Abstract
BackgroundThere is growing evidence that endothelial failure and subsequent blood brain barrier (BBB) breakdown initiate cerebral small vessel disease (CSVD) pathology. In spontaneously hypertensive stroke-prone rats (SHRSP) endothelial damage is indicated by intraluminal accumulations of erythrocytes (erythrocyte thrombi) that are not observed with current magnetic resonance imaging techniques. Two-photon microscopy (2 PM) offers the potential for real-time direct detection of the small vasculature. Thus, within this pilot study we investigated the sensitivity of 2 PM to detect erythrocyte thrombi expressing initiating CSVD phenomena in vivo.MethodsEight SHRSP and 13 Wistar controls were used for in vivo imaging and subsequent histology with haematoxylin-eosin (HE). For 2 PM, cerebral blood vessels were labeled by fluorescent Dextran (70 kDa) applied intraorbitally. The correlation between vascular erythrocyte thrombi observed by 2 PM and HE-staining was assessed. Artificial surgical damage and parenchymal Dextran distribution were analyzed postmortem.ResultsDextran was distributed within the small vessel walls and co-localized with IgG.Artificial surgical damage was comparable between SHRSP and Wistar controls and mainly affected the small vasculature. In fewer than 20% of animals there was correlation between erythrocyte thrombi as observed with 2 PM and histologically with HE.ConclusionsContrary to our initial expectations, there was little agreement between intravital 2 PM imaging and histology for the detection of erythrocyte thrombi. Two-photon microscopy is a valuable technique that complements but does not replace the value of conventional histology.
Highlights
Human cerebral small vessel disease (CSVD) is commonly found in the brains of the elderly and in Alzheimer’s disease (AD) as demonstrated in autopsy and human imaging studies [1,2,3,4,5,6,7,8]
Hypertensive stroke-prone rats (SHRSP) develop all features of human CSVD including an endothelial dysfunction with resulting blood brain barrier (BBB) damage indicated by plasma protein leakage into the small vessel walls and the perivascular parenchyma [13]
spontaneously hypertensive rats (SHR) and spontaneously hypertensive stroke-prone rats (SHRSP) both develop arterial hypertension and an associated vascular pathology; the pathology is more severe in SHRSP [33]. Within this first pilot study we aimed to investigate whether 2 Two-photon microscopy (PM) could be performed safely in SHRSP, an appropriate model of CSVD pathology, with consecutive high spontaneous infarct frequencies
Summary
Human cerebral small vessel disease (CSVD) is commonly found in the brains of the elderly and in Alzheimer’s disease (AD) as demonstrated in autopsy and human imaging studies [1,2,3,4,5,6,7,8]. Hypertensive stroke-prone rats (SHRSP) develop all features of human CSVD including an endothelial dysfunction with resulting BBB damage indicated by plasma protein leakage into the small vessel walls and the perivascular parenchyma [13]. There is growing evidence that endothelial failure and subsequent blood brain barrier (BBB) breakdown initiate cerebral small vessel disease (CSVD) pathology. In spontaneously hypertensive stroke-prone rats (SHRSP) endothelial damage is indicated by intraluminal accumulations of erythrocytes (erythrocyte thrombi) that are not observed with current magnetic resonance imaging techniques. Two-photon microscopy (2 PM) offers the potential for real-time direct detection of the small vasculature Within this pilot study we investigated the sensitivity of 2 PM to detect erythrocyte thrombi expressing initiating CSVD phenomena in vivo
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