The Pathologic Cascade of Cerebrovascular Lesions in SHRSP: Is Erythrocyte Accumulation an Early Phase?

Abstract

Cerebral small vessel disease (CSVD) is associated with vessel wall changes, microbleeds, bloodbrain barrier (BBB) disturbances, and reduced cerebral blood flow (CBF). As spontaneously hypertensive stroke-prone rats (SHRSP) may be a valid model of some aspects of human CSVD, we aimed to identify whether those changes occur in definite temporal stages and whether there is an initial phenomenon beyond those common vascular alterations. Groups of 51 SHRSP were examined simultaneously by histologic (Hematoxylin-Eosin, IgG-Immunohistochemistry, vessel diameter measurement) and imaging methods (Magnetic Resonance Imaging, 201-ThalliumDiethyldithiocarbamate/99m-Technetium-HMPAO Single Photon Emission Computed Tomography conducted as pilot study) at different stages of age. Vascular pathology in SHRSP proceeds in definite stages, whereas an age-dependent accumulation of erythrocytes in capillaries and arterioles represents the homogeneous initial step of the disease. Erythrocyte accumulations are followed by BBB disturbances and microbleeds, both also increasing with age. Microthromboses, tissue infarctions with CBF reduction, and disturbed potassium uptake represent the final stage of vascular pathology in SHRSP. Erythrocyte accumulations-we parsimoniously interpreted as stases-without cerebral tissue damage represent the first step of vascular pathology in SHRSP. If that initial phenomenon could be identified in patients, these erythrocyte accumulations might be a promising target for implementing prophylactic and therapeutic strategies in human CSVD.

Associations between arterial stiffness, depressive symptoms and cerebral small vessel disease: cross-sectional findings from the AGES-Reykjavik Study

“…Although higher CFPWV was associated with presence of Virchow-Robin spaces and cerebral microbleeds, these lesions were not associated with depressive symptoms. It is possible that Virchow-Robin spaces and cerebral microbleeds play a role early in the pathogenesis of cerebral small vessel disease, 40 whereas WMHs and subcortical infarcts represent more advanced disease states. In addition, although lower brain parenchyma volume was associated with a higher level of depressive symptoms, brain parenchyma volume was not associated with CFPWV.…”

Cerebral blood flow and metabolism associated with cerebral microbleeds in small vessel disease

“…CMBs have not yet sufficiently been examined in association with CBF and metabolism. Schreiber et al [23] demonstrated that reduced CBF accompanied by infarcted tissue additionally exhibited microthromboses or CMBs using 201-Thallium-Diethyldithiocarbamate/99 m-Technetium hexamethylpropyleneamine oxime single photon emission computed tomography in spontaneously hypertensive stroke-prone rats, as a valid model of human small vessel disease. They emphasized that erythrocyte accumulations without cerebral tissue damage represent the first step in hypertensive vascular pathology, followed by disturbance of the blood-brain barrier and CMBs.…”

Pre-clinical models of human cerebral small vessel disease: Utility for clinical application

“…First, animals allow us to explore pathological processes at the cell/molecular level in vivo. Examples relevant to SVD and VCI are fibrotic thickening of artery walls and other vascular pathology [27][28][29]32,[49][50][51][52][53][54] or ischemic white matter damage [16,38,55,56]. There is a clear caveat that such models do not allow deductions regarding pathogenesis of human SVD.…”

“…MRI studies of stroke-free SHRSP reported no leukoaraiosis-like white matter changes up to 5-8 months of age [31,32]. In a longitudinal MRI study focal leakage of intravascular contrast agent (indicative of local blood-brain barrier breakdown) was seen up to 14 days prior to a stroke lesion in the affected brain area [33].…”