Retinal Microvascular Calibers Are Associated With Enlarged Perivascular Spaces in the Brain
Background and Purpose—Perivascular enlargement in the brain is a putative imaging marker for microvascular brain damage, but this link has not yet been confirmed using direct in vivo visualization of small vessels. We investigated the relation between microvascular calibers on retinal imaging and enlarged perivascular spaces (ePVSs) on brain magnetic resonance imaging.
Methods—We included 704 participants from the Rotterdam study. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. ePVSs were counted in the centrum semiovale, basal ganglia, hippocampus, and mesencephalon, using a standardized rating method. We determined the association between retinal microvascular calibers and ePVSs with negative binomial regression models, adjusting for age, sex, the other vascular caliber, structural brain magnetic resonance imaging markers, and cardiovascular risk factors.
Results—Both narrower arteriolar and wider venular calibers were associated with more ePVSs in the centrum semiovale and hippocampal region. Rate ratios (95% confidence interval) for arterioles in the centrum semiovale and hippocampus were 1.07 (1.01–1.14) and 1.13 (1.04–1.22), respectively, and for venules 1.08 (1.01–1.16) and 1.09 (1.00–1.18), respectively. These associations were independent from other brain magnetic resonance imaging markers and cardiovascular risk factors.
Conclusions—Retinal microvascular calibers are related to ePVSs, confirming the putative link between microvascular damage and ePVSs.
Enlarged perivascular spaces (ePVSs) in the brain, also known as Virchow–Robin spaces, have emerged as a promising imaging biomarker for vascular brain pathology.1 These are spaces filled with interstitial fluid that surround the blood vessels as they extend into the brain. Increasing evidence suggests that ePVSs are affected by vascular risk factors, including high blood pressure and inflammation.2 Additionally, ePVSs are strongly associated with other structural imaging markers, such as white matter lesions and lacunes, both hallmarks of cerebral small-vessel disease.3 In histopathology, ePVSs and characteristics of microvascular diseases are often found concomitantly, further indicating that ePVSs might reflect damage to cerebral microvessels.4 However, the link between microvascular damage and ePVSs has not yet been shown in vivo. The main difficulty is to directly assess the cerebral microvessels (<200 μm) in vivo with current brain imaging techniques. A robust alternative is visualization of the retinal microvasculature, as the retinal and cerebral microvasculature share anatomy, physiology, and embryology.5 Indeed, there is convincing evidence showing links between retinal microvascular damage and (sub)clinical vascular brain disease.6 Here, we investigated the association of retinal microvasculature with ePVSs in the general population.
See the online-only Data Supplement for detailed methods.
Setting and Study Population
This study was embedded within the population-based Rotterdam study.7 Between 2004 and 2006, we randomly invited 1073 people for brain magnetic resonance imaging (MRI), of which 704 nondemented people had complete scans and gradable fundus transparencies. The Rotterdam study has been approved by the medical ethics committee according to the Population Study Act Rotterdam Study. Written informed consent was obtained from all participants.
Measurement of Retinal Microvascular Calibers
Fundus photographs centered on the optic disc were analyzed with a semiautomated system (Interactive Vessel Analyzer [IVAN]) following standardized protocols.8 For each participant, 1 summary value was calculated for the arteriolar and venular calibers (in micrometer) and adjusted for possible magnification variations to approximate absolute measures.
Enlarged Perivascular Spaces Rating
Perivascular enlargements were counted according to a previously published protocol9 in the centrum semiovale, basal ganglia, hippocampus, and mesencephalon, areas in which ePVSs frequently occur. PVSs were identified by their linear, ovoid, or round shape and considered enlarged when their diameter was ≥1 mm.9
We used negative binomial regression models to determine the association between retinal vascular calibers and count of ePVSs. Rate ratios (interpreted as ratios of ePVSs count) with 95% confidence intervals were estimated per SD decrease in arterioles or increase in venules. We adjusted for age, sex, and the other vascular caliber and additionally for structural brain MRI markers (intracranial volume, white matter lesion volume, infarcts, and microbleeds) and for cardiovascular risk factors. We explored effect modification by stratifying for sex, hypertension, diabetes mellitus, and smoking. Analyses were performed using SPSS 21.0 for Windows.
Study population characteristics are reported in Table 1. Average age was 66.0 years, and 52% were females. We found that narrower arteriolar calibers and, to a lesser extent, wider venular calibers were significantly associated with more ePVSs in the hippocampus and centrum semiovale. Adjusting for structural brain MRI markers and cardiovascular risk factors slightly attenuated these associations, but these remained statistically significant (Table 2). Figure I in the online-only Data Supplement shows the difference in count of ePVSs for tertiles of arterioles and venules compared with the reference tertile. Excluding participants with a history of stroke (n=11) did not change the associations. Stratified analyses revealed no interactions (Pinteraction>0.05).
We found that narrower arteriolar and wider venular calibers were associated with more ePVSs, independently of structural brain MRI markers and cardiovascular risk factors. Previous studies showed that ePVSs are related to subclinical and clinical vascular brain disease,1,2 supporting that perivascular enlargements reflect microvascular damage. However, no study has directly investigated in vivo the association of ePVSs with microvasculature. We provide the first in vivo evidence that microvascular calibers are related to ePVSs, but the mechanism remains undetermined. First, PVSs drain interstitial and cerebrospinal fluid to the subarachnoid space, and eventually into cervical lymph nodes. Hence, a failure in this transmission may result in hemodynamic pressure differences that might manifest themselves in changed vascular calibers. Future studies are warranted to show how that would specifically lead to narrower arterioles. Second, narrower arterioles may lead to a state of cerebral hypoperfusion, eventually resulting in atrophy, and thus to perivascular enlargement. This ischemic mechanism is further supported by findings showing wider venular calibers to be associated with cerebral hypoxia.10 Finally, it is also possible that shared risk factors explain the relation between retinal microvascular calibers and ePVSs. Structural MRI markers of cerebral small-vessel disease, or cardiovascular risk factors, are likely candidates as confounders, but these factors did not fully explain the association in our study, indicating that other processes also play a role. These include arteriolosclerosis, inflammation, venous collagenosis, and cerebral amyloid angiopathy. Interestingly, ePVSs in the brain regions most associated with the retinal microvessels, namely the centrum semiovale and hippocampus, are related to cerebral amyloid angiopathy.11 The perivascular drainage system in the basal ganglia is thought to process amyloid more efficiently and ePVSs there are associated more to vascular pathology. However, we did not find a significant association of retinal vascular calibers and ePVSs in the basal ganglia. Strengths of our study are the population-based setting, the standardized rating protocol, and the extensive available data on brain MRI markers and cardiovascular risk factors. A limitation is the cross-sectional design of our study, which precludes inferences on the temporal link between microvascular damage and ePVSs. Also, it is difficult to completely rule out misclassification of small infarcts as perivascular enlargements. This potential differential misclassification may have led to overestimation of our associations. However, because we used count data on PVSs as outcome, a single or even a few misclassified infarcts are unlikely to have majorly influenced our results. Finally, we used a static measure of the microcirculation instead of dynamic functional measures synchronized on the cardiac cycle. This may have caused random misclassification, leading to an underestimation of our associations. In conclusion, our study shows that microvascular calibers are related to ePVSs, independent of structural MRI markers of cerebral small-vessel disease, and cardiovascular risk factors.
Sources of Funding
The Rotterdam study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.012438/-/DC1.
- Received December 14, 2015.
- Accepted February 11, 2016.
- © 2016 American Heart Association, Inc.
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