Department of Radiology, The First Affiliated Hospital, Xi’an Jiaotong University     Yang Jian

Background:

Alzheimer disease (AD) is a progressive neurodegenerative disease. As the disease progresses, the main manifestations includes memory loss, cognitive dysfunction, and significant changes in behavior, which seriously affect their normal life. It is reported that there are about 44 million AD patients worldwide, and there is currently no effective treatment in clinical practice. Exploring the pathophysiological mechanism of AD is of great significance for guiding early clinical intervention and effective treatment. Studies have indicated that the Virchow Robin spaces (VRS) showed certain correlation with β-amyloid pathologies. It is noted that dilated Virchow Robin spaces (dVRS) has been frequently observed on the conventional brain magnetic resonance image (MRI) in AD patients. However, the characteristics of VRS in AD patients have not been systematically studied, especially for the brain white matter regions. Therefore, this study will evaluate the VRS status in brain white matter regions of AD patients by MRI and explore its correlation with the degree of AD. It is hypothesized that dVRS may be a biomarker of AD.

Objectives:

To assess the severity of dVRS in the brain white matter of patients with AD, and to study the relationship between dVRS and AD disease degree, and patients' memory and cognitive function.

Materials and Methods:

This study was a case-control study. We retrospectively included 53 AD patients (male/female, 28/25; age range: 50-89 years) and 40 control subjects (male/female, 23/17; age range: 50-89 years) who underwent 3.0T MRI in our hospital from 2013 to 2018.

Included criteria in AD patients: (1) age ≥ 50 years; (2) met the AD diagnostic criteria by National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA); (3) complete the conventional MRI examination; (4) complete the MMSE (mini-mental state examination) assessment.  Excluded criteria: (1) any neuropsychiatric disease other than AD; (2) image with artifacts.

Inclusion criteria in the control group: (1) age ≥ 50 years; (2) complete the conventional MRI; (3) complete the MMSE assessment. Excluded criteria: (1) abnormalities on MRI; (2) MMSE score <24 points; (3) image artifacts.

The dVRS in the white matter region on T2 weighted imaging (T2WI) was evaluated by semi-quantitative and quantitative analysis, respectively. Semi-quantitative method: visually graded assessment of dVRS in the brain white matter region: 0 (none), 1 (1-10), 2 (11-20), 3 (21-40), and 4 ( >40). In addition, Fazekas scoring method was used to evaluate the white matter hyperintensity. Correlations between the Fazekas scores and dVRS grades were analyzed by the Spearman correlation analysis.

Quantitative methods: it mainly includes pre-skull pretreatment, quantitative calculations of VRS number and volume, and registration with standard brain white matter template. The Mann-Whitney U test was used to compare the differences between AD and control groups. Spearman correlation analysis was used to analyze the correlation between dVRS number and volume fraction (dVRS total volume/total white matter volume) and AD duration and MMSE score.

Results:

The comparison of baseline characteristics of the 53 AD patients and 40 healthy controls showed that more hypertension ( 35.85% versus 10% , P = 0.017 ), dyslipidemia ( 13.2% versus 5%, P < 0.001 ), and cerebrovascular disease ( 17% versus 2.5%, P = 0.026 ) were observed in AD group; moreover, lower MMSE scores were found in AD group (AD: 16.3 ± 6.4; control: 27.1 ± 1.5, P < 0.001 ), and a significant difference in severity of dilated VRS were found between case and control (P < 0.001).

Semi-quantitative dVRS counts showed high agreement between the observers themselves (ICC = 0.91; 95% CI, 0.81-0.96) and between observers (ICC = 0.89; 95% CI, 0.81-0.93). The white matter high signal Fazekas score showed good agreement among the observers (ICC = 0.86; 95% CI, 0.80-0.91).

AD patients showed more dVRS than the control group (semi-quantitative assessment: 52.8 ± 17.7 vs. 17.7 ± 7.9, P < 0.001; quantitative assessment: 1110.3 ± 396.7 vs. 235.7 ± 121.9, P < 0.001), and higher volume fraction (2.3 ± 1.0 vs. 1.7 ± 1.7; P = 0.018). The number of dVRS was positively correlated with the duration of AD (Spearman’s rho [rs] = 0.43, P < 0.001). With age, the number of dVRS in the control group increased (rs = 0.37, P = 0.019), but not in AD patients (rs = 0.37, P = 0.019). The number of dVRS was negatively correlated with the MMSE score (rs = -0.45, P < 0.01).  The atlas based whole brain white matter analysis showed that cingulum of the brain was highly influenced with dilated VRS clusters and volume.

Conclusions:

1. AD patients had more counts and higher volume fraction of dVRS than the control group.

2. The count of dVRS significantly correlated with the AD duration and MMSE score, and was the highest in AD-related white matter region, i.e. cingulum, suggesting the potential role of it as a biomarker in evaluating the progression of AD.

KEY WORDS:

Magnetic resonance imaging, Dilated Virchow Robin’s space, Alzheimer’s disease, Central nervous system.