Iron Deposition in the Aging Brain Correlates with Glymphatic System Function

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Evidence to date suggests that disruption of the pathways by which fluid clears from the brain is important in the development of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and many others. These conditions are associated with raised amounts of specific forms of metabolic waste in the brain, including aggregates of amyloid-β, that are harmful to cell function. In a young brain, drainage of cerebrospinal fluid from the brain carries away some fraction of these wastes. As drainage pathways are disrupted with age, however, the balance between processes of creation and removal is altered in favor of an ever-increasing presence of amyloid-β and other metabolic byproducts in brain tissue.

One drainage pathway for cerebrospinal fluid is the cribriform plate, behind the nose. This structure ossifies with age, reducing fluid flow. When permeable, the cribriform plate route allows drainage from the olfactory bulb region of the brain, and the company Leucadia Therapeutics is founded on the thesis that loss of cribriform plate drainage is exactly why Alzheimer's pathology, and the buildup of amyloid-β, first appears in the olfactory bulb. Studies conducted by Leucadia staff have recreated this process in ferrets, and the company plans to develop a therapy based on implanting a small device into the cribriform plate in order to restore drainage of cerebrospinal fluid.

Another interesting discovery of recent years, and the subject of today's open access paper, is the existence of the glymphatic system. This is a more general drainage route for cerebrospinal fluid. The glymphatic system, like the cardiovascular system and lymphatic system, also declines in function with age. This decline may well contribute to rising levels of metabolic waste throughout the brain. The evidence for this proposition is still in the early stages of assembly, but is so far fairly convincing.

Dysfunction of the Glymphatic System Might Be Related to Iron Deposition in the Normal Aging Brain

Iron is an electron facilitator and is involved in many brain functions, including oxygen transport, myelin production, electron transfer, and neurotransmitter synthesis. Both imaging and postmortem analyses have shown that the concentration of iron in the brain is not uniform. Previous studies have demonstrated that iron accumulates in the normal aging brain, which might damage cognitive function. However, the exact mechanism of iron deposition in the aging brain remains unclear.

Recent work has led to the discovery of the "glymphatic system," which is a coined phrase that combines "gl" for glia cell with "lymphatic system". Within the glymphatic system, cerebrospinal fluid enters the brain via peri-arterial spaces, passes into the interstitium via astrocytic aquaporin-4, and then drives the peri-venous drainage of interstitial fluid and its solute. Evidence suggests that the glymphatic system is an important fluid clearance system in the brain. Numerous neurological disorders have been found to be closely related to the dysfunction of the glymphatic system, including Alzheimer's disease and Parkinson's disease.

Evidence also revealed that iron deposition was one of the most important underlying mechanisms in Alzheimer's disease and Parkinson's disease. Some scholars also believe that the glymphatic system may be the major contributory factor to the deposition and clearance of iron in brain tissue, but evidence is still lacking. In this study, we recruited 213 healthy participants. We evaluated the function of the glymphatic system using the index for diffusivity along the perivascular space (ALPS-index), assessed iron deposition on quantitative susceptibility mapping (QSM), and analyzed their relationship. The main finding of the current study is that the regional brain iron deposition was related to the function of the glymphatic system.

Previously, the glymphatic system has been speculated to be responsible for the clearance and homeostasis of waste in the brain. Our results support that in a healthy aging brain, the glymphatic system might also be involved in the clearance of iron, suggesting that iron metabolism shared the same pathway as other waste metabolisms. Moreover, a study has demonstrated that injury of the microvasculature and capillary-level microhemorrhages coincided with amyloid beta (Aβ) deposits in senile plaques. Iron deposition plays an important role in cerebral small vessel diseases. Therefore, we inferred that dysfunction of the glymphatic system might lead to the damage of microvasculature via deposition of Aβ, then leading to iron deposition.

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source https://www.fightaging.org/archives/2021/01/iron-deposition-in-the-aging-brain-correlates-with-glymphatic-system-function/