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Association between Matrix Metalloproteinases, Their Tissue Inhibitor and White Matter Lesions in Mild Cognitive
Noriyuki Kimura1, Miki Aikawa2, Kasumi Etou2
1Department of Neurology, Oita University, Faculty of Medicine, Graduate School of Medicine, Oita 879-5593, Japan.
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-β 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.
Insights
Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are linked to white matter lesions in early Alzheimer's disease. Higher MMPs and lower TIMPs correlate with lesion severity in mild cognitive impairment.
Area of Science:
- Neuroscience
- Biochemistry
- Radiology
Background:
- White matter lesions are common in mild cognitive impairment (MCI) and Alzheimer's disease (AD).
- Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) influence amyloid-beta metabolism and blood-brain barrier integrity.
- Their specific role in white matter lesions in AD remains unclear.
Purpose of the Study:
- To investigate the association between MMPs, TIMPs, and white matter degeneration in amyloid-positive MCI patients.
Main Methods:
- 30 MCI subjects underwent MRI, PET scans (amyloid and glucose metabolism), and plasma MMP/TIMP level measurements.
- Subjects were grouped based on white matter lesion presence (Fazekas scale).
- Cognitive function, neuroimaging, and biomarker levels were compared between groups; correlations with Fazekas score were analyzed.
Main Results:
- MMP-2, -8, -9 levels and MMP/TIMP ratios were elevated in subjects with white matter lesions.
- TIMP-1 and -2 levels were decreased in subjects with white matter lesions.
- MMP levels positively correlated with Fazekas scores, while TIMP levels negatively correlated.
Conclusions:
- Plasma MMPs (-2, -8, -9) and TIMPs (-1, -2) are associated with white matter lesions in MCI.
- These biomarkers may indicate white matter degeneration in the early stages of Alzheimer's disease.
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