Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases

The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (A?). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer’s disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that A? is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of A? in the glia limitans in Alzheimer’s disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of A?. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance

Cerebrospinal fluid transport from the spinal subarachnoid compartment

grantor: University of TorontoSignificant CSF transport occurs through the cribriform plate into the nasal submucosa where it is absorbed by cervical lymphatics. We observed that cribriform plate obstruction reduced CSF clearance. Estimates of the proportional flow through cribriform and non-cribriform routes suggested that cranial CSF absorption occurred primarily through the cribriform plate at low ICPs. Additional drainage sites appeared to be recruited only when intracranial pressures were elevated. Clearance through non-cribriform routes appeared to be greater when CSF had access to spinal absorption sites. Following this observation, we designed several experiments to quantify spinal transport and to determine the relative proportion of total CSF drainage that occurred from the cranial and spinal CSF compartments. These studies revealed that 20%-25% of the total CSF volume is cleared from the spinal subarachnoid compartment. These results challenge the conventional view on CSF dynamics and indicate that spinal subarachnoid compartment plays an important role in CSF transport.M.Sc

Elevated CSF outflow resistance associated with impaired lymphatic CSF absorption in a rat model of kaolin-induced communicating hydrocephalus

<p>Abstract</p> <p>Background</p> <p>We recently reported a lymphatic cerebrospinal fluid (CSF) absorption deficit in a kaolin model of communicating hydrocephalus in rats with ventricular expansion correlating negatively with the magnitude of the impediment to lymphatic function. However, it is possible that CSF drainage was not significantly altered if absorption at other sites compensated for the lymphatic defect. The purpose of this study was to investigate the impact of the lymphatic absorption deficit on global CSF absorption (CSF outflow resistance).</p> <p>Methods</p> <p>Kaolin was injected into the basal cisterns of Sprague Dawley rats. The development of hydrocephalus was assessed using magnetic resonance imaging (MRI). In one group of animals at about 3 weeks after injection, the movement of intraventricularly injected iodinated human serum albumin (¹²⁵I-HSA) into the olfactory turbinates provided an estimate of CSF transport through the cribriform plate into nasal lymphatics (n = 18). Control animals received saline in place of kaolin (n = 10). In a second group at about 3.5 weeks after kaolin injection, intraventricular pressure was measured continuously during infusion of saline into the spinal subarachnoid space at various flow rates (n = 9). CSF outflow resistance was calculated as the slope of the steady-state pressure versus flow rate. Control animals for this group either received no injections (intact: n = 11) or received saline in place of kaolin (n = 8).</p> <p>Results</p> <p>Compared to saline injected controls, lateral ventricular volume in the kaolin group was significantly greater (0.087 ± 0.013 ml, n = 27 versus 0.015 ± 0.001 ml, n = 17) and lymphatic function was significantly less (2.14 ± 0.72% injected/g, n = 18 versus 6.38 ± 0.60% injected/g, n = 10). Additionally, the CSF outflow resistance was significantly greater in the kaolin group (0.46 ± 0.04 cm H₂O.μL^-1.min, n = 9) than in saline injected (0.28 ± 0.03 cm H₂O.μL^-1.min, n = 8) or intact animals (0.18 ± 0.03 cm H₂O.μL^-1.min, n = 11). There was a significant positive correlation between CSF outflow resistance and ventricular volume.</p> <p>Conclusions</p> <p>The data suggest that the impediment to lymphatic CSF absorption in a kaolin-induced model of communicating hydrocephalus has a significant impact on global CSF absorption. A lymphatic CSF absorption deficit would appear to play some role (either direct or indirect) in the pathogenesis of ventriculomegaly.</p