Dynamic Investigation of Lymphatic Pathway Interconnections for Cerebrospinal Fluid Clearance of the Human Central Nervous System In Vivo Under Physiological Conditions

• Applicant: Dr. Lina Anderhalten, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565359158

Overall, this project aims to elucidate interconnecting pathways in meningeal lymphatic clearance and the effect of age on cerebrospinal fluid (CSF) dynamics in vivo in a pilot study of ten healthy volunteers that will receive low-dose macrocyclic gadobutrol via lumbar intrathecal (IT) injection after having previously undergone intravenous injection (IV). By comparing data from both IV and IT injection approaches within the same healthy individuals, we aim to reconcile differences in tracer distribution, temporal dynamics, and pathway connections that were previously observed separately as well as explore age-related alterations in CSF dynamics under physiological conditions. We specifically aim to 1) investigate dynamic meningeal lymphatic clearance pathway interconnections and the compartmentalization of the subarachnoid space (SAS) in vivo under physiological conditions in ten healthy human volunteers; 2) assess potential direct connections for CSF clearance between the SAS and meningeal lymphatics at the junction of the parasagittal dura and bridging veins by evaluating enhancement patterns in relation to the gadobutrol injection route; and 3) investigate the effect of aging on meningeal lymphatic clearance dynamics and if aging-related clearance impairments may be reflected in CSF and peripheral blood biomarkers. With this, we will provide new insights into physiological meningeal lymphatic drainage pathway interconnections and SAS compartmentalization in healthy volunteers. By determining dynamic tracer enhancement patterns after IT administration of gadobutrol using serial contrast-enhanced magnetic resonance imaging in vivo, we will be able to leverage the IT route to bypass the blood-brain barrier and eliminate confounding from blood tracer transfer for clear differentiation of tracer origin. We will further elucidate pathway interconnections for CNS drainage between the brain, SAS, and parasagittal dura, particularly at the junction with bridging veins, by combining imaging results from in vivo IT and previous IV tracer studies. These studies performed in the same healthy volunteers with comparable imaging time points will allow us to evaluate differences/similarities in tracer enhancement patterns between the two injection routes. Ultimately, we will investigate the effects of aging on CSF-to-blood (and blood-to-urine) clearance of gadobutrol tracer and search for CSF and peripheral blood biomarkers reflecting clearance alterations in association with aging-related CNS impairments using proteomics. This will enable us to develop more effective and tailored diagnostic and therapeutic strategies for conditions involving altered CNS drainage linked to advancing age.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Daniel S. Reich, Ph.D.