Glymphatic brain clearance
The path to reducing small vessel disease.
Thursday’s session, Glymphatic Brain Clearance and Small Vessel Disease, will spotlight recent developments in the field as well as the expertise of multiple researchers who have studied methodological approaches to glymphatic brain clearance in rodents and humans.
Clearing a “path” — the body’s glymphatic system — may lower the risk of brain diseases, potentially including Alzheimer’s disease and cerebral amyloid angiopathy.
But when the “path” is impaired by metabolic waste-filled fluid, it impedes the well-orchestrated network of perivascular compartments and their adjoining vascular and parenchymal tissue components.
“The glymphatic system has emerged as a key pathway for clearance of potentially toxic substances from the interstitial fluid of the brain and an important interface between cerebrovascular function and brain health,” said Steven M. Greenberg, MD, PhD, FAHA, professor of neurology at Harvard Medical School in Boston, Massachusetts and session moderator.
“A large body of studies of the glymphatic system in rodent models is now beginning to be translated to humans with the potential for gaining insights into how diseases of the cerebral small vessels affect clearance of disease-causing molecules like β-amyloid from the brain.”
Failure to clear these disease-causing molecules from the brain can worsen small vessel function, creating a pathogenic feedback loop (small vessel disease worsens clearance, which worsens small vessel disease), Dr. Greenberg said.
One emerging insight in the study of small vessel disease is the concept that slow oscillations (at frequencies around 0.1 Hz) of cerebral blood vessels termed “vasomotion” may play a key role in glymphatic clearance, said William Van Nostrand, PhD, professor of neuroscience at the George & Anne Ryan Institute for Neuroscience at the University of Rhode Island in Kingston. Vasomotion appears to be impaired by cerebral small vessel disease, creating a link between small vessel disease and brain clearance.
One tool for predicting or detecting glymphatic flow dysfunction, Dr. Van Nostrand said, is the emerging ability of MRI to detect impaired glymphatic clearance in rodent models. It provides a foundation for potential translation of MRI-based methods to human studies.
“A recent study from Dr. Benveniste’s group (DOI: 10.1038/s43587-022-00181-4) used MRI scanning of rodent models to show that the small vessel disease cerebral amyloid angiopathy impaired glymphatic clearance,” Dr. Van Nostrand said.
“Another important advance are large-scale computational methods to make predictions about the effects of small vessel disease on the structure and function of the vascular tree that is required to feed the brain and clear toxic waste products.”
Researchers already know that successful glymphatic brain clearance is essential for brain health and the role β-amyloid accumulation plays as an accelerator of Alzheimer’s disease and cerebral amyloid angiopathy. β-amyloid is only one example of a broader class of toxic molecules whose accumulation can injure the brain. Other candidate toxic proteins that can accumulate in and around brain vessels include Notch ECD, cystatin C, ABri and basement membrane proteins.
“In light of recent approval of β-amyloid immunotherapies — treatments that enhance clearance of β-amyloid from the brain parenchyma but may also promote its accumulation in cerebral small vessels — the importance of understanding glymphatic clearance and identifying approaches to maintaining its normal function continues to grow,” Dr. Greenberg said.
