How does the brain rid itself of waste products? It surprised me that this question was not empirically answered until 10 years ago, by a Danish neuroscientist named Maiken Nedergaard.
Analogous to the lymphatic system, the glymphatic system (named for its dependence on glia) is a vascular waste clearance mechanism in the brain that facilitates transporting of solutes and waste products from cerebrospinal fluid and the interstitial fluid. CSF from the subarachnoid space enters the brain’s periarterial spaces into the interstitium via protein channels (e.g., aquaporin 4) on so-called astrocytic endfeet and exchanges with brain ISF before perivenous drainage of solutes and waste. (In 2014, scientists from the University of Helsinki and the University of Virginia independently published research demonstrating the existence of a meningeal lymphatic system. It was historically believed that both the brain and meninges were devoid of lymphatic vasculature (although suggestions that they existed can be traced back to the 18th century anatomist, Paolo Mascagni.) In general, the work of the Finnish and American scientists is thought to extend that of Nedergaard in identifying the pathway connecting the glymphatic system to the meningeal compartment.)
Much of the interest in the glymphatic system is due to its association with sleep. Glymphatic activity is dramatically enhanced then while its function is suppressed during wakefulness. The sleep state is particularly conducive to convective fluid fluxes and thereby to clearance of metabolites. Thus, a major function of sleep appears to be that the glymphatic system is turned on and that the brain clears itself of neurotoxic waste products produced during wakefulness.
Another important aspect of the glymphatic system is its relation to aging; the system is more effective in younger mammals. A recent assessment of glymphatic function in old vs. young mice showed a dramatic reduction by 80-90% in aged compared to young mice, the suppression of glymphatic activity including both influx of CSF tracers and clearance of radiolabeled beta-amyloid and inulin. The failure of the GS in aging might contribute to accumulation of misfolded and hyper-phosphorylated proteins and thereby render the brain more vulnerable to developing a neurodegenerative pathology or perhaps escalate the progression of cognitive dysfunction.
Other research has suggested that CSF-mediated removal of the tau protein via glymphatic routes is crucial for limiting secondary neuronal damage following traumatic brain injury. Thus, impairment of glymphatic pathway function can be said to promote tau pathology after such a trauma. The large amplitude of interstitial tau may lead to cellular uptake and initiation of fibrillary aggregates, which attracts additional tau leading to formation of neurofibrillary tangles ultimately resulting in a prion-like spread of the pathology.
The development and/or progression of neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases have been linked to glymphatic system failure via proteinopathic phenomena. Abnormal enlargement of the perivascular space is more frequently observed in Alzheimer’s disease compared to age-matched control subjects, suggesting a spiral of glymphatic routes and further reduction in protein clearance and pathology.
However, abnormalities at the perivascular space are also prominent in non-Alzheimer’s dementia. Only surpassed by AD, vascular dementias are the second most common cause of dementia, and these diseases are also characterized by deformation of the perivascular space. Changes in or surrounding cerebral blood vessels due to hypertension, atherosclerosis or hereditary diseases can cause vascular dementia, which is often the result of pathology in small cerebral blood vessels and capillaries, collectively termed small vessel disease. Enlargement of the perivascular space is frequently observed in small vessel disease.
Tying together sleep, aging and dementia, one could say that the slow and consistent brain activity experienced during deep, non-REM sleep is ideal for the brain’s glymphatic system, which effectively “cleans” the brain of toxic proteins like beta amyloid and tau. The buildup of these proteins, as noted, has been linked to the development of dementia. But because sleep becomes lighter and more disrupted as people age, it’s important for older people especially to take the established guidelines of sleep hygiene seriously.
~ Rylan Dray, Ph.D. – November 2023
neuropsychsoc 