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The Importance of Keeping Your Brain's Pipes Clean: The role of Meningeal Lymphatics in Ageing and Alzheimer's Disease.

The Importance of Keeping Your Brain’s Pipes Clean: The role of Meningeal Lymphatics in Ageing and Alzheimer’s Disease Aging is a major risk factor for the development of neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Abnormal buildup of misfolded proteins is a central histopathologic hallmark common to each of these neurodegenerative disorders. Despite increased understanding of the pathways involved in protein aggregation, the search for an initiating pathogenic event shared among such different disorders continues.1,2 Fluid balance, protein homeostasis, and immune surveillance are some of the essential physiologic functions carried out by lymphatic networks which extend throughout the entire body—except in the brain parenchyma. In the absence of its own lymphatic system, the brain parenchyma is dependent on paravascular (glymphatic) routes and the recently (re)discovered meningeal lymphatics for removal of metabolic waste and toxic metabolites.3 While both excretory pathways utilize cerebrospinal fluid (CSF) as a sink for metabolic waste, little is known about the physiological and pathophysiological interactions that exist between them. The “glymphatic” system represents a brain-wide intraparenchymal pathway which mediates clearance of brain metabolites via convective interstitial fluid (ISF)–CSF exchange. Natural aging has recently been shown to affect peripheral tissue lymphatics as well as normal ISF– CSF circulation,2-4 leading to impaired “glymphatic” clearance of misfolded proteins from the brain parenchyma. These findings suggest a domino effect, whereby age-related impaired “glymphatic” clearance of misfolded proteins (such as amyloid beta) leads to increased plaque deposition, which in turn drives plaque aggregation and subsequent cognitive decline and neurodegeneration.1,4 Building on this literature, Da Mesquita et al5 used surgical, pharmacological, and transgenic models to manipulate drainage through meningeal lymphatics in order to further characterize their role in brain function, specifically in the context of normal aging and AD. In their study,5 recently published in Nature, the Kipnis group at the University of Virginia pharmacologically ablated meningeal lymphatic vessels of mice by injecting a photodynamic drug capable of selectively destroying lymphatic endothelial cells. The authors employed a variety of tools to confirm their findings, including surgically disrupting lymphatic drainage to the deep cervical nodes, engineering mice with genetically altered/impaired lymphatics, and utilizing multiple tracers to assess drainage. In mice lacking meningeal lymphatics, intrathecal and intraparenchymal injection of fluorescent tracers failed to reach the deep cervical nodes. Interruption of normal meningeal lymphatic drainage impaired glymphatic exchange of CSF and interstitial solutes, suggesting the existence of a functional link between processes governing ISF–CSF exchange and CSFlymphatic drainage. In a transgenic mouse model of AD, the authors observed that impaired lymphatic drainage promoted amyloid-beta deposition in the brain and meninges to a degree which resembled human pathology (Figure). Moreover, compromising lymphatic drainage in young adult mice resulted in impaired CSF brain perfusion and accompanying neurocognitive deficits. Aged mice, in particular, demonstrated decreased meningeal lymphatic function, which the authors postulated may contribute to features of age-associated cognitive decline. Additionally, when gadolinium (Gd) signal intensity was used as a proxy for brain perfusion, intrathecal administration of Gd resulted in lower Gd influx in the brain parenchyma (most evident in the hippocampus and cortex) and higher contrast in signal intensity in the ventricles, suggesting accumulation of Gd in the CSF. Notably, this radiographic finding is characteristically observed in patients with idiopathic normal pressure hydrocephalus (iNPH), and is often referred to as “ventricular CSF reflux.”6 Finally, treatment of the aged mice with vascular endothelial growth factor C enhanced meningeal lymphatic drainage and CSF–ISF clearance, improving brain perfusion and cognitive performance. The comprehensive and elegant work by Da Mesquita et al5 comes at a time when several groups1,3,4,7 are attempting to increase our knowledge of these pathways and their role in neurodegenerative disease. This research provides a firm biological foundation for the potential application of neurosurgery to a broader range of age-related neurocognitive disorders than iNPH, where CSF diversion can improve clinical outcome regardless of the directionality of dysfunction or extent of AD comorbidity.8 Whether aspects of meningeal lymphatic function contribute to the waning of shunt benefit in many iNPH patients remains to be determined. Modulation of meningeal lymphatics represents a promising and novel therapeutic avenue, and future studies such as this are crucial to establishing their role in neurocognitive diseases and brain proteinopathies.