Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment.

This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent 11C-Pittsburgh compound B positron emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging or computed tomography, and CSF analysis. PET uptake of the frontal and temporoparietal lobes and posterior cingulate gyrus was assessed using the cerebellar cortex as the reference region. WMLs were assessed by the Fazekas scale. CSF levels of MMPs and TIMPs were measured with bead-based multiplex assays. After adjusting for covariates, multiple linear regression analysis showed that CSF levels of MMP-2 were negatively correlated with global PiB uptake (p = 0.035), especially in the parietotemporal lobe and posterior cingulate gyrus (p = 0.016 and p = 0.041, respectively). Moreover, CSF levels of MMP-7 were positively correlated with the severity of WMLs (p = 0.033). CSF levels of MMP-2 and MMP-7 are associated with brain amyloid deposition and severity of WMLs, respectively. These findings provide valuable insights into the role of MMPs in amyloid ß catabolism and blood-brain barrier integration at the MCI stage.

Association between Matrix Metalloproteinases, Their Tissue Inhibitor and White Matter Lesions in Mild Cognitive Impairment.

BACKGROUND: White matter lesions are frequently found in mild cognitive impairments and Alzheimer's disease. Matrix metalloproteinases and the tissue inhibitor of metalloproteinases are implicated in amyloid-ß catabolism and blood brain barrier permeability. However, it remains unclear whether they are associated with white matter lesions in Alzheimer's disease. OBJECTIVE: The aim of this study was to examine the association of matrix metalloproteinases and tissue inhibitor of metalloproteinases with white matter degeneration in subjects with amyloid-positive mild cognitive impairment. METHODS: Thirty subjects with amnestic mild cognitive impairment (14 men and 16 women; mean age, 75.6 ± 5.8 years) underwent magnetic resonance imaging, 11C-Pittsburgh Compound B positron emission tomography, and 18F-fluorodeoxyglucose positron emission tomography. Levels of plasma matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured using multiplex assays. All subjects had an abnormal brain amyloid burden. Subjects were divided into two groups according to the presence of white matter lesions using the Fazekas scale. Cognitive function testing results i.e., mean 11C-Pittsburgh Compound B and 18F-fluorodeoxyglucose uptake, concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases, and matrix metalloproteinases/tissue inhibitor of metalloproteinases ratios were compared between the groups. Correlation analysis was conducted to investigate the association between Fazekas scale score and clinical and neuroimaging variables as well as concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases. RESULTS: Matrix metalloproteinases-2, -8, and -9 levels, matrix metalloproteinases-2/ tissue inhibitor of metalloproteinases-2, matrix metalloproteinases-8/ tissue inhibitor of metalloproteinases-1, and matrix metalloproteinases-9/tissue inhibitor of metalloproteinases-1 significantly increased and tissue inhibitor of metalloproteinases-1 and-2 levels significantly decreased in the group with white matter lesions compared with the group without white matter lesions. Matrix metalloproteinases-2, -8, and -9 levels correlated positively and tissue inhibitor of metalloproteinases-1 and -2 levels correlated negatively with Fazekas scale score. CONCLUSION: Plasma matrix metalloproteinases-2, -8, -9 and tissue inhibitor of metalloproteinases-1 and -2 levels are associated with white matter lesions in the mild cognitive impairment stage of Alzheimer's disease.