes mellitus (previously diagnosed and treated, or fasting blood glucose ≥126 mg/dL and/or postprandial 2 hour glucose ≥200 mg/dL), hyperlipidemia (previously diagnosed and treated, or total cholesterol ≥200 mg/dL or low density lipoprotein-cholesterol ≥130 mg/dL), and history of coronary artery disease and atrial fibrillation.

Rating of dVRS and other MRI parameters

All subjects had MRI scan using Achieva 1.5-T MRI (Philips, Eindhoven, the Netherlands). The imaging protocol included the axial sequences with 5.0 mm-thickness of T2-weighted [repetition time (TR)/echo time (TE) 3018.7/100.0 msec], fluid attenuated inversion recovery (FLAIR; TR/TE 11000.0/140.0 msec), gradient echo (GRE; TR/TE 400.0/30.0 msec) images and coronal sequences with 3.0 mm-thickness of T1-weighted images (TR/TE 10.0/3.7 msec).

dVRS were defined as CSF-like signal lesions (hypointense on T1 and hyperintense on T2) of round, ovoid, or linear shape with smooth delineated contours. Each of the axial slices was initially searched to identify the slice containing the greatest number of dVRS in the BG and deep WM (Fig. 1). Then, we rated the severity of dVRS using an arbitrary three-level scale from the slice containing the greatest number of dVRS in the BG (dVRS-BG) and deep WM (dVRS-WM), respectively. The grading of dVRS was defined as follows: 'grade 1' when there were less than 10 dVRS; 'grade 2' when there were between 10 and 20 dVRS; 'grade 3' when there were more than 20 dVRS (Fig. 1).


Fig. 1
Representative MRI scans showing the severity of dilated Virchow-Robin spaces in the basal ganglia (dVRS-BG) and deep white matter (dVRS-WM).
Click for larger image

We also assessed MRI markers of small vessel disease such as white matter hyperintensities (WMH), lacunar infarcts and microbleeds. The degree of WMH severity was rated on the axial FLAIR images using a Clinical Research for Dementia of South Korea rating scale.18 Each periventricular and deep WM changes were rated separately and the results were combined to give a final score of minimal, moderate, or severe. Lacunar infarcts were defined as small lesions less than 15 mm-diameter with high signal intensities on T2- and low signal intensities on T1-weighted images, and the perilesional halo on FLAIR images. Microbleeds were defined as round-shaped and homogeneously low signal lesions with less than 10 mm-diameter on GRE images.19 Lacunar infarcts and microbleeds were rated by two methods to use adequate variables according to each of the statistical analyses: counting the number or the presence of the lesions.

Statistical analysis

The differences of demographic and clinical characteristics among the three groups were analyzed by analysis of variance or Kruskal-Wallis test for age and K-MMSE score, and by chi-square test or Fisher's exact test for sex and the presence of vascular risk factors. The statistical significance was defined as p<0.05. For the evaluation of the association of the severity of dVRS with cognitive function, we used a cumulative logit model in which the severity of cognitive dysfunction was a dependent variable, subdivided as the groups of subjects with SMI, MCI, and AD. The statistical significance was defined as p<0.2 in univariate analysis, and p<0.05 in multivariable analysis. For the comparison of the degree of the correlation between dVRS and MRI markers of small vessel disease among the three groups, Spearman's correlation analysis was done and the statistical significance was defined as p<0.05. A commercial software package (SPSS, version 19.0, IBM, Armonk, NY, USA) was used for statistical analysis.

RESULTS

Table 1 shows the demographic characteristics and vascular risk factors of subjects with SMI, MCI, and AD. The mean age of the AD group was significantly higher than the other groups, followed by the MCI group and the SMI group (74.0±8.6 years vs. 68.0±10.3 years vs. 62.0±8.7 years, p<0.001). The mean K-MMSE score was significantly lower in the AD group than the other groups, followed by the MCI group and the SMI group (18.7±5.1 vs. 24.6±4.0 vs. 28.2±2.3, p<0.001). The prevalence of hypertension was higher in the AD group compared with the SMI group (53.3% vs. 29.2%, p=0.018). There were no significant differences among the three groups in terms of sex, and the prevalence of diabetes mellitus, hyperlipidemia, and cardiac disease. A cumulative logit model revealed that the severity of cognitive dysfunction was associated with age [odds ratio (OR) 1.09, 95% confidential interval (CI) 1.06-1.12; p<0.001], hypertension (OR 2.003, 95% CI 1.217-3.296; p=0.006), diabetes mellitus (OR 1.909, 95% CI 1.023-3.560; p=0.042), the severity of dVRS-BG (OR 3.64, 95% CI 1.64-8.06; p=0.001), the severity of WMH (OR 2.93, 95% CI 0.90-9.54; p=0.074) and the presence of lacunar infarcts (OR 2.63, 95% CI 1.54-4.49; p<0.001) and microbleeds (OR 2.45, 95% CI 1.36-4.41; p=0.003) in univariate analysis (Table 2). However, after adjusting for other confounding variables, the severity of dVRS-BG was not a significant discriminating factor among subjects with SMI, MCI, and AD (OR 1.24, 95% CI 0.49-3.11; p=0.651). Spearman's correlation analysis showed a trend that the correlation between the severity of dVRS-BG and the severity of WMH became more prominent in subjects with AD than in those with MCI or SMI (r=0.191, p=0.128 in SMI; r=0.284, p=0.004 in MCI; r=0.312, p=0.015 in AD) (Table 3). The same is true of the relationship between dVRS-BG and lacunar infarcts (r=0.390, p=0.001 in SMI; r=0.306, p=0.002 in MCI; r=0.395, p=0.002 in AD).


