Publication / Source: Neurology Central
Authors: Kristian P. Doyle (University of Arizona, AZ, USA)
Worldwide, approximately 10 million individuals survive ischemic stroke each year (1) and although the pathophysiology of stroke injury in the brain during the acute stage is well defined, much less is known about the pathophysiology of the chronic stage. In addition to this, relatively little is understood about the mechanisms by which recovery occurs, and there are no FDA-approved therapies currently available to improve patients’ recovery following stroke. Furthermore, more than one-third of stroke survivors develop new onset dementia after stroke, the causes of which are still unclear. There is therefore a pressing need for the development of treatments for these stroke-related dementia patients as well as increased investment in characterizing the pathophysiology of chronic stroke lesions, in both animal models and humans.
During the acute stage of ischemic stroke, which encompasses the first 24 hours or so, the restriction of blood flow to an area of the brain results in a reduction of oxygen and glucose to levels below the threshold required to support cellular homeostasis. This leads to cell death by excitotoxicity, the induction of oxidative and nitrative stress, and inflammation. During the next few days, in the subacute stage, excitotoxicity and the induction of oxidative and nitrative stress subside, but cell death continues due to inflammation. Over the next two weeks inflammation and apoptosis abate and the infarct begins to be resolved (2), and at approximately two weeks the area of damage is sealed by an immature glial scar and compartmentalized away from the adjacent parenchyma. Gliosis continues for the following few weeks, and by seven weeks a mature glial scar is evident and the lesion manifests as a chronic infarct. However, this is not the end of the healing process; at seven weeks, necrotic tissue and edema have yet to be fully resorbed, the blood-brain barrier has yet to be fully restored, and immune cells and proinflammatory cytokines are still prevalent within the lesion (3-5).
A key focus area for future stroke research is therefore to more comprehensively characterize the pathophysiology of chronic stroke. We must determine precisely how long inflammation and blood-brain barrier dysfunction last following stroke, as each of these processes could still be causing mild, but sustained, cell death to the parenchyma surrounding stroke lesions for weeks, months and possibly even years following stroke. These processes could be the cause of stroke-related dementia in some patients. In support of this, atrophy of the tissue surrounding stroke lesions (6), blood-brain barrier dysfunction and increased inflammation in the blood are observed in stroke-related dementia patients (7-10).