Unraveling the Pathophysiology of Chronic Stroke Lesions Could Yield Treatments for Stroke-Related Dementia

KEYWORDS:

• chronic stroke
• glial scars
• inflammation
• liquefactive necrosis
• post-stroke dementia

First draft submitted: 30 November 2015; Accepted for publication: 8 December 2015; Published online: 11 January 2016

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 US FDA-approved therapies currently available to improve patients’ recovery following stroke. Furthermore, more than a third of stroke survivors develop new onset dementia after stroke, the causes of which are still unclear. Therefore, there is 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 h 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 2 weeks, inflammation and apoptosis abate and the infarct begins to be resolved [2], and at approximately 2 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 7 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 7 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].

Furthermore, my colleagues and I recently developed a mouse model of delayed cognitive dysfunction following stroke and discovered that cognitive dysfunction correlates with the appearance of a delayed adaptive immune response in the stroke lesion. The response is apparent at 7 weeks, but not 1 week following stroke, and coincides with infiltration of antibodies, cytokines and T cells into adjacent brain regions. Importantly, we showed that the genetic and pharmacologic ablation of B lymphocytes is one way to prevent the development of delayed cognitive deficits following stroke in C57BL/6 mice [3].

This provides impetus for investigating whether B cells could be a cause of delayed cognitive impairment in some patients diagnosed with stroke-related dementia. However, although 100% of the C57BL/6 mice in our study developed a delayed and chronic B-cell response within the stroke lesion in the weeks following stroke, in humans, we could only find evidence of B-cell infiltrates within chronic stroke lesions in 45% of the stroke-related dementia patients we analyzed [3]. Patients diagnosed with stroke-related dementia, a subcategory of vascular dementia, often have multiple comorbidities, such as age, periventricular white matter disease, other types of vascular dementia and Alzheimer's disease [11–16]. Therefore, targeting the B-cell response to stroke is not a panacea for stroke-related dementia, but ongoing research indicates an aberrant B-cell response could soon be added to its differential diagnosis.

Further characterization of chronic stroke lesions may reveal other aspects of the pathophysiology of stroke that may be interfering with recovery. For example, in the course of our research into the relationship between B lymphocytes and the appearance of delayed cognitive deficits following stroke, we strikingly failed to detect B lymphocytes or plasma cells in brain tissue outside of the stroke core in any of the mice we evaluated. This was true for multiple time points, as late as 3 months following stroke. Rather, it appeared instead, that antibodies produced by plasma cells within the stroke core were crossing the glial scar in the weeks after stroke to penetrate the surrounding brain tissue and mediate delayed cognitive dysfunction. Importantly, this indicates that glial scars fail to contain molecules with potentially neurodegenerative properties being produced, or otherwise present, within chronic stroke lesions.

The concerning implication of this, is that to an unknown extent, stroke lesions may be chronic and unregulated entry sites into the neuropil for neurodegenerative molecules present within stroke lesions, such as antibodies and cytokines being produced within the lesion, and factors leaking out of immature blood vessels that persist for months within cerebral infarcts [17]. Chronic leakage of these factors via the glial scar into the neuropil may be a general impediment to recovery. When stroke lesions are adjacent to brain regions important for memory, judgment, language, complex motor skills or other important intellectual functions, this could also be a cause of stroke-related dementia.

In support of this possibility, it is unlikely that astrocytes that comprise the front line of glial scars connect to each other with tight junctions. This is because, despite decades of research into the physiology of the blood–brain barrier and the location of tight junctions within the brain, glial scar astrocytes have never been reported to adhere to each other in such a manner. Therefore how, and how effectively, glial scars seal areas of damage in the brain warrants further investigation. At best glial scars have evolved mechanisms for sealing areas of damage that do not require the presence of tight junctions, and at worst, sites of ischemic injury are incompletely sealed and allow entry into the brain of neurotoxic factors present in stroke lesions indefinitely. The true answer likely lies somewhere between these two possibilities and varies from patient to patient.

Although we previously focused on B cells as a potential cause of stroke-related dementia in our studies with mice, it still remains to be determined if there are other aspects of the chronic inflammatory response to stroke that contribute to the development of delayed cognitive deficits. For example, following stroke, the brain is subject to a unique and somewhat slow process termed liquefactive necrosis. This process occurs in abscesses throughout the body and is usually caused by bacterial infection. However, liquefactive necrosis is a defining feature of wound healing in brain injuries such as stroke and traumatic brain injury, even in the absence of bacterial infection.

Liquefactive necrosis could therefore be a feature of the pathophysiology of chronic stroke that intensifies post-stroke injury. Our unpublished data suggest that at the macroscopic, microscopic and molecular levels, liquefactive necrosis shares similar properties to atherosclerosis. In that regard, it is known that high levels of oxidized low-density lipoprotein, the bad form of cholesterol, cause atherosclerosis. Importantly, cholesterol is an important structural component of neuronal membranes and myelin, and is therefore a major constituent of the human brain [18]. It is possible that liquefactive necrosis in response to brain injury is caused by the elevated cholesterol content of the brain. As a result, neuronal tissue damage may elicit a more chronic and aggressive proinflammatory (M1) polarized macrophage response rather than a more beneficial reparative (M2) macrophage response, such as that seen in less lipid rich tissues following injury [19]. This is another unexplored area of chronic stroke that warrants investigation.

In support of this possibility, Wang et al. recently demonstrated that lipid accumulation in macrophages following spinal cord injury leads them to develop characteristics of foam cells, and adopt a chronic proinflammatory phenotype. It will be interesting to see if this process is an impediment to recovery in both the spinal cord and the brain [20]. Wang et al. propose that treatments that promote the regression of atherosclerosis, such as statins, and/or agents that suppress proinflammatory macrophage responses, could reduce or even prevent chronic inflammatory responses to CNS injury, promote healthier healing and improve recovery. In the case of stroke, perhaps they could even prevent the development of post-stroke dementia.

Summary

Over the past few decades, there has been extensive research in both animal models and humans that has characterized the pathophysiology of stroke during the first few weeks. By contrast, however, there has been very little research into the chronic stage of infarction. This is an important area for future research because, as previously mentioned, more than 10 million individuals worldwide survive stroke each year and more than a third of these survivors subsequently develop dementia. The cause, or causes, of this dementia are unclear, and there are currently no neuroprotective drugs that can improve recovery and provide cognitive protection in the chronic time period. It is possible that there are still neurodegenerative processes that take place during the chronic stage of stroke recovery and this is a promising target for developing treatments for stroke-related dementia.

Financial & competing interests disclosure

This work was supported by NIH grant K99NR013593. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by NIH grant K99NR013593. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.