_:b521493692 . _:b521493826 . _:b521493786 . _:b521493835 . . _:b521493949 . . . . . _:b521493834 . _:b521493845 . _:b521493950 . _:b521493844 . . . _:b521493847 . . _:b521493846 . _:b521493838 . _:b521493841 . _:b521493768 . _:b521493840 . . . _:b22280367 "We compare the influx kinetics and parenchymal distribution of these tracers with those corresponding to intracisternal CSF tracer infusion described previously [>>16<<,20]. 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" . _:b22280391 "This is consistent of with diameters of hydration measured for both 3 kD dextrans (<20\u00A0nm) and 500 kD dextrans (>20\u00A0nm) [>>34<<]." . _:b521493843 . _:b521493983 . _:b521493842 . _:b521493748 . . _:b521493853 . . _:b521493661 . _:b521493667 . _:b521493852 . _:b521493737 . _:b521493855 . _:b521493973 . _:b521493854 . . _:b521493849 . _:b521493899 . . _:b521493933 . . _:b521493848 . . . . _:b521493851 . _:b521493968 . _:b521493850 . _:b521493902 . _:b521493861 . . . _:b521494060 . . _:b521493860 . _:b521493683 . _:b521493863 . . _:b521493862 . . _:b521493703 . _:b521493857 . . _:b521493986 . . _:b521493861 . _:b521493856 . _:b521493859 . _:b521493945 . _:b22280383 . _:b22280384 "CSF moves through the ventricular and subarachnoid compartment through the process of bulk flow [13,>>31<<,32]. Because under bulk flow, the movement of the solvent is typically more rapid than the movement of the solute by passive diffusion, bulk flow-dependent movement is largely independent of molecular weight [31]." . _:b521493858 . _:b22280365 "and digital subtraction myelography to diagnose dural leaks associated with SIH, pseudomeningocele, and superficial siderosis [22,23], as well as the integrity of the spinal cord in the setting of injury or tumor [24,>>25<<]. 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" . . . _:b521493869 . . _:b521493943 . _:b521493868 . . . _:b521493871 . _:b521493909 . _:b521493870 . _:b521493790 . _:b521493865 . _:b521493832 . _:b521493704 . _:b521493864 . . _:b521493867 . _:b521493856 . _:b521493936 . _:b521493866 . . _:b521493685 . _:b521493669 . . _:b521493877 . . . _:b521494052 . _:b521493876 . _:b521494053 . _:b521493845 . _:b521494054 . _:b521494055 . . _:b521494048 . _:b521493879 . _:b521494049 . _:b22280396 . _:b521493887 . _:b521494050 . _:b22280397 . _:b521494051 . _:b521494060 . _:b521493878 . _:b521494061 . _:b521494062 . _:b521494063 . _:b521494056 . _:b521493873 . _:b521494057 . _:b521494058 . _:b521494059 . _:b521494068 . _:b521493872 . _:b521494069 . _:b521494070 . _:b521494071 . _:b521494064 . _:b521494016 . _:b521493875 . _:b521494065 . _:b521494066 . _:b521494067 . _:b521494076 . _:b521494036 . _:b521493874 . _:b521494077 . . _:b521494078 . _:b521494079 . _:b521494093 . _:b521494072 . _:b521493885 . _:b521494073 . _:b521494074 . _:b521494075 . _:b521494020 . _:b521493884 . _:b521494021 . . _:b521494022 . . _:b521494023 . _:b521494016 . _:b521493887 . _:b521494017 . _:b521494018 . . _:b521494019 . _:b521494028 . _:b521493886 . _:b521494029 . _:b521494030 . . _:b521494031 . _:b521494024 . _:b521493881 . _:b521494025 . . _:b521494026 . _:b521494027 . _:b521494036 . _:b521493880 . _:b521494037 . _:b521494038 . _:b521494039 . _:b521494032 . _:b521493883 . _:b521493776 . _:b521494033 . _:b521494034 . _:b521494035 . _:b521494044 . _:b521493882 . _:b521494045 . _:b521494046 . _:b22280366 "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." . _:b521494047 . _:b521494040 . _:b521493893 . _:b521494041 . _:b521494042 . _:b521494043 . _:b521493892 . _:b521493895 . _:b521493894 . _:b521493889 . _:b521494013 . _:b521493873 . _:b521493888 . . _:b521493885 . _:b521493746 . _:b521493891 . _:b521493673 . _:b521493890 . _:b521493901 . _:b521493874 . _:b521494084 . _:b521493900 . _:b521494085 . _:b22280346 "This infusion volume was the same as was used previously to define perivascular CSF-ISF exchange by in vivo 2-photon microscopy [>>16<<]." . _:b521494086 . _:b521494087 . _:b521494080 . _:b521493903 . _:b521494081 . _:b521493698 . _:b521494082 . _:b521494083 . _:b521494092 . _:b521494070 . _:b521493902 . _:b521494093 . . _:b521494094 . _:b521494095 . _:b521494088 . _:b521493897 . _:b521494089 . _:b521494090 . _:b22280393 "A recent analysis showed that the glymphatic system can be evaluated in the rats using contrast-enhanced MRI following intracisternal gadolinium-based contrast infusion [>>20<<]. Intracisternal infusions, however, are rarely used in a clinical setting due to their high potential for iatrogenic complications, including traumatic tissue injury [17]. In contrast, the lumbar intrathecal delivery route is routinely" . _:b521494091 . _:b521493896 . . _:b521493967 . _:b521494031 . _:b521493899 . . _:b521493960 . _:b521493898 . _:b22280390 "We surmised that the perivascular astrocytic endfeet acted as a sieve to restrict the movement of large solutes from the perivascular spaces into the brain interstitium [>>16<<]. This is consistent of with diameters of hydration measured for both 3 kD dextrans (<20\u00A0nm) and 500 kD dextrans (>20\u00A0nm) [34]." . . _:b22280352 "In the case of AD, it is widely believed that amyloid deposition results from an age-related failure of soluble A\u03B2 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 A\u03B2 clearance efficiency to be directly measured in" . _:b521493653 . . _:b521493909 . . _:b521493908 . . . _:b521493849 . _:b521493911 . . _:b521493910 . _:b521493805 . . _:b521493979 . _:b521493905 . . _:b521493664 . _:b521493904 . . . _:b521494043 . _:b521493907 . . _:b521493811 . _:b521493906 . . _:b521493917 . _:b521494010 . _:b521493916 . _:b521493680 . _:b521493820 . _:b521493919 . _:b521493918 . _:b521493913 . _:b521493649 . _:b521493769 . _:b521493912 . . _:b22280347 "Slice fluorescence (fluorescent tracer accumulation) was quantified using ImageJ software (NIH), as described previously [>>16<<]. Anatomical brain regions of interest (ROIs) were generated based upon the DAPI emission channel for the cortex, white matter (including corpus callosum, internal and external capsule), subcortical structures (striatum, thalamus," . _:b521493915 . . _:b521493914 . _:b521493925 . _:b521493924 . _:b22280388 "In our prior study in mice [>>16<<], we noted that while CSF tracers of all sizes moved rapidly into the brain along perivascular spaces, large molecular weight tracers such as FITC-d2000 (MW 2000 kD) became trapped in the perivascular space and could not move freely into" . _:b521493927 . _:b521493893 . _:b521494069 . _:b521493926 . _:b521493994 . _:b521493921 . _:b22280342 "methods" . _:b521493920 . . _:b521493841 . . _:b521493923 . _:b521493922 . _:b521493766 . _:b521494024 . . _:b521493933 . . _:b521493677 . _:b521493843 . . . _:b521493932 . . . _:b521493935 . _:b521493934 . . _:b521493934 . _:b521493929 . . _:b521494078 . _:b521493928 . . . _:b521493931 . . . _:b521493930 . _:b521493941 . _:b521493854 . _:b521493796 . _:b521494000 . _:b521493940 . . _:b521493797 . _:b521493798 . . _:b521493799 . . _:b521493753 . _:b521493943 . _:b521493792 . _:b521493793 . _:b521493794 . _:b521493795 . _:b521493804 . _:b521493942 . _:b521493805 . _:b521493759 . _:b521493782 . _:b521493806 . _:b521493807 . _:b521493800 . _:b521493937 . _:b521493801 . _:b521493802 . . . _:b521493803 . _:b521493812 . _:b521493936 . _:b521493813 . _:b521493744 . _:b521493814 . _:b521493672 . _:b521493815 . _:b521493808 . _:b22280358 . _:b521493939 . _:b521493722 . _:b521493809 . _:b521493921 . _:b521493810 . _:b521493811 . _:b521493820 . _:b521493938 . _:b521493821 . _:b521493822 . _:b22280361 "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,>>21<<]." . _:b521493823 . _:b521493816 . _:b521493949 . _:b521493853 . _:b521493817 . _:b521493818 . _:b521494044 . _:b521493819 . . _:b521493948 . _:b521493764 . _:b521493765 . . _:b521493766 . _:b521493767 . _:b521493760 . _:b521493951 . . _:b521493937 . _:b521493761 . _:b521493762 . _:b521493763 . . _:b521493950 . _:b521493772 . . _:b521493773 . . _:b521493774 . _:b521493702 . _:b521493775 . _:b521493768 . _:b521493945 . _:b521493769 . _:b521494051 . _:b521493770 . _:b521493771 . . _:b521493944 . _:b521493780 . _:b521493781 . _:b521493782 . _:b521493783 . _:b521493776 . _:b521493947 . _:b521493777 . _:b521493778 . _:b521493779 . _:b22280385 "CSF moves through the ventricular and subarachnoid compartment through the process of bulk flow [13,31,>>32<<]. Because under bulk flow, the movement of the solvent is typically more rapid than the movement of the solute by passive diffusion, bulk flow-dependent movement is largely independent of molecular weight [31]." . _:b521493788 . _:b521493946 . _:b521493789 . _:b521494073 . _:b521494021 "2"^^ . _:b521493790 . _:b521493791 . _:b521493784 . _:b521493957 . _:b521493785 . _:b521494020 "2"^^ . _:b521493786 . _:b521493787 . _:b521493803 . _:b521493860 . _:b521493956 . _:b521493861 . _:b521494023 "2"^^ . _:b521493862 . _:b521493863 . _:b22280391 . _:b521493856 . _:b521493959 . _:b521493857 . _:b521494022 "2"^^ . _:b521493858 . _:b521493859 . . _:b521493868 . _:b521493958 . _:b521493869 . _:b521494017 "2"^^ . _:b521493870 . _:b521493871 . _:b521493864 . _:b521493953 . _:b521493865 . _:b521494016 "2"^^ . _:b521493866 . _:b521493867 . _:b521493859 . . _:b521493876 . _:b521493952 . _:b521493877 . _:b521494019 "2"^^ . _:b521493878 . _:b521493879 . _:b521493872 . _:b521493955 . _:b521493873 . _:b521494018 "2"^^ . _:b521493874 . _:b521493875 . _:b521493816 . . _:b521493954 . _:b521493884 . . _:b521494029 "2"^^ . _:b521493885 . _:b521493886 . _:b521493887 . . _:b521493880 . _:b521494053 . _:b521493965 . _:b521493881 . _:b521494028 "2"^^ . _:b521493882 . _:b521493851 . _:b521493883 . _:b521493828 . _:b521493964 . _:b521493829 . _:b521494031 "2"^^ . _:b521493830 . _:b521493831 . _:b521493824 . _:b521493967 . . _:b22280355 . _:b521494030 "2"^^ . _:b521493825 . _:b521493826 . _:b521493827 . _:b521494020 . . _:b521493836 . _:b521493966 . _:b521493837 . _:b521494025 "2"^^ . _:b521493810 . . _:b521493838 . _:b521493839 . _:b521493832 . _:b521493961 . _:b521493833 . _:b521494024 "2"^^ . _:b521493834 . _:b521493835 . . _:b521493960 . _:b521493844 . _:b521493845 . _:b521494027 "2"^^ . _:b521493987 . . _:b521493846 . _:b521493846 . _:b521493847 . _:b521493840 . _:b521493984 . _:b521493963 . _:b521493841 . _:b521494026 "2"^^ . _:b521493842 . _:b521493843 . _:b521493852 . _:b521493962 . _:b521493853 . _:b521494037 "2"^^ . _:b521493842 . _:b521493854 . _:b521493855 . _:b22280383 "CSF moves through the ventricular and subarachnoid compartment through the process of bulk flow [>>13<<,31,32]. Because under bulk flow, the movement of the solvent is typically more rapid than the movement of the solute by passive diffusion, bulk flow-dependent movement is largely independent of molecular weight [31]." . _:b521493848 . _:b521493973 . _:b521493849 . _:b22280351 . _:b521494036 "2"^^ . _:b521493850 . _:b521493851 . _:b521493924 . _:b521493972 . _:b521493925 . _:b521494039 "2"^^ . _:b521493926 . _:b521493927 . . _:b521493920 . _:b521493975 . _:b521493921 . _:b521494038 "2"^^ . _:b521493922 . _:b521493795 . _:b521493923 . _:b521493932 . _:b521493974 . _:b521493933 . _:b22280365 . _:b521494033 "2"^^ . _:b521493839 . . _:b521493934 . _:b521493935 . _:b521493928 . _:b521493969 . _:b521493929 . _:b521494032 "2"^^ . _:b521493930 . _:b521493734 . _:b521493931 . _:b521493940 . _:b521493968 . _:b521493941 . _:b521494035 "2"^^ . _:b521493942 . _:b521493791 . . _:b521493943 . _:b521493936 . _:b521493971 . _:b521493937 . _:b521494034 "2"^^ . _:b521493938 . _:b521493939 . _:b521493948 . _:b521493970 . _:b521493949 . _:b521494045 "2"^^ . _:b521493950 . _:b521493951 . _:b521493944 . _:b521493981 . _:b521493945 . _:b521494044 "2"^^ . _:b521493946 . _:b521493947 . . . _:b521493980 . _:b521493892 . _:b521493893 . _:b521494047 "2"^^ . _:b521493894 . _:b521493895 . _:b521493888 . _:b521493983 . _:b521493889 . _:b521494046 "2"^^ . _:b521493890 . . _:b521493742 . _:b521493891 . _:b521493900 . _:b521493996 . _:b521493982 . _:b521493901 . _:b521494041 "2"^^ . _:b521493902 . _:b521493903 . _:b521493896 . _:b521493977 . . _:b521494040 "2"^^ . _:b521493897 . _:b521493898 . _:b521493850 . . _:b521493899 . _:b521493908 . _:b521493976 . . _:b521493909 . _:b521494043 "2"^^ . _:b521493910 . _:b521493911 . _:b521493904 . _:b521493979 . _:b521493894 . _:b521493905 . _:b521494042 "2"^^ . _:b521493906 . _:b521493907 . _:b521493916 . _:b521493978 . _:b521493917 . _:b521494053 "2"^^ . _:b521493918 . . _:b521493919 . . _:b521493989 . _:b521493912 . _:b521493913 . _:b521494052 "2"^^ . _:b521493914 . _:b521493915 . . _:b521493988 . _:b521493988 . _:b521493989 . _:b521494055 "2"^^ . _:b521493990 . _:b521493991 . _:b521493984 . _:b521493991 . _:b521493985 . _:b521494054 "2"^^ . . _:b521493986 . _:b521493987 . _:b521493996 . _:b521493990 . _:b521493997 . _:b521494049 "2"^^ . _:b521493998 . _:b521493679 . _:b521493999 . _:b521493992 . _:b521493985 . _:b521493993 . _:b521494048 "2"^^ . _:b521493897 . _:b521493994 . _:b521493995 . _:b521494004 . _:b22280362 . _:b521493984 . _:b521494005 . _:b521494051 "2"^^ . . _:b521494006 . _:b521494007 . _:b521494000 . _:b521493987 . _:b521494001 . _:b521494050 "2"^^ . _:b521494002 . _:b521494003 . _:b521493705 . _:b521494012 . _:b521493986 . _:b521493926 . _:b521494013 . _:b521494061 "2"^^ . _:b521494014 . _:b521494015 . . _:b521494072 . _:b521493997 . _:b521493835 . _:b521494008 . . _:b521494060 "2"^^ . _:b521494009 . _:b521494010 . _:b521493650 "23"^^ . _:b521494011 . _:b521493956 . _:b521493996 . _:b521493957 . _:b521494063 "2"^^ . . _:b521493958 . _:b521493651 "23"^^ . _:b521493959 . _:b521493952 . _:b521493999 . . _:b521493953 . _:b521494062 "2"^^ . _:b521493954 . _:b521493955 . _:b521493895 . _:b521493964 . _:b521493998 . . _:b521494057 "2"^^ . _:b521494034 . _:b521493965 . _:b521493966 . . _:b521493967 . . _:b521493993 . _:b521493960 . _:b521493648 "28"^^ . _:b521493649 "25"^^ . _:b521494056 "2"^^ . _:b521493961 . _:b521493962 . _:b521493963 . _:b521493972 . _:b521493992 . _:b521493973 . _:b521494059 "2"^^ . _:b521493974 . _:b521493975 . _:b521493968 . _:b521493995 . . _:b521494058 "2"^^ . _:b521493969 . _:b521493652 "22"^^ . _:b521493970 . _:b521493971 . _:b521493655 "20"^^ . _:b521493994 . _:b521493980 . _:b521493981 . _:b22280370 "2-photon in vivo imaging in mice and dynamic contrast-enhanced MRI in rats were used to demonstrate the existence of a brain-wide perivascular route, termed the \u2018glymphatic pathway\u2019, that permits CSF to exchange with the brain ISF [>>16<<,20]. CSF-ISF exchange along these perivascular pathways was supported by astroglial aquaporin-4 water channels and the movement of fluid through this pathway facilitated the clearance of interstitial solutes, including soluble A\u03B2, from" . _:b521494069 "2"^^ . _:b521493653 "22"^^ . _:b521493982 . . _:b521493983 . _:b521493654 "20"^^ . _:b521494005 . _:b521493976 . _:b521493977 . _:b22280363 "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,>>23<<], as well as the integrity of the spinal cord in the setting of injury or tumor [24,25]." . _:b521494068 "2"^^ . _:b521493978 . . . _:b521493979 . _:b521493656 "16"^^ . _:b521494004 . _:b521494071 "2"^^ . _:b521493662 "10"^^ . . _:b521494007 . . _:b521493663 "9"^^ . _:b521494070 "2"^^ . _:b521493661 "10"^^ . _:b521493668 . . _:b521494006 . . _:b521494065 "2"^^ . _:b521494039 . _:b521493813 . _:b521493694 . _:b521493660 "11"^^ . _:b521494001 . _:b521494064 "2"^^ . _:b521493659 "12"^^ . _:b521494000 . . _:b521494067 "2"^^ . . _:b521493658 "12"^^ . _:b521494003 . _:b521493690 . _:b521494066 "2"^^ . . . . _:b521494002 . . _:b521493657 "12"^^ . _:b521494077 "2"^^ . . _:b521493938 . _:b521494013 . . _:b521494076 "2"^^ . _:b521493958 . _:b521494012 . _:b22280387 . _:b521493670 "9"^^ . _:b521494079 "2"^^ . _:b521493723 . _:b521493671 "8"^^ . _:b22280386 . _:b521494015 . _:b521493751 . _:b521493725 . _:b521494078 "2"^^ . . . _:b521494014 . _:b521493668 "9"^^ . _:b521494073 "2"^^ . _:b521494009 . _:b22280384 . _:b521493669 "9"^^ . _:b521494072 "2"^^ . . _:b521494008 . _:b521493666 "9"^^ . _:b521494075 "2"^^ . _:b22280343 "FITC-d500 and TR-d3 were selected to roughly correspond with the molecular weights of Gd-DTPA (MW\u2009~\u20091 kD) and GadoSpin\u2122 (MW 200 kD), which are commonly used MRI contrast agents [>>27<<]. Tracers were constituted in isobaric artificial CSF at a concentration of 0.25%. In a companion study [20], we evaluated CSF-ISF exchange after intracisternal infusion of MRI contrast agents and found that two key components of the" . . _:b521494011 . _:b521493667 "9"^^ . _:b521494074 "2"^^ . . _:b521494010 . _:b521493664 "9"^^ . _:b521494085 "2"^^ . . _:b521493684 . . _:b22280381 "be deposited along each vertebral segment along the natural CSF clearance pathway, resulting a reduced delivery of tracer to the distant cisternal spaces surrounding the brain which form the entrance to the brain-wide glymphatic system [>>16<<,20]. Despite these differences in influx magnitude and kinetics, tracer distribution after lumbar and intracisternal infusion followed a similar pattern and encompassed the entire brain parenchyma (compare Figure 2B,E and Figure 3A)." . _:b521494084 "2"^^ . _:b521493665 "9"^^ . _:b521493678 "7"^^ . _:b521494087 "2"^^ . _:b22280350 . _:b521493679 "7"^^ . _:b521493681 . _:b521494086 "2"^^ . . _:b521493819 . _:b521493676 "8"^^ . _:b521494081 "2"^^ . _:b521493677 "8"^^ . _:b521494042 . _:b521494080 "2"^^ . _:b521493674 "8"^^ . _:b521494083 "2"^^ . . . _:b521493675 "8"^^ . . _:b521494082 "2"^^ . _:b521493672 "8"^^ . . _:b521494093 "2"^^ . _:b521493939 . _:b521493673 "8"^^ . _:b521494092 "2"^^ . _:b521493686 "7"^^ . _:b22280377 . _:b521494095 "2"^^ . _:b521493687 "7"^^ . . _:b521494094 "2"^^ . _:b521493684 "7"^^ . _:b521493904 . _:b22280345 "In order to permit comparison with this prior study [>>20<<], in the present study intracisternal and lumbar infusions in rats were conducted in the same manner:" . _:b521494089 "2"^^ . _:b22280386 "Because under bulk flow, the movement of the solvent is typically more rapid than the movement of the solute by passive diffusion, bulk flow-dependent movement is largely independent of molecular weight [>>31<<]. To evaluate whether the rate of intrathecal lumbar tracer influx into the brain parenchyma was dependent upon molecular size, we co-infused large molecular weight fluorescent FITC-d500 (MW 500 kD) and small molecular weight TR-d3 (MW 3" . . _:b521494038 . _:b521493685 "7"^^ . . _:b521494088 "2"^^ . _:b521493682 "7"^^ . _:b22280381 . . _:b521494091 "2"^^ . _:b521493683 "7"^^ . _:b521494090 "2"^^ . _:b521493680 "7"^^ . _:b521493749 . _:b521493681 "7"^^ . . _:b521493694 "6"^^ . _:b521493668 . . _:b521493812 . _:b521493669 . _:b521493695 "6"^^ . _:b521493670 . _:b521493671 . _:b521493664 . . . _:b521493665 . _:b521493692 "6"^^ . _:b521493666 . _:b521493735 . _:b521493667 . _:b521493676 . _:b521493677 . _:b521493693 "6"^^ . _:b521493678 . _:b521493679 . _:b22280370 . _:b521493672 . _:b521493673 . _:b521493690 "6"^^ . _:b521493674 . . _:b521493675 . _:b521493684 . _:b521493685 . _:b521493999 . _:b521493954 . . . _:b521493686 . _:b521493691 "6"^^ . _:b521493687 . _:b22280372 . _:b521493680 . _:b521493890 . . _:b521493681 . . _:b521493682 . _:b521493688 "6"^^ . _:b521493683 . _:b22280375 . _:b521494007 . . _:b521493692 . . _:b521493869 . _:b521493693 . . _:b521493694 . . _:b521493689 "6"^^ . _:b521493687 . _:b22280374 . _:b521493948 . _:b521493695 . _:b521493688 . _:b521493689 . _:b521493702 "6"^^ . . _:b521493690 . . _:b521493691 . _:b521493804 . _:b521494045 . _:b521493703 "6"^^ . _:b521493829 . _:b521493700 "6"^^ . _:b521493800 . _:b521493701 "6"^^ . . . _:b521493698 "6"^^ . _:b521493652 . . _:b521493653 . _:b521493699 "6"^^ . _:b521493654 . _:b521493655 . _:b521493648 . . _:b521493649 . . _:b521493650 . _:b521493696 "6"^^ . _:b521493651 . _:b22280367 . . _:b521493660 . _:b521493661 . _:b521493697 "6"^^ . _:b521493662 . _:b521493663 . _:b521493656 . . _:b521493657 . _:b521493658 . _:b521493659 . _:b521493732 . _:b521493709 "5"^^ . _:b521493972 . _:b521493733 . . _:b521493734 . . _:b521493735 . _:b521493728 . _:b22280394 . _:b521493708 "5"^^ . _:b521493729 . _:b521493730 . _:b521493731 . _:b521493740 . _:b521493711 "5"^^ . . _:b521493741 . _:b521493742 . _:b521493743 . _:b521493736 . _:b521493710 "5"^^ . _:b521493737 . _:b521493706 "6"^^ . _:b521493738 . _:b521493739 . _:b22280357 . _:b521493748 . _:b521493749 . _:b521493750 . _:b521493751 . _:b22280356 . _:b521493744 . _:b521493745 . _:b521493704 "6"^^ . _:b22280374 "Consistent with our prior study in mice [>>16<<], we observed that intracisternally-infused TR-d3 moved rapidly into the rat brain parenchyma, both across the pial surface and along perivascular pathways (Figure 2B,E) and exchanged broadly with the brain interstitium." . _:b521493746 . _:b521493747 . _:b521493756 . _:b521493707 "5"^^ . _:b521493757 . _:b521493705 "6"^^ . _:b521493758 . _:b521493759 . . _:b521493752 . _:b521493753 . _:b521493754 . . _:b521493755 . _:b521493700 . _:b521493717 "5"^^ . _:b521493701 . _:b521493702 . _:b521493703 . _:b521493696 . _:b521493716 "5"^^ . _:b521493697 . _:b521493698 . _:b22280343 . _:b521493699 . _:b22280347 . _:b521493708 . _:b521493995 . _:b521493719 "5"^^ . _:b521493709 . _:b521493710 . . _:b22280346 . _:b521493711 . _:b521493704 . _:b521493789 . _:b521493718 "5"^^ . _:b521493705 . _:b521493706 . _:b521493784 . _:b521493707 . _:b521493716 . _:b521493713 "5"^^ . _:b22280373 "Intracisternal CSF tracer infusions were carried out in a parallel group of animals to provide a direct comparison to the infusion route used previously [16,>>20<<]." . _:b521493717 . . . _:b521493718 . _:b521493719 . . _:b521493975 . _:b521493712 . _:b521493712 "5"^^ . _:b521493713 . _:b521493714 . . _:b521493715 . _:b521493724 . _:b22280354 "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<<]\u2013[14]. 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" . _:b521493844 . . _:b521493715 "5"^^ . _:b521493725 . . _:b521493726 . _:b521493727 . _:b521494074 . . _:b521493720 . . _:b521493714 "5"^^ . _:b521493721 . _:b521493722 . _:b521494079 . _:b521493723 . _:b521494052 . _:b521493725 "5"^^ . _:b521493883 . _:b521493724 "5"^^ . . _:b521493731 . _:b521493727 "5"^^ . . . . _:b521493726 "5"^^ . . . _:b22280351 . . _:b521493721 "5"^^ . _:b22280344 "Tracers were constituted in isobaric artificial CSF at a concentration of 0.25%. In a companion study [>>20<<], we evaluated CSF-ISF exchange after intracisternal infusion of MRI contrast agents and found that two key components of the glymphatic system (i.e. para-arterial CSF tracer influx and size-dependent CSF-ISF exchange) could be visualized" . _:b521493720 "5"^^ . . _:b521493831 . . _:b521493723 "5"^^ . . _:b521493722 "5"^^ . _:b521493733 "4"^^ . . _:b521493732 "5"^^ . _:b22280399 "In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [23,25], spinal anesthetics and post-operative analgesics [35,36], as well as chemotherapeutics [>>37<<]. By utilizing an intrathecal, rather than a trans-blood brain barrier route for contrast delivery, the difficulties associated with therapeutic agent delivery into the CNS [38] can be circumvented." . _:b521493735 "4"^^ . _:b22280375 "This is consistent with our prior observation that subcortical regions enjoy the largest influxes of subarachnoid CSF along large caliber penetrating arteries from the ventral brain surface [>>16<<]. Furthermore, these regions are most proximate to the para-venous clearance pathways that drain medially along the internal cerebral veins. When anterior versus posterior tracer fluxes were compared, both peak values at 30\u00A0min and the" . . _:b521493912 . _:b521493734 "4"^^ . _:b521494001 . . _:b521493714 . _:b521493729 "5"^^ . _:b521494048 . . _:b521494068 . _:b521493728 "5"^^ . . . _:b521493731 "5"^^ . _:b521493730 "5"^^ . _:b521493741 "4"^^ . . _:b521494026 . _:b521494012 . _:b521493740 "4"^^ . _:b521493868 . _:b521493743 "4"^^ . _:b521494088 . _:b22280348 _:b22280349 . . _:b22280348 _:b22280350 . _:b521493742 "4"^^ . . _:b22280348 _:b22280351 . . _:b521493737 "4"^^ . _:b521493697 . _:b521493815 . _:b521493736 "4"^^ . . _:b521493739 "4"^^ . _:b521493993 . _:b521493696 . _:b521493738 "4"^^ . _:b521493749 "4"^^ . _:b521493748 "4"^^ . . _:b521493783 . _:b22280342 _:b22280344 . _:b22280348 _:b22280368 . _:b22280342 _:b22280345 . _:b521493969 . _:b521493751 "4"^^ . _:b22280342 _:b22280346 . _:b22280342 _:b22280347 . _:b521494047 . _:b521493750 "4"^^ . _:b521493989 . . _:b22280342 _:b22280343 . _:b521493745 "4"^^ . _:b521493891 . _:b22280348 _:b22280356 . _:b22280348 _:b22280357 . _:b521493744 "4"^^ . _:b22280348 _:b22280358 . . _:b22280348 _:b22280359 . . _:b22280348 _:b22280352 . _:b22280348 _:b22280353 . . _:b22280348 _:b22280354 . . _:b521493747 "4"^^ . _:b521493752 . . _:b22280348 _:b22280355 . _:b22280348 _:b22280364 . _:b22280348 _:b22280365 . _:b521493746 "4"^^ . _:b22280348 _:b22280366 . . _:b22280348 _:b22280367 . _:b22280348 _:b22280360 . _:b521493990 . _:b22280348 _:b22280361 . _:b521494021 . _:b521493757 "4"^^ . _:b22280348 _:b22280362 . . _:b22280387 "This finding is consistent with the movement of fluorescent tracer from the lumbar site of infusion to the brain subarachnoid and perivascular spaces via bulk flow rather than by simple diffusion [>>31<<]." . _:b521493808 . _:b22280348 _:b22280363 . . _:b521493886 . _:b521493965 . _:b521493756 "4"^^ . _:b521493759 "4"^^ . _:b521494054 . _:b521493671 . _:b521493758 "4"^^ . . _:b22280362 "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<<,23], as well as the integrity of the spinal cord in the setting of injury or tumor [24,25]." . _:b521493753 "4"^^ . _:b521493701 . _:b521493752 "4"^^ . _:b521493978 . _:b22280400 "By utilizing an intrathecal, rather than a trans-blood brain barrier route for contrast delivery, the difficulties associated with therapeutic agent delivery into the CNS [>>38<<] can be circumvented." . _:b521493755 "4"^^ . _:b521493754 "4"^^ . . _:b521493765 "3"^^ . _:b521493825 . _:b521493997 . . _:b521493764 "3"^^ . _:b22280368 "We compare the influx kinetics and parenchymal distribution of these tracers with those corresponding to intracisternal CSF tracer infusion described previously [16,>>20<<]. 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" . . _:b521493767 "3"^^ . . _:b521494077 . . _:b521493766 "3"^^ . . . _:b521493797 . _:b521494085 . _:b521493761 "4"^^ . _:b521493966 . _:b521493760 "4"^^ . _:b22280349 . _:b22280354 . _:b521493763 "3"^^ . . _:b521493762 "3"^^ . . . _:b521493773 "3"^^ . _:b521493793 . _:b521493772 "3"^^ . . . _:b521493775 "3"^^ . _:b521493774 "3"^^ . _:b521494092 . . . _:b521493985 . _:b521493955 . . _:b521493769 "3"^^ . _:b521493917 . _:b521493768 "3"^^ . . _:b22280369 _:b22280370 . _:b22280369 _:b22280371 . _:b22280359 . _:b22280369 _:b22280372 . _:b521493771 "3"^^ . _:b521494021 . _:b22280369 _:b22280373 . _:b22280369 _:b22280374 . _:b521493976 . _:b22280369 _:b22280375 . _:b22280369 _:b22280376 . _:b521494019 . . _:b521494020 . _:b22280369 _:b22280377 . _:b521493770 "3"^^ . . "10.1186%2F1479-5876-11-107" . _:b22280369 _:b22280378 . _:b521493666 . _:b22280369 _:b22280379 . _:b22280369 _:b22280380 . _:b521493781 "3"^^ . _:b521494023 . _:b22280369 _:b22280381 . _:b22280369 _:b22280382 . _:b22280369 _:b22280383 . _:b521494011 . _:b521493780 "3"^^ . _:b521494022 . . . . . _:b521493783 "3"^^ . _:b521494017 . _:b521493782 "3"^^ . _:b521494016 . _:b521493730 . _:b521493777 "3"^^ . _:b521494019 . . . _:b521493776 "3"^^ . _:b521494018 . . _:b521493779 "3"^^ . _:b521494029 . . _:b521493778 "3"^^ . _:b521494028 . . _:b521493789 "3"^^ . _:b521494031 . _:b521493788 "3"^^ . _:b521494030 . . _:b521494057 . _:b521493791 "3"^^ . _:b521494025 . . . _:b521493790 "3"^^ . _:b521494024 . _:b22280360 "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<<,21]." . _:b521493785 "3"^^ . _:b521494027 . . _:b521493784 "3"^^ . _:b521494032 . _:b521494026 . _:b521493787 "3"^^ . _:b521494037 . _:b521493977 . _:b521493882 . _:b521493786 "3"^^ . _:b521494036 . _:b521493750 . . _:b521493797 "3"^^ . _:b521494039 . _:b22280369 _:b22280384 . _:b22280369 _:b22280385 . _:b521494038 . _:b521493796 "3"^^ . _:b22280369 _:b22280386 . _:b22280369 _:b22280387 . _:b22280369 _:b22280388 . _:b22280369 _:b22280389 . _:b521494033 . _:b521493799 "3"^^ . _:b22280369 _:b22280390 . _:b22280369 _:b22280391 . . _:b521493798 "3"^^ . _:b521494032 . _:b521493991 . _:b521493793 "3"^^ . _:b521494035 . _:b521494029 . _:b22280350 . . . _:b521493792 "3"^^ . _:b521494034 . . . _:b521493795 "3"^^ . _:b521494045 . _:b521493794 "3"^^ . _:b521494044 . _:b521493981 . . _:b521493805 "3"^^ . _:b521494047 . _:b521493804 "3"^^ . _:b521494046 . _:b521493807 "3"^^ . _:b521494041 . . . _:b22280392 _:b22280396 . _:b22280392 _:b22280397 . _:b521494040 . _:b521493806 "3"^^ . _:b521493760 . _:b22280392 _:b22280398 . _:b22280392 _:b22280399 . _:b22280392 _:b22280393 . _:b521494043 . _:b521493801 "3"^^ . _:b22280392 _:b22280394 . _:b22280392 _:b22280395 . _:b521493800 "3"^^ . _:b22280388 . _:b521494042 . . . . _:b22280392 _:b22280400 . _:b521493803 "3"^^ . _:b521494053 . . . _:b22280390 . _:b521494052 . _:b521493802 "3"^^ . . . _:b521494064 . _:b521493728 . _:b521494055 . _:b521493813 "3"^^ . . _:b521494054 . _:b521493812 "3"^^ . . . _:b521494049 . _:b521493815 "3"^^ . . . . _:b521494048 . _:b521494028 . _:b521493911 . _:b521493814 "3"^^ . _:b22280398 . _:b521493675 . _:b521493809 "3"^^ . _:b521494051 . _:b521493875 . . _:b521494050 . _:b521493808 "3"^^ . . _:b521493811 "3"^^ . _:b521494061 . _:b521493810 "3"^^ . _:b521494060 . _:b521493653 . _:b521493915 . . _:b521493865 . _:b521493821 "2"^^ . _:b521493777 . _:b521494063 . _:b521493652 . _:b22280348 "background" . _:b521494062 . _:b521493820 "3"^^ . _:b521493655 . _:b521493823 "2"^^ . _:b521493781 . _:b521494057 . _:b521493654 . _:b521493662 . _:b521493822 "2"^^ . _:b521494056 . _:b521493649 . _:b521493840 . _:b521493817 "3"^^ . _:b521494059 . _:b521493648 . _:b521493866 . . _:b521493816 "3"^^ . _:b521494058 . _:b521493651 . . . . _:b521494069 . _:b521493819 "3"^^ . . _:b521493716 . _:b521493770 . _:b521493650 . _:b22280355 "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]\u2013[>>14<<]. 