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 SIVDshow 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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroscience and Disease Study Section (CND)
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Corriveau, Roderick A
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University of New Mexico
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Rosenberg, Gary A (2017) Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia. J Neurochem :
Rosenberg, Gary A (2016) Vascular cognitive impairment: Biomarkers in diagnosis and molecular targets in therapy. J Cereb Blood Flow Metab 36:4-5
Taheri, Saeid; Shah, N Jon; Rosenberg, Gary A (2016) Analysis of pharmacokinetics of Gd-DTPA for dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 34:1034-40
Rosenberg, Gary A; Wallin, Anders; Wardlaw, Joanna M et al. (2016) Consensus statement for diagnosis of subcortical small vessel disease. J Cereb Blood Flow Metab 36:6-25
Rosenberg, Gary A (2016) Matrix Metalloproteinase-Mediated Neuroinflammation in Vascular Cognitive Impairment of the Binswanger Type. Cell Mol Neurobiol 36:195-202
Rosenberg, Gary A; Prestopnik, Jillian; Adair, John C et al. (2015) Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials. J Neurol Neurosurg Psychiatry 86:1324-30
Huisa, Branko N; Caprihan, Arvind; Thompson, Jeffrey et al. (2015) Long-Term Blood-Brain Barrier Permeability Changes in Binswanger Disease. Stroke 46:2413-8
Rosenberg, Gary A; Bjerke, Maria; Wallin, Anders (2014) Multimodal markers of inflammation in the subcortical ischemic vascular disease type of vascular cognitive impairment. Stroke 45:1531-8
Rosenberg, G A (2014) Blood-Brain Barrier Permeability in Aging and Alzheimer's Disease. J Prev Alzheimers Dis 1:138-139
Huisa, Branko N; Rosenberg, Gary A (2014) Binswanger's disease: toward a diagnosis agreement and therapeutic approach. Expert Rev Neurother 14:1203-13

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