Pathobiology of Vascular Cognitive Impairment

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DESCRIPTION (provided by applicant): Vascular cognitive impairment (VCI) is a heterogeneous disorder that is a major cause of dementia. Selection of patients with small vessel disease, subcortical ischemic vascular dementia (SIVD), provides a more homogenous population that would facilitate clinical trials. Pathological studies in SIVD show thickening of the basal lamina around blood vessels with fibrinoid necrosis and hyalinosis secondary to hypertension, diabetes mellitus, and congenital vascular diseases. Ischemia/hypoxia leads to the production of matrix-degrading metalloproteinases (MMPs) as part of both an inflammatory response and tissue remodeling after injury. We have shown that brain tissues from patients with VCI immunostain for MMPs in reactive astrocytes and macrophage/microglia cells, MMPs disrupt the matrix around blood vessels and open the blood-brain barrier (BBB). In addition, MMPs break down myelin, which could contribute to the vascular demyelination seen in SIVD. Recently, we reported that increased levels of MMPs are found in the CSF of patients with VCI, but not in patients with Alzheimer's disease (AD). We hypothesize that MMPs are secreted by ischemic/hypoxic brain cells and contribute to the pathobiology of VCI. The specific aims are: 1) to develop a SIVD rating scale based on rnultimodal testing, including clinical evaluation, magnetic resonance imaging (MRI) and multivoxel proton spectroscopy (1H-MRS), neuropsychological testing, and CSF studies; 2) to identify the source of MMPs in the CSF by indexing the MMPs in the CSF and blood to albumin; 3} to determine the involvement of the BBB qualitatively with Gadolinium-DTPA enhancement and quantitatively with the Patlak Graphical Method and to correlate the opening with MMP levels; and 4) to correlate the levels of MMPs in a blinded fashion with the results of the SIVD rating scale that has been validated by long-term follow-up of the patients. These studies will determine the role of protease-mediated nflammation in the progressive form of SIVD, and could lead to novel treatments to suppress proteases.