Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals

Mari Aksnes; Elettra Capogna; Didac Vidal-Piñeiro; Farrukh Abbas Chaudhry; Marius Myrstad; Ane-Victoria Idland; Nathalie Bodd Halaas; Shams Dakhil; Kaj Blennow; Henrik Zetterberg; Kristine Beate Walhovd; Leiv Otto Watne; Anders Martin Fjell

doi:10.1016/j.neurobiolaging.2023.05.012

Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals

Neurobiol Aging. 2023 Nov:131:11-23. doi: 10.1016/j.neurobiolaging.2023.05.012. Epub 2023 May 29.

Affiliations

¹ Department of Geriatric Medicine, University of Oslo, Oslo, Norway. Electronic address: mari.aksnes@medisin.uio.no.
² Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
³ Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁴ Department of Internal Medicine, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway; Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
⁵ Oslo Delirium Research Group, Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
⁶ Oslo Delirium Research Group, Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁸ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Center for Neurodegenerative Diseases, Hong Kong, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁹ Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway; Computational Radiology and Artificial Intelligence, Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
¹⁰ Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway.

PMID: 37549446
DOI: 10.1016/j.neurobiolaging.2023.05.012

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β₄₂ and phosphorylated tau₁₈₁. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.

Keywords: Cerebrospinal fluid; Cognitively unimpaired older adults; Magnetic resonance imaging; Matrix metalloproteinases; Tissue inhibitor of metalloproteinases.

MeSH terms

Alzheimer Disease* / pathology
Atrophy / pathology
Biomarkers / cerebrospinal fluid
Brain / diagnostic imaging
Brain / pathology
Humans
Matrix Metalloproteinase 2* / cerebrospinal fluid
Matrix Metalloproteinase 3

Substances

Matrix Metalloproteinase 2
Matrix Metalloproteinase 3
Biomarkers