Glymphatic dysfunction in cognitive impairment: a memory clinic study

Alzheimer*s disease (AD), the most frequent neurodegenerative disorder and most
common cause of dementia in the elderly, is characterized by the accumulation
of amyloid-β (Aβ) plaques and neurofibrillary tangles. Solute clearance in the
brain is not only dependent on transport across the blood-brain barrier (BBB),
but also on the clearance of interstitial fluid (ISF) in the brain tissue and
the perivascular spaces by the glymphatic system. In addition is the brain
highly vulnerable to increased arterial pulsatility due to the low resistance
of the brain arterioles. Reduction in vascular elasticity and increased
arterial pulsatility affect the perivascular clearance of ISF, altering the
physiologic transport of metabolites out of the brain including Aβ. Therefore,
a link between glymphatic function and AD has been hypothesized.
The number of patients with AD will increase dramatically in the upcoming
decades. The cause remains to be elucidated and effective options for treatment
are therefore not yet developed.

The current study aims to obtain a better understanding of glymphatic
dysfunction in dementia of the Alzheimer*s type and its preclinical stages.The
main objective of this study is to improve our understanding of the potential
link between glymphatic dysfunction and cognition in dementia of the
Alzheimer*s type and its preclinical stages, in the setting of a memory clinic
using ultra-high-field (7T) MRI.
In addition, non-invasive imaging of the glymphatic system might be able to
provide an early biomarker of patients at risk (i.e. before the onset of overt
symptoms).
We hypothesize that glymphatic dysfunction can be related to cognitive
impairments. We will investigate the relationship between MRI-derived metrics
indicative of the glymphatic system, namely interstitial fluid (ISF)
characteristics and arterial pulsatility, with (1) brain tissue markers, (2)
cognitive performance, and (3) AD fluid biomarkers (Aβ/tau) in a memory clinic
population. This study could aid the development of optimal delivery strategies
of therapeutic drugs to the brain, and could be used to assess the efficacy of
pharmacological interventions.

The present study is an observational, cross-sectional, ultra-high-field (7T)
MRI study.

For the control subjects, the following actions will be performed for study
purposes: blood will be sampled, tear fluid will be taken, neuropsychological
examination will be performed, and a short questionnaire about the demographic
and medical background will be completed.

In addition, all subjects will fill in a questionnaire on physical activities
and sleep behaviour, the blood pressure will be measured and a brain MRI scan
will be performed with the 7 Tesla MRI scanner. High-field (7T) will be used to
noninvasively assess various features of the glymphatic system, such as to
quantifying the fraction of ISF and ISF dynamics (using intravoxel incoherent
motion imaging, IVIM) and measuring the pulsatility of various small arteries
(using velocity sensitive MRI). Furthermore, structural and functional images
will be obtained to study brain tissue alterations.

As part of the study, subjects will undergo a 7T MRI scan. 7T MRI has been
shown to be safe for study in human subjects. The space inside the scanner is
very narrow and the scanner produces loud acoustic noise, which can be
experienced as uncomfortable. Ear protection will be available and is mandatory
during the MRI examination. Although 7T MRI is completely safe if attention is
paid for presence of contra-indications and if operated by certified users, a
small amount of people (5%) may experience vertigo or nausea while entering the
scanner. However, these symptoms will be minimized by slowing the subject*s
entry and exit time (low speed table shift) into the magnetic field. Some
people experience a metallic taste in their mouth while lying in the scanner.
However, this taste will disappear after leaving the scanner and is not
harmful.

This study has no immediate benefit for patients with cognitive impairment. But
it may unravel which role the glymphatic system plays in cognitive decline.
This will result in better knowledge about the disease process, which may be
beneficial for future treatment and/or prevention.
In addition, increased ISF fractions and arterial pulsatility possibly provide
early biomarkers of patients at risk and better knowledge about the disease
process may be beneficial for the development of novel, effective treatment
options.