Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by progressive loss of neurons, sensory and motor impairments, and severe cognitive decline [1
]. Extracellular depositions of amyloid β (Aβ) peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [2
], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington’s disease and amyotrophic lateral sclerosis (ALS) [5
]. In the case of AD, it is widely believed that amyloid deposition results from an age-related failure of soluble Aβ clearance from the brain [8
]. Although neuroimaging approaches are now widely available to detect the deposition of amyloid plaques and the static evolution of plaque burden [9
], no approach yet exists that allows Aβ clearance efficiency to be directly measured in real time. The ability to detect changes in the efficiency of Aβ clearance would be a significant advance in evaluating susceptibility to and progression of AD in addition to potentially opening up a totally novel therapeutic approach to treatment.
The cerebrospinal fluid (CSF) circulation is widely regarded as a major sink for the clearance of interstitial fluid (ISF) and its solutes from the brain. As CSF is reabsorbed across arachnoid granulations, along cranial and spinal nerve sheaths, or along the brain microvasculature, solutes are cleared from the cranial cavity [10
]. In a recent study we reported that a large proportion of subarachnoid cerebrospinal fluid (CSF) recirculates through the brain parenchyma along perivascular spaces, exchanging with brain interstitial fluid (ISF) before being cleared via peri-venous pathways [15
]. The continuous circulation of CSF along this pathway facilitates the clearance of extracellular solutes, including soluble Aβ, from the brain. We termed this brain-wide pathway the ‘glymphatic system’, based upon the critical role that astroglial water transport through the astrocytic aquaporin-4 water channel plays in facilitating CSF-ISF exchange and solute clearance [16
]. One implication of these findings is that changes in glymphatic pathway function may contribute to the failure of Aβ clearance in the pre-clinical stages of AD, while a method to measure glymphatic pathway function in clinical populations might allow AD disease susceptibility and progression to be evaluated.
Our initial characterization of the glymphatic system utilized in vivo two-photon microscopy and ex vivo fluorescence imaging of intracisternally infused CSF tracers to map the brain-wide pathway and to quantify the efficiency of solute clearance in mice. These approaches are not appropriate for clinical application, given the optical limitations of fluorescence-based imaging and the complications that are associated with intracisternal infusions in humans [17
]. In the clinical setting, dynamic nuclear imaging modalities such as magnetic resonance imaging (MRI) are routinely used to monitor CSF flux in the diagnosis of spontaneous intracranial hypotension (SIH) and post-traumatic CSF rhinnorrhea or otorrhea [18
]. These approaches permit time-sequenced three-dimensional (3D) representation of the brain with high spatial and temporal resolution of tracer distribution. In a follow-up pre-clinical study we have successfully utilized dynamic contrast-enhanced MRI after intrathecal infusion of gadolinium-based contrast agent into the cisterna magna to measure glymphatic pathway function in rats [20
In contrast to intracisternal infusions, lumbar intrathecal injections of radio-tracer are presently used along with computer-tomography/mylography and digital subtraction myelography to diagnose dural leaks associated with SIH, pseudomeningocele, and superficial siderosis [22
], as well as the integrity of the spinal cord in the setting of injury or tumor [24
]. Lumbar intrathecal injections are additionally used in everyday practice for the delivery of local anesthetics [26
], opioids and other analgesics, and would thus provide an ideal delivery route for contrast agents that could then be used in conjunction with dynamic contrast-enhanced MRI to evaluate glymphatic clearance in humans.
In the present pre-clinical study, we extend these recent findings to evaluate whether perivascular CSF-ISF exchange within the brain can be evaluated after lumbar intrathecal CSF tracer infusion. We compare the influx kinetics and parenchymal distribution of these tracers with those corresponding to intracisternal CSF tracer infusion described previously [16
]. Our data demonstrate that CSF tracer infused at the lumbar spine enters the brain through perivascular spaces and exchanges with the ISF in a manner consistent with our previous characterization of the glymphatic pathway, suggesting that the lumbar intrathecal infusion is a clinically viable contrast delivery route to asses glymphatic function in humans.