Perivascular spaces as a potential biomarker of Alzheimer's disease.

Alzheimer's disease (AD) is a highly damaging disease that affects one's cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.
Competing Interests: Outside of the present work, the authors report additional funding from: Author TO’B reported funding from the National Health and Medical Research Council (NHMRC), Medical Research Future Fund (MRFF), Department of Industry, Science and Resources, and the National Institute of Neurological Disorders and Stroke (NINDS). Author TO’B institution has also received consultancy and research funding from UCB Pharma, Eisai, ES Therapeutics, Zynerba, Praxis Pharmaceuticals, and Biogen. Author LV reported research funding from Biogen, Eisai, and Life Molecular Imaging and research grants from the National Health and Medical Research Council (NHMRC), Medical Research Future Fund (MRFF), National Institute of Health (NIH), Department of Industry, Science and Resources, Victorian Accelerator Fund, Medical Research Future Fund (MRFF), and Multiple Sclerosis Research Australia (MSRA). Author MLa reported funding from the National Health and Medical Research Council (NHMRC), Medical Research Future Fund (MRFF), National Institute of Health (NIH), Australian Research Council (ARC), the Australian National Imaging Facility (NIF), American Society of Neuroradiology, and the Aftershock Foundation. Author MLa institution has also received consultancy and research funding from Siemens Healthineers and GE Healthcare. Author BS reported funding from the Department of Industry, Science, Energy, and Resources. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Lynch, Pham, Sinclair, O’Brien, Law and Vivash.)