WP1a: Brain clearance of intrathecally injected gadobutrol (gMRI) - Lead: Oslo
Aim: define clinically suitable imaging biomarkers for assessment of brain molecular clearance function and compare gMRI with minimally invasive intravenous injection as performed in Bonn (WP2). Validation of gMRI by animal studies in collaboration with Copenhagen (WP5).

WP1b: Brain clearance of intravenously injected gadobutrol - Lead: Bonn
Aim: determine optimal post injection times for delayed imaging, semi-quantitative signal intensity (SI)-time-curves from which time-to-peak-SIs and clearance-times can be estimated; assess the intra-individual reproducibility of these measures and to establish semi-automatic image analysis, which will allow further application of this minimally-invasive method, e.g. to assess the impact of sleep deprivation (compare WP3).

WP 2a. CSF-mobility at ultra-high field MRI - Lead: Leiden
Aim: Assess and compare the intensity and orientation of CSF-mobility in various brain regions relevant to brain clearance and compare the obtained results with those from WP1 in order to validate this non-invasive technique. Investigate the contributions of the proposed driving forces on CSF-mobility to further elucidate the mechanisms of brain clearance.

WP 2b. Translation to clinical field strengths - Lead: Umeå
Aim: Non-invasive markers of brain clearance using DTI and fMRI will become available in all centers to provide an overlapping technology across centers.

WP3a: Non-invasive markers of clearance and sleep - Lead: Oslo and Leiden
The newly developed non-invasive biomarkers allow to study the interaction between sleep and brain clearance. WP3a will study the relation between sleep, sleep deprivation and brain clearance as assessed by non-invasive markers, including CSF-mobility in perivascular spaces, diffusion weighted MRI, and CSF-waves in the fourth ventricle.

WP3b: Invasive markers of clearance and sleep - Lead: Bonn
Intra-individual comparison of SI-time-curves in the perivascular spaces following intravenous gadobutrol administrations with and without sleep deprivation to assess whether sleep deprivation alters gadobutrol clearance from the CNS.

Aims: (1) Investigate the relationship between brain clearance MRI biomarkers and clinical symptoms in iNPH and AD. (2) Analyze and model GBCA tracer transport after intrathecal injection, based on a comprehensive CSF dynamic model including CSF mobility along vessels and typical cardiac and vasomotion-related CSF pressure and flow characteristics. (3) Investigate and model the CSF flow communication between brain and the eye focusing on the optic nerve sheet subarachnoid space, and determination of the CSF-dynamic parameters for the axoplasmic flow over the lamina cribrosa in the optic nerve head.

Study 1: iNPH patients. Lead: Umeå and Oslo

Study 2: Patients from the memory clinic. Lead: Bonn, Umeå and Leiden

Lead: Copenhagen. The preclinical studies will in parallel with the human neuroimaging collect data on glymphatic transport in rodents. We will compare the novel biomarkers approaches with already established, but invasive glymphatic techniques. This design of the preclinical studies will provide critical insight into the development of glymphatic biomarkers. In addition, we expect that the inverse translational approach will result in the discovery of fundamental novel aspects of brain fluid transport.