Vignesh Subramanian ’24

Alzheimer’s disease (AD) is a neurodegenerative disorder and form of dementia that causes progressive loss of memory, critical thinking skills, and behavioral capabilities. Among other pathophysiological mechanisms, the disease is characterized by disruptions in the glymphatic system, which is responsible for the facilitation of cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange driving macroscopic waste and solute clearance. Breakdowns in this clearance process are believed to allow for the extracellular aggregation of beta (β)-amyloid plaques, whose buildups gradually interfere with proteostasis, the regulation of protein synthesis and degradation, and decrease levels of neurotransmitter signaling between neurons in AD. As the glymphatic system itself was only recently discovered, no means of visualizing this paravascular pathway in detail previously existed. Dr. Helene Benveniste of Stony Brook University and her team aimed to establish a brain-wide map of the glymphatic pathway using applicable imaging techniques.

The researchers first submitted anesthetized Sprague Dawley rats to brief surgical procedures involving catheter insertions and incisions made to expose their durae matres, one of three layers of connective tissue enclosing the brain. Two paramagnetic contrast agents, Magnevist (Gd-DTPA) and GadoSpin P, were then administered to the rats via injections into the spinal canal to attempt to visualize their full glymphatic pathways via contrast-enhanced magnetic resonance imaging (MRI). Finally, a combination of in vivo 2-photon and ex vivo fluorescence imaging of brain slices and processing modalities such as cluster analyses mapped the full CSF-ISF exchange pathway and critical influx nodes and clearance routes from the brain parenchyma (functional tissue).

By virtue of the inherent three-dimensional nature of MRI, the researchers identified major CSF influx nodes and simultaneously observed CSF-ISF exchange at multiple sites and in the para-arterial pathways that reach them. Furthermore, signal change analysis demonstrated that the molecular weight of the administered contrast molecules and other solutes largely determined their ability to access the interstitial space. Finally, the researchers discovered that CSF recirculates within the wider subarachnoid space via a rapid transport pathway composed of external brain surface arteries. Together, these findings present the first proof-of-concept data indicating that glymphatic pathway functions can be imaged, with newly defined kinetic parameters reflecting rates of CSF-ISF exchange. Such an imaging technique may eventually be used to develop an AD diagnostic capable of mapping plaque clearance and thus a patient’s relative susceptibility to AD. 

Works Cited:

[1] J. J. Iliff, et al., Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. Journal of Clinical Investigation 123, 1-12 (2013). doi: 10.1172/JCI67677

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:T1-weighted-MRI.png