Table 1
Demographic and clinical characteristics of the subjects
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Table 2
Risk factors for the severity of cognitive dysfunction
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Table 3
Correlation between the severity of dVRS and MRI markers of small vessel disease among subjects with SMI, MCI, and AD
Click for larger image

DISCUSSION

In this study, we correlated the severity of cognitive dysfunction with various risk factors including the severity of dVRS. Univariate analysis revealed that the severity of dVRSBG was a risk factor for cognitive dysfunction along with age, hypertension, diabetes mellitus, severity of WMH and the presence of lacunar infarcts and microbleeds. Multivariable analysis using these factors as covariates, however, showed that the severity of dVRS-BG may affect the cognitive dysfunction in association with other risk factors such as WMH. One study reported dVRS in a higher frequency in patients with AD and MCI than normal controls (F=16.50, p<0.001; AD>MCI>normal).20 However, dVRS were associated with leukoaraiosis (r=0.55, p<0.001), indicating that small vessel pathology may be a confounding factor. Another study reported that dVRS were associated with increased risk of dementia including pure vascular dementia during a 4-year follow up period [hazard ratio (HR)=5.8, 95% CI 1.2-28.4, p=0.03 for dVRS-BG; HR=9.8, 95% CI 1.7-55.3, p=0.01 for dVRS-WM],10 suggesting that the increased risk of dementia may also be due to vascular pathology. Taken together, dVRS themselves are not directly associated with cognitive dysfunction. Rather, dVRS may contribute to dementia through cerebrovascular pathology, particularly small vessel disease.

In regard to the relationship between dVRS and small vessel disease markers, our study exhibited a close correlation between dVRS-BG and WMH or lacunar infarcts. This correlation was more prominent in subjects with AD than in those with MCI or SMI, which is in consistent with the previous report where the dVRS were correlated with lacunes and WMH only in AD patients (r=0.3, p<0.01), not in normal elderly controls.21 Our results suggest that dVRS themselves may not be a definite risk factor for AD, but may affect cognitive dysfunction by contributing to small vessel disease pathology, independent of AD pathology. In another study comparing dVRS in patients with AD, vascular dementia, or frontotemporal dementia, there was no significant difference of dVRS between normal controls and AD patients but dVRS-BG were significantly associated with vascular dementia patients as compared to AD patients (p<0.001) or normal controls (p<0.001).22 This also supports the findings of our study in that dVRS can be a marker of cerebral small vessel disease.

In contrast to dVRS-BG, dVRS-WM were neither associated with cognitive dysfunction, nor with WMH or lacunar infarcts in our study, which is consistent with previous studies that dVRS in the BG rather than in WM were related to a higher rate of cognitive decline10 and that dVRS-WM showed no difference between AD patients and vascular dementia patients.22, 23 An autopsy based study revealed that small lacunes in the BG and thalamus correlated with cognitive decline in elderly patients, while lacunes in the deep WM did not.24 According to another study, arteriosclerosis in AD initially affects the BG rather than WM,25 and arteriosclerosis has been shown to be related to dVRS in the BG.26 Therefore, the different results between dVRS-BG and dVRS-WM may be explained by a different underlying pathogenesis.

The limitation of our study is the use of an arbitrary visual scale for measurement of dVRS. However, this problem was inherent in those studies dealing with dVRS because there is no standardized method available for use. Previous studies also used their own scales. A recent work using a verified scale lacked correlation with pathologic confirmation.27 Instead, we devised a scale with reference to previous studies, combining both qualitative and quantitative aspects. Secondly, our study is a cross-sectional one which hinders the inference of temporal relationship and causality between dVRS and dementia. Longitudinal prospective study involving a larger number of subjects is warranted to further explore the implication of dVRS in the context of AD dementia.

In conclusion, the severity of dVRS was associated with cognitive dysfunction, which appeared to be confounded by other well-known risk factors. The correlation between dVRSBG and MRI markers of small vessel disease was more significant in subjects with AD. These results suggest that dVRS may be considered as another marker of small vessel disease and implicated in cognitive decline.

Notes

Conflicts of Interest:The authors have no financial conflicts of interest.

Acknowledgements

This study was supported by a grant from the Korea Institute of Medicine (KIOM) (#2011-0569).

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