While bound to desk work during home office, many of us have experienced swollen legs at the end of the day. This type of peripheral edema is caused by insufficient clearing of interstitial fluid. The process of fluid exchange and reabsorption at the capillary bed, governed by colloidal pressure, hydrostatic pressure and the functioning of local lymphatic vessels, is very well described in the periphery but less so in the brain.
How does the brain dispose of its interstitial fluid? How is brain waste eliminated? How are these processes relevant for dementia and neurodegeneration? In a recent review published in Science, Drs. Maiken Nedergaard and Steven Goldman from the University of Copenhagen Denmark, and Rochester Medical Center, USA, offer a comprehensive overview of the current understanding of fluid dynamics in the brain in health and disease. They provide a thorough description of the key mechanisms and cellular-molecular players governing the brain glymphatic system, with particular emphasis on the role of sleep in promoting fluid flow and brain waste elimination. They further propose that a dysfunction of such mechanisms is a key, common basis to many neurodegenerative diseases involving protein aggregation, including Alzheimer’s disease, Parkinson’s and tau-related dementias. Here, we provide additional aspects to highlight the relevance of such findings in the broader field of neuroimmunology and the implications for neurodegeneration and therapy.
The CSF as an immunologically active fluid
Evidence in the past 20 years has shown that multiple processes of fluid transport exist in the brain, involving the interstitial fluid (ISF) and the cerebrospinal fluid (CSF). The glymphatic system, which is described in the present paper, refers to the peri-arterioral, polarized circulation of ISF within the brain. Such glymphatic fluids eventually drain to the CSF at perivascular spaces in venules. Studies led by Drs. Carare and Weller have described additional mechanisms of ISF drainage, through the basement membrane of cerebral capillaries and arteries, towards peripheral lymph nodes.
CSF itself can be cleared from the brain and drains to deep cervical lymph nodes in at least two ways: lymphatic drainage in the dura via bona-fide lymphatics , and drainage through the cribriform plate foramina in association with the olfactory nerves.
The exact connection of these CSF and ISF movement pathways is still unclear. However, it is well established that the CSF (in communication with the brain ISF) works as an immunologically active fluid, carrying both antigen presenting cells and brain-derived antigens to the periphery and thus allowing brain immune surveillance. This finding has profound implications for neuroimmunology and neurology .
Interestingly, several lines of evidence have further indicated that the clearance of extracellular brain solutes and sleep are interconnected. Indeed, research in rodents has shown that the glymphatic system and the exchange between CSF and brain ISF is modulated by the sleep-wake cycle, and that glymphatic solute clearance is most active during sleep. As a consequence, sleep disturbances and poor sleep quality might alter this important homeostatic mechanism, which is needed for brain waste removal and, thus, be implicated in neurodegeneration.
The chicken-egg question and beyond
Sleep disturbances are common with aging and occur in neurodegenerative dementias, such as Alzheimer´s disease, along with altered glymphatic activity . Human studies have found associations between poor sleep quality, cognitive decline and brain amyloid deposition , and meta-analyses support the link between poor sleep and increased Alzheimer’s disease risk. However, whether amyloid pathology accumulation is the cause or consequence of altered sleep is an area of emerging research, and these theories are not necessarily mutually exclusive. As described by Nedergaard and Goldman, it is clear that poor sleep can alter the brain’s glymphatic dynamics, leading to impaired clearance and protein aggregation; however, in support of a bidirectional relationship, animal studies have also shown that amyloid-beta itself can lead to increased wakefulness and altered sleep. But what about tau or other protein aggregates which are common in the brains of demented patients? How do they fit into these pathological loops? A better understanding of the interconnection between these phenomena and how they feedback into each other could offer insights for preventive and therapeutic strategies against brain dysfunction.
The time course of alterations to the brain glymphatic system is another area that deserves further research, as dementia represents the advanced stage of a decades-long process of neuropathology accumulation, when the brain’s waste elimination mechanisms could be altered before symptoms emerge. The implementation of biomarkers to define preclinical at-risk populations will help define these questions across the Alzheimer’s disease continuum. Indeed, some studies have reported sleep alterations in mild cognitive impairment, associated to cognitive difficulties, which would point to early alterations in the brain glymphatic system.
The brain-vascular connection is also a fascinating area of further development. As described in the discussed Review, pulsatility in the brain’s penetrating arteries has been identified as an important driver of fluid movement through the perivascular space, with reductions or increases in pulsatility resulting in parallel changes in glymphatic flow. However, it should also be considered that increased pulsatility in the smaller, non-elastic brain vessels may not always account for positive effects on paravascular flow, as endothelial cells are vulnerable to the effects of increased pulsatility, and may respond through the increased production of oxidative radicals from NADPH activation which in turn can feed forward other pathological pathways such as inflammation and neurodegeneration.
Another aspect to consider is whether glymphatic reduction due to sleep alterations might lead to neurodegeneration via reduced drainage of CNS-derived antigens to the periphery. Indeed, impairment of the meningeal CSF drainage to peripheral lymph nodes has been shown to slow the efflux of macromolecules from the ISF and cause cognitive impairments in wild type mice. Impairment of ISF glymphatic drainage might cause a similar build-up of brain derived macromolecules, accompanied by reduced drainage to the periphery; in this scenario, the immune system would ‘loose connection’ with the brain, with severe impairment of brain immune surveillance.
The more we learn, the more to discover
As any new frontier in science, exciting findings open more exciting questions. There are at least three aspects we would like to highlight here as they might inform future research:
The use of biomarkers
The molecular underpinnings of glymphatic system function continue to be elucidated. Clearly, astrocytic aquaporin-4 is a main player, but additional molecular hallmarks will be identified. Dedicated tracers and imaging techniques are being refined and becoming available for human studies. This could contribute to the development of future novel biomarkers, to assess glymphatic status and profile patients.
The role of sex
Biological sex is emerging as an important driver of variability in brain health and disease, including neurodegenerative diseases, and is poised to have a role in this process too. On the one hand, sex-differences in circadian rhythms exist; therefore, it is conceivable that women and men might have different vulnerability to the same sleep alteration. On the other hand, factors that are known to contribute to poor sleep quality such as obesity, depression and inflammation might also differ between the sexes, warranting future investigations with these considerations.
Promoting sleep education
The importance of sleep for brain and mental health is well accepted by the scientific and medical community. It is our responsibility as health professionals to advocate and educate on the importance of these findings to the general public. We should invest in sleep education and the teaching of ‘sleep hygiene’ practices particularly in the young and middle-age generations, when the impact of these lifestyle changes is more likely to have an effect in the long term. The same way we are conscious about taking care of our diet to prevent heart disease, we should think of taking care of our sleep to promote brain health and prevent brain dysfunction. While thinking of future targets to treat glymphatic dysfunction, having a good sleep routine is something we can do, and act upon, at this very moment.