Reduced Cerebrospinal Fluid Inflow to the Optic Nerve in Glaucoma

Author(s): Mathieu E (1,2,3), Gupta N (1,2,3,4,5), Paczka-Giorgi LA (1,2), Zhou X (1,2), Ahari A (1,2), Lani R (1), Hanna J (1,2,3), Yücel YH (1,2,3,6,7,8)

1 Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
2 Department of Ophthalmology and Vision Sciences, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
3 Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
4 Glaucoma Unit, St. Michael's Hospital, Toronto, Ontario, Canada.
5 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
6 Department of Physics, Faculty of Science, Ryerson University, Toronto, Ontario, Canada.
7 Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario, Canada.
8 Institute of Biomedical Engineering, Science and Technology (iBEST), St. Michael's Hospital, Ryerson University, Toronto, Ontario, Canada.

Purpose: To determine whether cerebrospinal fluid (CSF) entry into the optic nerve is altered in glaucoma.

Methods: Fluorescent 10-kDa dextran tracer was injected into the CSF of 2-month-old (n = 9) and 10-month-old DBA/2J glaucoma mice (n = 8) and age-matched controls (C57Bl/6; n = 8 each group). Intraocular pressure (IOP) was measured in all mice before tracer injection into CSF. Tracer distribution was assessed using confocal microscopy of optic nerve cross-sections of mice killed 1 hour after injection. Paravascular tracer distribution in the optic nerve was studied in relation to isolectin-stained blood vessels. Tracer intensity and cross-sectional area in the laminar optic nerve were quantitatively assessed in all four groups and statistically compared. Aquaporin 4 (AQP4) and retinal ganglion cell axonal phosphorylated neurofilament (pNF) were evaluated using immunofluorescence and confocal microscopy.

Results: IOP was elevated in 10-month-old glaucoma mice compared with age-matched controls. One hour after tracer injection, controls showed abundant CSF tracer in the optic nerve subarachnoid space and within the nerve in paravascular spaces surrounding isolectin-labeled blood vessels. CSF tracer intensity and signal distribution in the optic nerve were significantly decreased in 10-month-old glaucoma mice compared with age-matched controls (P = 0.0008 and P = 0.0033, respectively). AQP4 immunoreactivity was similar in 10-month-old DBA and age-matched control mice. Half of the 10-month-old DBA mice (n = 4/8) showed a decrease in pNF immunoreactivity compared to controls. Altered pNF staining was seen only in DBA mice lacking CSF tracer at the laminar optic nerve (n = 4/5).

Conclusions: This study provides the first evidence that CSF entry into the optic nerve is impaired in glaucoma. This finding points to a novel CSF-related mechanism that may help to understand optic nerve damage in glaucoma.

Invest Ophthalmol Vis Sci. 2018 Dec 3;59(15):5876-5884. doi: 10.1167/iovs.18-24521.

http://www.ncbi.nlm.nih.gov/pubmed/30543343

Experimental Paper of the Month manager: Andreas Boehm