Extracellular matrix inflammation in vascular cognitive impairment and dementia
1Department of Neurology, UNM Memory and Aging Center, University of New Mexico, Albuquerque NM 87131-0001, U.S.A. grosenberg@salud.unm.edu.
Insights
Small vessel disease causes brain damage in vascular cognitive impairment and dementia (VCID). Chronic hypertension leads to hypoperfusion, damaging white matter and causing inflammation, demyelination, and cognitive decline.
Area of Science:
- Neuroscience
- Vascular Biology
- Pathology
Background:
- Vascular cognitive impairment and dementia (VCID) encompasses chronic effects of vascular disease, including large vessel strokes and small vessel disease (SVD).
- Small vessel disease (SVD) manifests as lacunar strokes and white matter (WM) injury, primarily driven by chronic hypertension-induced brain hypoperfusion.
- Hypoperfusion triggers astrocyte degeneration, extracellular matrix (ECM) fibrosis, and stiffened cerebral vessels, impairing metabolic response.
Purpose of the Study:
- To elucidate the complex pathophysiology of white matter (WM) injury in the small vessel disease (SVD) form of VCID.
- To identify potential therapeutic targets for mitigating progressive WM damage in SVD-related VCID.
Main Methods:
- The study reviews the molecular injury cascade initiated by intermittent hypoxia/ischaemia in deep WM.
- It examines the role of neuroinflammation, microglia/macrophage activation, and protease release in perpetuating ECM and neurovascular unit (NVU) damage.
- Focuses on the impact of matrix metalloproteinases (MMPs) on the blood-brain barrier (BBB) and myelinated fibers.
Main Results:
- Intermittent hypoxia/ischaemia causes incomplete infarction, predominantly affecting deep WM.
- Neuroinflammation involves microglia/macrophages releasing proteases and free radicals, damaging ECM and NVU components.
- Matrix metalloproteinases (MMPs) contribute to BBB opening and demyelination, characteristic of subcortical ischaemic vascular disease (SIVD), also known as Binswanger's disease.
Conclusions:
- Understanding WM injury-related inflammation in SVD-VCID is crucial for developing novel therapeutic strategies.
- Targeting ECM damage could prevent progressive WM injury in VCID.
- Interventions aimed at reducing neuroinflammation and MMP activity may offer therapeutic benefits for SVD-VCID.
Abstract:
Vascular cognitive impairment and dementia (VCID) include a wide spectrum of chronic manifestations of vascular disease related to large vessel strokes and small vessel disease (SVD). Lacunar strokes and white matter (WM) injury are consequences of SVD. The main vascular risk factor for SVD is brain hypoperfusion from cerebral blood vessel narrowing due to chronic hypertension. The hypoperfusion leads to activation and degeneration of astrocytes with the resulting fibrosis of the extracellular matrix (ECM). Elasticity is lost in fibrotic cerebral vessels, reducing the response of stiffened blood vessels in times of increased metabolic need. Intermittent hypoxia/ischaemia activates a molecular injury cascade, producing an incomplete infarction that is most damaging to the deep WM, which is a watershed region for cerebral blood flow. Neuroinflammation caused by hypoxia activates microglia/macrophages to release proteases and free radicals that perpetuate the damage over time to molecules in the ECM and the neurovascular unit (NVU). Matrix metalloproteinases (MMPs) secreted in an attempt to remodel the blood vessel wall have the undesired consequences of opening the blood-brain barrier (BBB) and attacking myelinated fibres. This dual effect of the MMPs causes vasogenic oedema in WM and vascular demyelination, which are the hallmarks of the subcortical ischaemic vascular disease (SIVD), which is the SVD form of VCID also called Binswanger's disease (BD). Unravelling the complex pathophysiology of the WM injury-related inflammation in the small vessel form of VCID could lead to novel therapeutic strategies to reduce damage to the ECM, preventing the progressive damage to the WM.
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