An MRI-Histological Study of White Matter in Stroke-Free SHRSP

Hypertension is linked with an increased risk of white matter hyperintensities; however, recent findings have questioned this association. We examined whether hypertension and additional cerebrovascular risk factors impacted on white matter integrity in an inducible hypertensive rat. No white matter hyperintensities were observed on magnetic resonance imaging either alone or in conjunction with ageing and high-fat diet. Aged hypertensive rats that were fed a high-fat diet had moderately reduced fractional anisotropy in the corpus callosum with no overt pathological features. Herein we show that moderate hypertension alone or with additional risk factors has minimal impact on white matter integrity in this model.

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Hypertension Fails to Disrupt White Matter Integrity in Young Or Aged Fisher (F44) Cyp1a1Ren2 Transgenic Rats

Holland

Pannozzo

Bastin

et al. 2014

“…Recent evidence from animal models also suggest that hypertension is not the key driver of white matter changes. 36,37 Our results show that some radiologic, pathologic, and cognitive features of human SVD can be recapitulated in a mouse model by common carotid stenosis. Our findings also provide evidence that hypoperfusion may precipitate SVD-like disease culminating in a progressive brain and gliovascular pathology.…”

Section: Discussionmentioning

confidence: 74%

Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

Holland

Searcy

Salvadores

et al. 2015

125

Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood-brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies. Keywords: cognition; diffusion-tensor imaging; hypoperfusion; magnetic resonance imaging; small vessel disease INTRODUCTION Cerebral small vessel disease (SVD) is a major cause of age-related cognitive decline and dementia. Journal of Cerebral Blood1 Hypertension is proposed to be a common risk factor (although it explains only a small proportion of imaging-determined SVD) and cerebral amyloid angiopathy is commonly present on pathologic examination.2,3 Clinically, SVD is associated with early impairment of attention and executive function with slowing of information processing and motor deficits.1 These clinical manifestations result primarily from the occurrence of lesions in the cerebral white matter, multiple lacunes within subcortical structures, atrophy, and, in some cases, microbleeds in deep gray matter, white matter, or at the corticosubcortical junction, identified by neuroimaging.2,4 White matter lesions, associated with increased extracellular fluid, varying degrees of myelin and axonal pathology, and glial responses, are predominantly detected as hyperintense regions on fluid attenuation inversion recovery and T2-weighted magnetic resonance imaging (MRI).5 Lacunes, which present as hypointense regions on fluid attenuation inversion recovery or T1-weighted MRI or hyperintense on T2-weighted MRI, are small deep cavities

“…19 Normally, SHR/SP can live up to 9 months without magnetic resonance imaging (MRI) or pathologic evidence of brain damage. 20 We have shown that feeding SHR/SP a diet consisting of low protein and high salt, the Japanese Permissive Diet (JDP), along with unilateral carotid artery occlusion (UCAO), produces an accelerated injury to the WM that is associated with MMP expression, BBB disruption, death of mature oligodendrocytes, and expression of oligodendrocyte precursor cells; the extent of injury can be monitored noninvasively with MRI and the behavioral changes with Morris water maze (MWM). 21 Using an oxygensensitive crystal with electron paramagnetic resonance, we showed an increase in oxygen extraction in the WM at 12 weeks of life with a drastic decrease in oxygen from the thirteenth to the sixteenth week when the animals died.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced Neuroinflammatory White-Matter Injury Reduced by Minocycline in SHR/SP

Jalal

Yang

Thompson

et al. 2015

105

Hypertensive small vessel disease is a major cause of vascular cognitive impairment (VCI). Spontaneously hypertensive/stroke prone rats (SHR/SP) with unilateral carotid artery occlusion (UCAO) and a Japanese permissive diet (JPD) have white-matter (WM) damage similar to that seen in VCI. We hypothesized that WM injury was due to hypoxia-mediated, blood-brain barrier (BBB) disruption. Twelve-week-old SHR/SP had UCAO/JPD and were studied with immunohistochemistry, biochemistry, multimodal magnetic resonance imaging (MRI), and Morris water maze (MWM) testing. One week after UCAO/JPD, WM showed a significant increase in hypoxia inducible factor-1α (HIF-1α), which increased further by 3 weeks. Prolyl hydroxylase-2 (PHD2) expression decreased at 1 and 3 weeks. Infiltrating T cells and neutrophils appeared around endothelial cells from 1 to 3 weeks after UCAO/JPD, and matrix metalloproteinase-9 (MMP-9) colocalized with inflammatory cells. At 3 weeks, WM immunostained for IgG, indicating BBB leakage. Minocycline (50 mg/kg intraperitoeally) was given every other day from weeks 12 to 20. Multimodal MRI showed that treatment with minocycline significantly reduced lesion size and improved cerebral blood flow. Minocycline improved performance in the MWM and prolonged survival. We propose that BBB disruption occurred secondary to hypoxia, which induced an MMP-9-mediated infiltration of leukocytes. Minocycline significantly reduced WM damage, improved behavior, and prolonged life.