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 a waste clearance system, the so- called glymphatic system [1-3]. In addition is the brain highly vulnerable to the (kinetic) energy deposition of the arterial pulsatility which is increased due to the low resistance of brain arterioles and age-related hardening of arterial walls. Reduction in vascular elasticity and increased arterial pulsatility affect the perivascular clearance of waste products in the ISF [4], altering the physiologic transport of catabolites out of the brain including Aβ [2]. Therefore, a link between glymphatic function and AD has been hypothesized.

The number of patients with AD will increase dramatically in the upcoming decades [5]. 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. In addition, non-invasive imaging of the glymphatic system might provide an early biomarker of patients at risk (i.e. before the onset of overt symptoms).

Seven Tesla (7T) MRI provides high signal to noise and spatial details, and the unique opportunity to noninvasively assess various features of the glymphatic system by quantifying the volumetric fraction and dynamics of the ISF (using intravoxel incoherent motion imaging, IVIM) and measuring the pulsatility of small perforating lenticulostriate arteries (LSA) and other supplying arteries (using velocity sensitive MRI). We hypothesize that these features of glymphatic dysfunction can be linked to cognitive impairment. 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 biomarkers (Aβ/tau) in a memory clinic population.

The aim of this study is to discover how these metrics are affected in different stages of cognitive impairment. In a cross-sectional observational study, 120 individuals with different states of cognitive condition will be included. This will include 40 healthy cognitively normal controls, 40 patients with Mild cognitive impairment and 40 patients with mild AD dementia.

1. Seven Tesla MRI can identify abnormalities of the glymphatic system associated with dementia and its preclinical stages relative to cognitively normal control (i.e. neurotypical) subjects.

2. More severe signs of dementia are associated with more affected glymphatic metrics: increased interstitial fluid fractions and arterial pulsatility are associated with neurodegeneration and more impaired cognitive performance.

One session at one time point

Control subjects will undergo the following study specific measurements:
-the 7T MRI scan
-the blood pressure measurement
-questionnaires (CHAMPS, PSQI) and questionnaires on medical and demographic information
-neuropsychological testing
-blood sampling via venepuncture
-tear fluid collection

The participating patients (MCI and AD) will undergo the following study specific measurements:
-the 7T MRI scan
-the blood pressure measurement
-questionnaires (CHAMPS, PSQI).
For the participating patients (MCI and AD), information will be retrieved from the BBACL-cohort concerning neuropsychological test results, medical and demographic information, blood- and tear fluid measurements, and CSF measurements (if a lumbar puncture is performed for diagnostic purposes and CSF-values are registered within the BBACL).