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" . _:b521493818 "3"^^ . _:b521494068 . _:b521493661 . _:b521494086 . _:b521493829 "2"^^ . _:b521494071 . _:b521493660 . _:b521493828 "2"^^ . _:b521494070 . _:b521493663 . _:b521493831 "2"^^ . _:b521494065 . _:b521493662 . . _:b521493830 "2"^^ . _:b521494064 . _:b521493657 . _:b521493825 "2"^^ . _:b521494067 . _:b521493656 . _:b521493658 . _:b521493824 "2"^^ . _:b521494066 . _:b521493659 . _:b521493764 . _:b521493761 . _:b521493699 . _:b521493827 "2"^^ . _:b521493916 . _:b521494077 . _:b521493658 . _:b521493826 "2"^^ . _:b521494076 . _:b521493669 . . . . _:b521493837 "2"^^ . _:b521493900 . _:b521494079 . _:b521493930 . _:b521493668 . . _:b521494061 . _:b521493836 "2"^^ . . _:b521494078 . _:b521493671 . . _:b521493839 "2"^^ . _:b521493738 . _:b521494073 . _:b521493670 . . _:b521493918 . _:b521493838 "2"^^ . _:b521494072 . _:b521493665 . . _:b521493833 "2"^^ . . _:b521494075 . _:b521493664 . _:b521493655 . _:b22280394 "Intracisternal infusions, however, are rarely used in a clinical setting due to their high potential for iatrogenic complications, including traumatic tissue injury [>>17<<]. In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [23,25], spinal anesthetics and post-operative analgesics [35,36], as well as chemotherapeutics [37]. By" . . _:b521493832 "2"^^ . . _:b521493686 . _:b22280398 "In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [23,25], spinal anesthetics and post-operative analgesics [35,>>36<<], as well as chemotherapeutics [37]." . _:b521494074 . _:b521493970 . _:b521493667 . _:b521494065 . _:b521493835 "2"^^ . _:b521494085 . _:b521493666 . . _:b521493834 "2"^^ . _:b521494084 . _:b521493677 . . _:b521493670 . _:b521493845 "2"^^ . _:b22280342 . . _:b521494087 . _:b521494009 . _:b521493927 . _:b521493676 . _:b22280343 . _:b521493799 . _:b22280364 "and digital subtraction myelography to diagnose dural leaks associated with SIH, pseudomeningocele, and superficial siderosis [22,23], as well as the integrity of the spinal cord in the setting of injury or tumor [>>24<<,25]. 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" . _:b521493844 "2"^^ . . _:b521494086 . _:b521493679 . _:b521493847 "2"^^ . . _:b521494081 . _:b521493678 . . _:b521493959 . _:b521493846 "2"^^ . _:b521493706 . _:b521494080 . _:b521493673 . _:b521493898 . _:b521493710 . _:b521493841 "2"^^ . _:b521494083 . _:b521493672 . _:b521493840 "2"^^ . _:b521494082 . _:b521493675 . _:b22280348 . _:b521493843 "2"^^ . _:b521494093 . _:b521493674 . _:b22280349 . _:b521493842 "2"^^ . . _:b521494092 . _:b521493685 . . . _:b22280350 . _:b521493853 "2"^^ . _:b22280350 . _:b521494095 . _:b521493684 . _:b22280351 . _:b521493852 "2"^^ . _:b521494094 . _:b521493687 . _:b22280344 . _:b521493855 "2"^^ . _:b521494089 . _:b521493686 . _:b22280345 . . _:b521493854 "2"^^ . . _:b521494088 . _:b521493681 . . _:b22280346 . _:b521493849 "2"^^ . _:b521494091 . _:b521493680 . . . _:b22280347 . _:b22280349 "Neurodegenerative disorders such as Alzheimer\u2019s disease (AD) are characterized by progressive loss of neurons, sensory and motor impairments, and severe cognitive decline [>>1<<]. Extracellular depositions of amyloid \u03B2 (A\u03B2) peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [2-4], while analogous misfolded proteins aggregate in" . _:b521493848 "2"^^ . _:b521494090 . _:b521493683 . . . _:b22280356 . . _:b521493851 "2"^^ . _:b521493682 . . _:b22280357 . _:b521493850 "2"^^ . _:b521493693 . _:b22280358 . . _:b521493861 "2"^^ . . _:b521493692 . _:b521494040 . _:b521493864 . _:b22280359 . _:b521493860 "2"^^ . _:b521493794 . _:b521493695 . _:b22280352 . _:b521493863 "2"^^ . _:b521493694 . _:b521494027 . _:b22280353 . _:b521493862 "2"^^ . _:b521494067 . _:b521493689 . . _:b22280354 . _:b521493726 . _:b521493857 "2"^^ . _:b521493796 . . _:b521493688 . _:b22280355 . _:b521493856 "2"^^ . . _:b521493691 . _:b22280364 . _:b521493859 "2"^^ . _:b521493771 . _:b521493690 . _:b521493678 . _:b22280365 . _:b521493858 "2"^^ . . _:b521493701 . _:b22280366 . _:b521493869 "2"^^ . _:b521493700 . _:b22280377 "Alternatively, this may reflect the lower levels of CSF tracer penetration into the subcortical white matter observed in our prior study [>>16<<]." . _:b22280367 . _:b521493868 "2"^^ . . _:b521493703 . . _:b22280360 . _:b521493871 "2"^^ . _:b521493702 . _:b22280361 . . _:b521493870 "2"^^ . _:b521493697 . . _:b22280362 . . _:b521493865 "2"^^ . _:b521493696 . . _:b521493729 . _:b521493908 . _:b22280363 . _:b521493864 "2"^^ . _:b521493699 . _:b22280372 . _:b521493867 "2"^^ . _:b22280345 . _:b521493919 . _:b521493698 . . _:b22280373 . _:b521493866 "2"^^ . _:b22280344 . _:b521494083 . _:b521493709 . _:b22280374 . _:b521493877 "2"^^ . _:b521494005 . _:b521493708 . _:b22280375 . _:b521493876 "2"^^ . _:b22280378 "Second, the prevailing direction of CSF bulk flow within the spinal subarachnoid is rostral-to-caudal [>>28<<], suggesting that during infusion, CSF tracer must traverse the intervening distance against the bulk CSF flow generated from CSF secretion in the cerebral ventricles." . _:b521493711 . _:b521494050 . _:b22280368 . _:b521493878 . _:b521493879 "2"^^ . _:b521494055 . _:b521493710 . . _:b22280369 . _:b521493878 "2"^^ . _:b521493705 . . _:b22280370 . _:b521493873 "2"^^ . _:b521493704 . . _:b22280371 . _:b521493872 "2"^^ . _:b521494094 . _:b521493707 . _:b22280380 . _:b521493875 "2"^^ . . _:b521493706 . _:b22280381 . _:b521493874 "2"^^ . _:b521493717 . _:b22280382 . . _:b521493885 "2"^^ . _:b22280379 "This difference is most likely the result of CSF reabsorption that occurs along the spinal column via the peripheral nerve roots [>>29<<], or perhaps subarachnoid CSF diversion along spinal cord perivascular routes and into the central canal, as has been reported following lumbar intrathecal infusion of horseradish peroxidase [30]." . _:b521493716 . _:b22280383 . . _:b521493884 "2"^^ . . . _:b521493906 . _:b521493719 . _:b22280376 . _:b521493887 "2"^^ . _:b521493718 . . _:b22280377 . _:b521493886 "2"^^ . _:b521493713 . _:b22280378 . _:b521493881 "2"^^ . . _:b521493712 . _:b22280379 . _:b521493880 "2"^^ . _:b521493931 . _:b521493715 . . _:b22280388 . _:b521493883 "2"^^ . . _:b521493714 . _:b22280389 . _:b521493882 "2"^^ . _:b521493974 . . _:b521493725 . . _:b22280390 . _:b521493893 "2"^^ . . _:b521493809 . _:b521493724 . _:b521494030 . _:b22280391 . _:b521493892 "2"^^ . _:b521493727 . _:b22280384 . _:b521493895 "2"^^ . _:b521493726 . _:b22280385 . _:b521493894 "2"^^ . . _:b521493721 . _:b22280386 . _:b521493757 . _:b521493889 "2"^^ . _:b521493964 . _:b521493720 . _:b521493818 . _:b22280387 . _:b521493888 "2"^^ . _:b521493723 . _:b521493660 . _:b521493962 . _:b22280396 . _:b521493891 "2"^^ . _:b521493722 . _:b22280397 . _:b521493656 . _:b521493890 "2"^^ . _:b521493785 . _:b521493733 . _:b22280398 . _:b521493901 "2"^^ . _:b521493732 . _:b22280399 . _:b521493900 "2"^^ . _:b521493901 . _:b521493879 . _:b521493735 . . _:b22280392 . _:b521493903 "2"^^ . _:b521493734 . _:b22280393 . _:b521493867 . _:b521493902 "2"^^ . _:b521493729 . . _:b22280394 . _:b521493897 "2"^^ . _:b521493728 . _:b22280395 . _:b521493872 . _:b521494082 . _:b521493896 "2"^^ . _:b521493731 . . _:b521493899 "2"^^ . . _:b521493730 . _:b521494095 . _:b521493807 . _:b22280376 . _:b521493898 "2"^^ . . _:b521494075 . _:b521493648 . . _:b521493741 . _:b521493909 "2"^^ . _:b521493740 . . _:b521493876 . _:b521493758 . _:b22280382 . _:b521493908 "2"^^ . _:b521494018 . _:b521493743 . _:b22280400 . _:b521493911 "2"^^ . _:b521493742 . _:b521493910 "2"^^ . _:b521493737 . _:b521493905 "2"^^ . _:b22280371 . _:b521493736 . _:b521493904 "2"^^ . _:b22280356 "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,>>16<<]. The continuous circulation of CSF along this pathway facilitates the clearance of extracellular solutes, including soluble A\u03B2, from the brain." . _:b22280380 "column via the peripheral nerve roots [29], or perhaps subarachnoid CSF diversion along spinal cord perivascular routes and into the central canal, as has been reported following lumbar intrathecal infusion of horseradish peroxidase [>>30<<]. As CSF tracer is infused into the lumbar subarachnoid space and moves rostrally towards the brain, a portion will be deposited along each vertebral segment along the natural CSF clearance pathway, resulting a reduced delivery of tracer" . _:b521493739 . . _:b521493907 "2"^^ . _:b521493700 . _:b521493738 . _:b521493906 "2"^^ . _:b22280368 . . _:b521493755 . _:b521493749 . _:b521494081 . _:b521493917 "2"^^ . _:b521493748 . . . _:b521493916 "2"^^ . . _:b521493751 . _:b521493834 . _:b521493881 . _:b521493896 . . _:b22280373 . _:b521493919 "2"^^ . . _:b521493750 . _:b521493918 "2"^^ . _:b521493745 . _:b22280361 . _:b521493913 "2"^^ . _:b521493744 . _:b521493855 . _:b521493912 "2"^^ . _:b521493747 . _:b521493915 "2"^^ . . _:b521493746 . _:b521493914 "2"^^ . _:b22280360 . _:b521493757 . _:b521493925 "2"^^ . . _:b521493756 . . _:b521493944 . _:b521493924 "2"^^ . . _:b521493759 . _:b22280357 "We termed this brain-wide pathway the \u2018glymphatic system\u2019, 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 A\u03B2 clearance in the pre-clinical stages of AD, while a method to measure glymphatic pathway function in clinical" . _:b521493927 "2"^^ . _:b521493814 . _:b521493758 . _:b521493926 "2"^^ . _:b521493753 . _:b521493892 . _:b521493663 . . _:b521493921 "2"^^ . _:b521493935 . _:b521493752 . _:b521493920 "2"^^ . _:b22280351 "tangles are believed to contribute to the pathophysiology of AD [2-4], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington\u2019s disease and amyotrophic lateral sclerosis (ALS) [>>5<<-7]. In the case of AD, it is widely believed that amyloid deposition results from an age-related failure of soluble A\u03B2 clearance from the brain [8]." . _:b521494058 . _:b521493755 . _:b521493923 "2"^^ . _:b521493754 . _:b521493922 "2"^^ . _:b521493933 "2"^^ . _:b521493932 "2"^^ . . . _:b521493935 "2"^^ . _:b521493988 . _:b521493934 "2"^^ . _:b521494087 . _:b521493721 . _:b521493929 "2"^^ . _:b521494091 . _:b521493858 . _:b521493928 "2"^^ . _:b521493931 "2"^^ . . _:b521493930 "2"^^ . _:b521493913 . _:b521493941 "2"^^ . . _:b521493940 "2"^^ . _:b521493828 . _:b521493943 "2"^^ . _:b22280363 . _:b521493942 "2"^^ . . . _:b521493937 "2"^^ . _:b22280382 "deposited along each vertebral segment along the natural CSF clearance pathway, resulting a reduced delivery of tracer to the distant cisternal spaces surrounding the brain which form the entrance to the brain-wide glymphatic system [16,>>20<<]. Despite these differences in influx magnitude and kinetics, tracer distribution after lumbar and intracisternal infusion followed a similar pattern and encompassed the entire brain parenchyma (compare Figure 2B,E and Figure 3A)." . _:b521493936 "2"^^ . _:b521493877 . _:b521494084 . _:b521493939 "2"^^ . . _:b521493992 . . _:b521493938 "2"^^ . _:b521493953 . _:b521493949 "2"^^ . . . . _:b521493948 "2"^^ . . _:b22280385 . _:b521493951 "2"^^ . _:b521493950 "2"^^ . . _:b521493773 . _:b521493945 "2"^^ . . _:b521493676 . _:b521493944 "2"^^ . _:b521493654 . _:b521493739 . _:b22280372 "Intracisternal CSF tracer infusions were carried out in a parallel group of animals to provide a direct comparison to the infusion route used previously [>>16<<,20]." . . _:b22280393 . _:b521493947 "2"^^ . . _:b521493925 . _:b521493946 "2"^^ . _:b521493957 "2"^^ . _:b521493956 "2"^^ . . _:b521494035 . _:b521493959 "2"^^ . _:b521494059 . _:b521493958 "2"^^ . _:b521494049 . _:b521493953 "2"^^ . _:b521493775 . _:b521494090 . _:b521493952 "2"^^ . _:b521493905 . . . . . _:b521494002 . _:b521493955 "2"^^ . . _:b521493954 "2"^^ . _:b22280392 . _:b521493965 "2"^^ . . _:b521493964 "2"^^ . . _:b22280369 . _:b521493967 "2"^^ . . _:b22280380 . _:b521493966 "2"^^ . _:b521493871 . _:b521493961 "2"^^ . _:b521493720 . _:b521493837 . . _:b521493960 "2"^^ . _:b521494003 . _:b521493778 . _:b521493963 "2"^^ . _:b521494025 . _:b521493922 . _:b521493962 "2"^^ . _:b521493711 . . _:b521493973 "2"^^ . _:b521493924 . _:b22280342 . _:b521493972 "2"^^ . . _:b521493975 "2"^^ . _:b521493907 . . _:b22280348 . _:b22280396 "In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [23,>>25<<], spinal anesthetics and post-operative analgesics [35,36], as well as chemotherapeutics [37]." . . _:b521493974 "2"^^ . _:b521493806 . . . _:b521493969 "2"^^ . _:b521493980 . _:b521493968 "2"^^ . . _:b521493971 "2"^^ . _:b521493957 . _:b521493970 "2"^^ . . _:b521493981 "2"^^ . . _:b521493657 . _:b521493980 "2"^^ . . _:b22280350 "Extracellular depositions of amyloid \u03B2 (A\u03B2) peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [>>2<<-4], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington\u2019s disease and amyotrophic lateral sclerosis (ALS) [5-7]." . _:b521493914 . _:b521493983 "2"^^ . . _:b521493888 . _:b521493982 "2"^^ . . _:b521493977 "2"^^ . _:b521493743 . _:b521493976 "2"^^ . _:b521493982 . _:b521493798 . _:b22280397 "In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [23,25], spinal anesthetics and post-operative analgesics [>>35<<,36], as well as chemotherapeutics [37]." . _:b521493979 "2"^^ . . _:b521493978 "2"^^ . _:b521493989 "2"^^ . . _:b521493833 . _:b521493988 "2"^^ . _:b521493991 "2"^^ . _:b521493990 "2"^^ . . _:b521493985 "2"^^ . _:b521493709 . _:b521493848 . _:b521493984 "2"^^ . _:b521493987 "2"^^ . . _:b22280395 "In contrast, the lumbar intrathecal delivery route is routinely employed for administration of contrast for CT-myelography [>>23<<,25], spinal anesthetics and post-operative analgesics [35,36], as well as chemotherapeutics [37]." . _:b521493986 "2"^^ . _:b521493823 . _:b521493997 "2"^^ . . _:b521493996 "2"^^ . . . _:b521493999 "2"^^ . . . _:b22280376 "with MRI findings in the rat in which glymphatic fluxes along anterior penetrating arteries were both faster and greater in magnitude than those that followed branches of mediolateral arteries such as the middle cerebral artery [>>20<<]. In both the anterior and posterior brain, TR-d3 fluorescence intensity in the white matter was significantly lower than the cortex at all time points (Figure 2H,J; ##P\u2009<\u20090.01 vs." . _:b521493998 "2"^^ . _:b521493993 "2"^^ . . . _:b521493774 . . _:b521493952 . _:b521493992 "2"^^ . _:b521493995 "2"^^ . . _:b521493688 . _:b521493994 "2"^^ . _:b521493963 . _:b521493724 . _:b521494005 "2"^^ . _:b22280352 . . _:b521493920 . _:b521494004 "2"^^ . . _:b521494007 "2"^^ . _:b521493942 . _:b521493780 . _:b521494006 "2"^^ . _:b521494001 "2"^^ . _:b521493695 . _:b521494000 "2"^^ . _:b521494033 . . _:b521494003 "2"^^ . . _:b521493772 . _:b521493765 . . _:b521494002 "2"^^ . _:b521493712 . . _:b521494066 . . _:b521493932 . _:b521494013 "2"^^ . _:b521494012 "2"^^ . _:b22280378 . _:b521493824 . _:b521494015 "2"^^ . _:b521493863 . . _:b521494014 "2"^^ . _:b521494009 "2"^^ . _:b521493745 . _:b521494008 "2"^^ . _:b521493693 . . . _:b521494011 "2"^^ . . _:b521494010 "2"^^ . . . . _:b521493715 . _:b521493707 . _:b521493802 . . _:b521493822 . . _:b521493691 . . _:b521493733 . . . . _:b521493652 . . _:b521493719 . _:b521493717 . . _:b521493910 . . _:b521493827 . _:b521494022 . _:b521494023 . . . . . _:b521493956 . . _:b521493765 . "PMC0" . _:b521493659 . _:b521493903 . _:b521493764 . _:b521493689 . _:b521493767 . . _:b521493766 . _:b521494089 . _:b521493761 . _:b521493665 . _:b521494004 . _:b22280395 . _:b521493760 . _:b521493923 . _:b521493788 . _:b521493763 . . _:b521493870 . _:b521493762 . . _:b521493773 . . _:b521493772 . _:b521493674 . . _:b521493775 . _:b521494071 . _:b521493774 . _:b521493708 . _:b521493769 . _:b521493768 . _:b521493847 . _:b521493951 . _:b521494063 . . _:b521493771 . . . . _:b521494076 . _:b521493770 . _:b521493781 . _:b521493801 . _:b521494046 . _:b22280392 "conclusion" . _:b22280353 . _:b521493779 . _:b521493780 . . _:b521493783 . . _:b521493782 . . . _:b521493777 . _:b521493947 . _:b521493776 . _:b22280351 . _:b22280389 . _:b521493779 . _:b521493778 . _:b521494015 . _:b521493789 . _:b22280389 "study, astrocytic endfoot processes completely cover the cerebral microcirculation; the only routes between the perivascular spaces and the wider brain interstitium being through ~20\u00A0nm clefts between overlapping astroglial endfeet [>>33<<]. We surmised that the perivascular astrocytic endfeet acted as a sieve to restrict the movement of large solutes from the perivascular spaces into the brain interstitium [16]." . _:b521493788 . . _:b521493971 . _:b521493862 . _:b521493791 . _:b521493790 . . . _:b521493940 . _:b521493785 . _:b521493961 . . . _:b521493762 . _:b521493784 . _:b521494006 . . _:b521493830 . _:b521493787 . . . . . _:b521493650 . _:b521493786 . _:b521493747 . _:b521493797 . _:b22280400 . _:b521494080 . . _:b521493796 . _:b521493857 . _:b521493799 . _:b521493998 . _:b521494062 . . . _:b521493718 . _:b22280364 . _:b521493798 . _:b521494056 . _:b521493793 . _:b521493792 . _:b22280399 . _:b521493795 . _:b521494037 . _:b22280379 . _:b521493727 . _:b521494014 . _:b521493794 . . _:b22280353 "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 A\u03B2 clearance efficiency to be directly measured in real time." . . _:b521493805 . _:b521493852 . _:b521493804 . _:b521493651 . . _:b521494041 . _:b521493732 . _:b521493807 . . _:b521493806 . _:b521493756 . _:b521493801 . _:b521493821 . _:b521493800 . . . . _:b521493803 . _:b521493889 . _:b22280371 "2-photon in vivo imaging in mice and dynamic contrast-enhanced MRI in rats were used to demonstrate the existence of a brain-wide perivascular route, termed the \u2018glymphatic pathway\u2019, that permits CSF to exchange with the brain ISF [16,>>20<<]. CSF-ISF exchange along these perivascular pathways was supported by astroglial aquaporin-4 water channels and the movement of fluid through this pathway facilitated the clearance of interstitial solutes, including soluble A\u03B2, from the" . _:b521493802 . . _:b521493813 . . _:b521494017 . _:b521493812 . _:b521493815 . _:b521493740 . _:b521493814 . _:b521493809 . _:b521493808 . _:b521494008 . _:b521493811 . . _:b521493810 . _:b521493817 . . _:b521493946 . _:b521493821 . _:b521493928 . _:b521493820 . _:b22280366 . _:b521493823 . _:b521493822 . _:b521493817 . _:b521493836 . _:b521493741 . _:b521493816 . . . . _:b521493819 . . . _:b521493818 . _:b521493767 . _:b521493829 . _:b22280359 "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,>>19<<]. These approaches permit time-sequenced three-dimensional (3D) representation of the brain with high spatial and temporal resolution of tracer distribution." . _:b521493880 . _:b521493754 . _:b521493828 . _:b521493763 . _:b521493831 . _:b22280369 "results and discussion" . _:b521493830 . _:b521493682 . _:b521493713 . . . _:b521493825 . _:b521493884 . . _:b521493824 . . . _:b521493827 . . _:b521493860 . _:b521493826 . _:b521493787 . _:b521493941 . _:b521493837 . _:b521493736 . _:b22280358 "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" . _:b521493836 . _:b521493929 . _:b521493839 . . . . _:b521493838 . . _:b521493833 . . . _:b521493792 . _:b521493832 .