A new project on dementias gets underway

We have launched a research project on dementias titled:

“The role of glymphatic system dysfunction in the early stages and progression of dementias”

Project Aim:

The project aims to deepen our understanding of the role of the glymphatic system in the early stages and progression of neurodegenerative dementias, in a large cohort of patients attending the Cognitive Disorders and Dementias Center of the Foundation. It has a dual objective: on one hand, to identify reliable and non-invasive biomarkers of glymphatic activity, and on the other, to explore biological mechanisms that can be modulated physiologically or pharmacologically/physically.

Background:

The human brain lacks a lymphatic drainage network comparable to other organs. Therefore, the mechanisms by which the brain transports nutrients and removes metabolic waste within the parenchyma have long remained unknown and are still only partially understood. The glymphatic system (GS), first described in 2012, is one such mechanism. The GS is an extensive perivascular drainage network throughout the brain, connected downstream to the meningeal lymphatic vessels and cranial venous sinuses. Its name derives from the fusion of the words “glia” and “lymphatic,” highlighting both its dependence on glial cells, particularly astrocytes surrounding arterial perivascular spaces and expressing the water channel protein aquaporin-4 (AQP4), and its functional similarity to the traditional lymphatic system.

Dysfunction of this system is associated with accumulation of waste products—including pathological proteins implicated in the pathophysiology of neurodegenerative diseases—within the brain parenchyma, potentially contributing to the development of various types of dementia. However, the lack of easily accessible biomarkers currently limits the ability to modulate its activity for neuroprotective purposes.

Methods:

A distinctive feature of our Center has always been the ability to integrate information obtained from biological fluid analyses with quantitative neuroimaging data.

Accordingly, our project will include:

• Biomarker analysis: Measurement of proteins linked to glymphatic activity, such as AQP4, GFAP, and YKL-40, in cerebrospinal fluid and serum samples. Isolation of neuron- and astrocyte-derived extracellular vesicles from plasma and saliva for RNA deep-sequencing to obtain a complete transcriptomic profile. These vesicles, which can be obtained peripherally and non-invasively, faithfully reflect the properties of the producing cells, providing unique insights into normal and pathological brain cell function.
• Advanced imaging studies: Patients will undergo structural and diffusion MRI protocols to quantify parameters such as DTI-ALPS index, free water fraction, number of enlarged perivascular spaces, and mean diffusion kurtosis, which have been proposed as glymphatic biomarkers. Serial MRI scans will also be acquired at different intervals after intravenous gadolinium infusion, currently the gold standard for non-invasive, in vivo dynamic assessment of glymphatic clearance.
• Intervention phase: A subgroup of patients will undergo transcranial alternating current stimulation (tACS), whose role in modulating glymphatic clearance is supported by encouraging, though preliminary, evidence.

Relevance:

Given its recent discovery, the physiological and pathological role of the glymphatic system is only now beginning to be clarified. Available evidence suggests that it is implicated across multiple neurological conditions.

Integrating data from biological fluids and neuroimaging, along with evaluating the effects of non-invasive brain stimulation, will allow a comprehensive characterization of the glymphatic system’s role in neurodegenerative dementias and lay the foundation for potential therapeutic interventions.

Expected Results:

• Clarification of the glymphatic system’s role in neurodegenerative diseases: Analysis of biological fluids and neuroimaging data will provide deeper insights into glymphatic function in both physiological and pathological conditions.
• Validation of glymphatic activity biomarkers: Recent developments in glymphatic biomarkers have opened the door to in vivo human studies. However, most require robust validation in large patient cohorts, which this project aims to provide.
• Development of potential therapeutic interventions: Identifying physiologically or pharmacologically/physically modulable pathways could greatly expand the therapeutic arsenal for treating neurodegenerative causes of cognitive decline, for which effective treatments are still limited.

Budget:

To get started, the project requires a budget of €80,000.