The glymphatic system is a glial-dependent waste clearance pathway in the brain, in place of lymphatic vessels, dedicated to drain away soluble waste proteins and metabolic products. Specifically, the glymphatic network serves as a “front end” for waste clearance, and is connected downstream to an authentic lymphatic network, associated with dura covering the brain as well as cranial nerves and large vessels at the skull exits. The anatomical and functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control glymphatic transport function and waste clearance from brain. In this review, we aim to provide an overview and discussion of the concept behind the glymphatic system, current evidence, and controversies, while specifically focusing on the consequences of aging and evidence of its existence in human brain. Discovering novel strategies for optimizing and maintaining efficient brain waste clearance across the lifespan may in the future prove to be important for preventing cognitive decline and sustaining healthy aging.

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD. The glymphatic system is described as a perivascular transit passageway for cerebrospinal fluid (CSF) for exchange with interstitial fluid (ISF), thereby facilitating waste drainage from the brain 1,2. Investigations of glymphatic system (GS) function have escalated given its important role in Aβ 1 and tau 3 clearance from brain and the inferred implication for neurodegeneration, including Alzheimer's disease 2,4-7. The GS is made up by the perivascular spaces (PVS), which connect with ISF via the aquaporin 4 (AQP4) water channels on astrocytic end-feet and through the small gaps between the overlapping astrocytic end-foot processes 1. The GS hypothesis states that advective CSF influx from the PVS rapidly drives interstitial solutes and waste products out via peri-venous channels 1,8. Although solute transport in the PVS along pial arteries on the surface of the brain is advective (bulk flow) and driven by cardiac pulsatility 1,9-11 , the presence of advective streams in parenchyma 12-14 is contested with the argument that advection does not occur in the neuropil and solutes are transported by diffusion only 15-21. No

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Dynamic contrast-enhanced magnetic resonance imaging (MRI) for tracking glymphatic system transport with paramagnetic contrast such as gadoteric acid (Gd-DOTA) administration into cerebrospinal fluid (CSF) requires pre-contrast data for proper quantification. Here we introduce an alternative approach for glymphatic system quantification in the mouse brain via T1 mapping which also captures drainage of Gd-DOTA to the cervical lymph nodes. The Gd-DOTA injection into CSF was performed on the bench after which the mice underwent T1 mapping using a 3D spoiled gradient echo sequence on a 9.4 T MRI. In Ketamine/Xylazine (KX) anesthetized mice, glymphatic transport and drainage of Gd-DOTA to submandibular and deep cervical lymph nodes was demonstrated as 25-50% T1 reductions in comparison to control mice receiving CSF saline. To further validate the T1 mapping approach we also verified increased glymphatic transport of Gd-DOTA transport in mice anesthetized with KX in comparison with ISO. The novel T1 mapping method allows for quantification of glymphatic transport as well as drainage to the deep and superficial cervical lymph nodes. The ability to measure glymphatic transport and cervical lymph node drainage in the same animal longitudinally is advantageous and time efficient and the coupling between the two systems can be studied and translated to human studies. The glymphatic system (GS) in rodents was first described by Iliff and Nedergaard in 2012 as a brain-wide perivascular transit passageway for cerebrospinal fluid (CSF) facilitating waste clearance in an aquaporin 4 (AQP4) water channel dependent manner 1. Visualization and quantification of GS transport in whole mouse brain was performed ex vivo by first allowing tracers administered into CSF to circulate for a prefixed time interval (30 min-2 h) after which the rodents were euthanized and their brains examined for tracer uptake using fluorescence microscopy 1. In 2013, we introduced dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as an in vivo method for tracking GS transport in the whole rodent brain 2 and later refined gadolinium based contrast administration into CSF and GS quantification 3,4. The DCE-MRI approach for brain-wide GS transport assessment has been widely used and adapted to different species including mice 5-7 , non-human primates 8 , and humans 9,10. Recently, the DCE-MRI approach for GS transport assessment was extended to studies in awake rats. The DCE-MRI GS method involves administering small molecular weight (MW) (e.g. gadopentetic acid MW 547 Da, gadoteric acid (Gd-DOTA), MW 559 Da) or large MW (e.g. GadoSpin P, MW 200 kDa) paramagnetic tracers into CSF via the cisterna magna (CM) 2,3 , cerebral lateral ventricles 11 or lumbar intrathecal route 9. Transport of the paramagnetic contrast molecule (a.k.a. 'solute') from CSF into brain parenchyma is tracked dynamically by a series of 3D T1-weighted MRI scans 1. The time series of 3D T1-weighted spoiled gradient echo (SPGR) brain images acquired before, during and after solute...

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Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Cerebral small vessel disease(s) (SVD) result from pathological changes of the small blood vessels in the brain and is common in older people. The diagnostic features by which SVD manifests in brain includes white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and atrophy. In the present study, we use in vivo MRI to characterize brain morphometry and longitudinal relaxation time (T1) of spontaneously hypertensive rats (SHR) to study the contribution of chronic hypertension to SVD relevant pathology. Male SHR and Wistar-Kyoto (WKY) rats underwent 3D variable flip angle spoiled gradient echo brain MRI at 9.4T at early (7 weeks old) and established (19 weeks old) stages of hypertension. The derived proton density weighted and T1 images were utilized for morphometry and to characterize T1 properties in grey matter, white matter (WM) and cerebrospinal fluid (CSF). Custom tissue probability maps were constructed for accurate computerized whole brain tissue segmentations and voxel-wise analyses. Characteristic morphological differences between the two strains included enlarged ventricles, smaller corpus callosum (CC) volumes and general 'thinning' of CC in SHR compared to WKY rats at both age groups. While we did not observe parenchymal T1 differences, the T1 of CSF was