Stroke promotes the development of brain atrophy and delayed cell death in hypertensive rats

 What the hell is your doctor doing to solve post-stroke cognitive impairment?

And since you lost 5 cognitive years from the stroke.

Just maybe you want your doctor to have a protocol to recover that.

Stroke promotes the development of brain atrophy and delayed cell death in hypertensive rats

• Mohammed A. Sayed,
• Wael Eldahshan,
• Mahmoud Abdelbary,
• Bindu Pillai,
• Waleed Althomali,
• Maribeth H. Johnson,
• Ali S. Arbab,
• Adviye Ergul &
• Susan C. Fagan 

Scientific Reports volume 10, Article number: 20233 (2020) Cite this article

Abstract

Post-stroke cognitive impairment (PSCI) is a major source of disability, affecting up to two thirds of stroke survivors with no available therapeutic options.(Why not?) The condition remains understudied in preclinical models due to its delayed presentation. Although hypertension is a leading risk factor for dementia, how ischemic stroke contributes to this neurodegenerative condition is unknown. In this study, we used a model of hypertension to study the development of PSCI and its mechanisms. Spontaneously hypertensive rats (SHR) were compared to normotensive rats and were subjected to 1-h middle cerebral artery occlusion or sham surgery. Novel object recognition, passive avoidance test and Morris water maze were used to assess cognition. In addition, brain magnetic resonance images were obtained 12-weeks post-stroke and tissue was collected for immunohistochemistry and protein quantification. Stroked animals developed impairment in long-term memory at 4-weeks post-stroke despite recovery from motor deficits, with hypertensive animals showing some symptoms of anhedonia. Stroked SHRs displayed grey matter atrophy and had a two-fold increase in apoptosis in the ischemic borderzone and increased markers of inflammatory cell death and DNA damage at 12 weeks post-stroke. This indicates that preexisting hypertension exacerbates the development of secondary neurodegeneration after stroke beyond its acute effects on neurovascular injury.

Introduction

Stroke has recently become the fifth leading cause of death in the United States¹. While stroke mortality has been steadily declining over the last decade due to the continuous improvement in health care standards², the number of stroke survivors with residual disability is steadily increasing³. Ischemic stroke is a condition characterized by an initial ischemic event that deprives brain tissue from blood supply and oxygenation, that is sometimes followed by reperfusion, leading to irreversible brain damage and subsequent motor and cognitive impairment⁴.

Post-stroke cognitive impairment (PSCI) is a condition that affects up to two-thirds of patients following ischemic stroke, with up to one third eventually developing dementia^5,6. Although PSCI is highly prevalent among stroke survivors, there is evidence suggesting that the criteria for diagnosis may underestimate the frequency of dementia and cognitive decline among stroke survivors^7,8. While it was traditionally thought that the cognitive impairment results from the recurrence of ischemic insults, newer evidence suggests that a very substantial portion of this impairment results from neuronal pathogenesis⁹. Published data from a large, NIH-funded, epidemiologic trial showed that patients, in addition to acute changes, suffer from a slowly progressive cognitive decline after a single-stroke lesion^10,11. This continuous deterioration occurs even in the absence of any evidence of new ischemic injuries^12,13.

Diagnosis and characterization of clinically apparent PSCI has proven to be a challenging task, owing to the heterogeneity of the condition itself. The incidence of PSCI and its severity depends largely upon the morphology of the vascular injury (focal or multifocal; large or small vessel), volume of brain tissue affected by ischemia and, most importantly, the location and number of lesions¹⁴. Histopathological studies have shown a clear link between the vascular aspects of brain injuries affecting cognition and the neurodegenerative aspects that resemble Alzheimer’s disease pathology¹⁵.

Hypertension is the most commonly occurring modifiable risk-factor for stroke worldwide and is being increasingly recognized as a risk factor for the development of PSCI^15,16. Chronic hypertension, particularly midlife high blood pressure (BP), has been associated with an increased risk for cognitive decline, vascular dementia and Alzheimer’s disease¹⁷. One of the mechanisms by which hypertension is believed to contribute to the development of cognitive impairment is exposing the cerebral microvasculature to pulsatile pressure causing tearing of the brain vascular endothelium and smooth muscle cells leading to lipohyalinosis and fibrinoid necrosis¹⁸. Clinical studies on hypertensive patients have shown that acute disruption of blood perfusion can lead to the formation of lacunar infarcts, while chronic ischemia can lead to the development of white matter lesions which are associated with the development of cognitive impairment^19,20.

In this study, we aimed to determine the role of hypertension in the development of cognitive impairment following experimental stroke in rats by comparing normotensive (Wistar) rats to spontaneously hypertensive rats (SHR). We hypothesized that hypertension plays a key role in exacerbating PSCI by inducing neurodegenerative processes, causing SHRs to be more susceptible to PSCI compared to normotensive animals.