Effects of aging and hypertension on cerebral ischemic susceptibility: Evidenced by MR diffusion–perfusion study in rat

doi:10.1016/j.expneurol.2010.12.003

Experimental Neurology

Volume 227, Issue 2, February 2011, Pages 314-321

https://doi.org/10.1016/j.expneurol.2010.12.003 Get rights and content

Abstract

Aging is the most significant non-modifiable risk factor and hypertension is the most significant modifiable risk factor for ischemic stroke. We used magnetic resonance imaging (MRI) to investigate the evidence of ischemic susceptibility after aging and hypertension. Four groups of rat were studied: young normotensive Wistar-Kyoto (WKY) rat, aged normotensive WKY rat, young spontaneously hypertensive rat (SHR) and aged SHR. Brain images were acquired at a 3.0T Tim-Trio MRI system. For diffusion-weighted images, apparent diffusion coefficient (ADC) was measured. Relative cerebral blood flow (CBF) was also calculated. Cerebral ischemic susceptibility was examined by using ischemic model of bilateral common carotid artery occlusion. In the MRI study of non-ischemic rat, aged SHR had significantly higher ADC (P < 0.01) and significantly lower CBF (P < 0.01) in the parietal cortex, but aged WKY rat had only significantly lower CBF (P < 0.01) when compared with young WKY rat. The ADC/CBF ratio in the parietal cortex was significantly higher in aged SHR when compared with young WKY rat, young SHR and aged WKY rat (P < 0.01, P < 0.05, P < 0.05, respectively) suggesting a significant diffusion–perfusion disparity in aged SHR. After bilateral common carotid artery occlusion, there was significantly larger damage in the parietal cortex of aged SHR when compared with young WKY rat, young SHR and aged WKY rat (all P < 0.05), but not in the hippocampus and thalamus (P > 0.05). Our study demonstrated a significantly increased ADC value and reduced CBF in the ischemia-vulnerable cortical area. This cerebral diffusion–perfusion disparity is seen mainly in aged rat and can be more evident if associated with hypertension indicating an increased susceptibility of brain tissue to ischemic injury.

Research Highlights

► Aging and hypertension are risk factors for stroke. ► Aging and hypertension reduce cerebral blood flow and cause vasogenic edema. ► Brain MR images show increased diffusion but reduced perfusion. ► Brain damage is seen in ischemic area with severe diffusion–perfusion disparity. ► Aging and hypertension increase ischemic susceptibility.

Introduction

Age is the most significant non-modifiable risk factor for stroke and it is estimated that the stroke rate is doubled each 10 years after age 55 (Goldstein et al., 2006). Epidemiological studies also showed that the incidence of ischemic stroke increased with aging population, and the development of stroke-induced pathology appeared to be much more severe in aged than in young human subjects (Rothwell et al., 2004). Hypertension is the most significant modifiable risk factor for both ischemic and hemorrhagic stroke (Goldstein et al., 2006). The relationship between blood pressure and the risk to develop cerebrovascular accident is continuous, consistent, and independent of other risk factors (Chobanian et al., 2003). The higher the blood pressure, the greater the stroke risk (Lewington et al., 2002), and antihypertensive treatment may result in a 35% to 44% reduction in stroke incidence (Neal et al., 2000).

Magnetic resonance diffusion- and perfusion-weighted imaging (DWI and PWI) has been developed as a simple and feasible method for investigation of the ischemic brain tissue at risk for infarction in the acute stage of stroke (Henninger et al., 2006). DWI can locate the acute focal ischemic brain injury at early time point and PWI can detect the presence of disturbances in microcirculatory perfusion (Fisher and Albers, 1999). Using these MRI techniques, it is possible to understand the acute stroke-induced pathology and help in the decision-making in the clinical management (Henninger et al., 2006, Tatlisumak and Li, 2003).

Permanent occlusion of bilateral common carotid arteries (two vessel occlusion (2-VO)) (Farkas et al., 2007) in rat can result in severe reduction of cerebral blood flow (CBF) and cause ischemic injury to cerebral cortex and hippocampus. This ischemic model has been established as a procedure to investigate the effects of chronic cerebral hypoperfusion on cognitive dysfunction and neurodegenerative processes.

In the present study, we aimed to study the evidence of aging and hypertension induced ischemic susceptibility by using apparent diffusion coefficient (ADC, obtained from DWI) and CBF (obtained from PWI) of magnetic resonance imaging (MRI) in the normal rat brain. We also used 2-VO ischemic model to examine the infarct size and correlate with the MRI findings.

Section snippets

Animal

Four groups of male rats were studied including (1) young normotensive Wistar-Kyoto (WKY) rat, (2) aged normotensive WKY rat, (3) young spontaneously hypertensive rat (SHR), and (4) aged SHR. For young rat, age range was 12–16 weeks and body weight was 250–320 g. For aged rat, age range was 56–60 weeks and body weight was 320–400 g. For MRI study, 13 rats were used in each group. For histopathological study, another 5 rats were treated with bilateral common carotid artery occlusion in each group.

MR imaging methods

Results

Among the four groups of rat, body weight was significantly higher in aged rat than in young rat (F_{3, 48} = 35.642, P < 0.0001; after post hoc analysis, P < 0.01, Table 1). The heart rate and systolic, diastolic and mean blood pressure were significantly higher in young and aged SHR when compared with young and aged WKY rats (F_{3, 48} = 18.136, P < 0.0001, F_{3, 48} = 95.694, P < 0.0001, F_{3, 48} = 89.756, P < 0.0001, F_{3, 48} = 104.309, P < 0.0001, respectively; after post hoc analysis, P < 0.01, Table 1). These data

Discussion

In the ADC analysis, there are controversial results in both human and animal studies related to aging, and the ADC values in various brain regions correlate differently in relation to aging. Some studies demonstrated there was an increase of ADCs with aging (Chen et al., 2001, Engelter et al., 2000, Fisher and Albers, 1999, Nusbaum et al., 2001), whereas others found no significant ADC change (Chun et al., 2000, Helenius et al., 2002) or a decreased ADC with aging (Heiland et al., 2002). In

Disclosure statement

There are no actual or potential conflicts of interests.

Acknowledgments and source of funding

National Science Council, Taiwan (Contract no. NSC 97-2314-B-182A-049) and Chang Gung Memorial Hospital under the Medical Research Project (Contract no. Animal Molecular Imaging Center CMRPG340203).

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Effects of aging and hypertension on cerebral ischemic susceptibility: Evidenced by MR diffusion–perfusion study in rat

Abstract

Research Highlights

Introduction

Section snippets

Animal

MR imaging methods

Results

Discussion

Disclosure statement

Acknowledgments and source of funding

Neurobiol. Aging

Neurobiol. Aging

Neuroimage

Neurobiol. Aging

Brain Res.

Brain Res. Rev.

Neurosci. Lett.

Brain Res.

Life Sci.

Lancet

J. Neurosci. Methods

Clin. Neurol. Neurosurg.

Differences in response to anaesthetics and analgesics between inbred rat strains

Lab Anim.

Conversion of ischemic brain tissue into infarction increases with age

Stroke

Age-dependent MRI-detected lesions at early stages of transient global ischemia in rat brain

Magma

Diffusion tensor trace mapping in normal adult brain using single-shot EPI technique. A methodological study aging brain

Acta Radiol.

The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report

JAMA

Diffusion changes in the aging human brain

AJNR Am. J. Neuroradiol.

Effects of cilazapril on the cerebral circulation in spontaneously hypertensive rats

Hypertension

Hypertension and cerebral blood flow: implications for the development of vascular cognitive impairment in the elderly

Stroke