Figure 1

Kinetic model of neurodegeneration, time course of risk (intraocular pressure) and MRI-based neurodegeneration in glaucomatous animals. (A) Four putative kinetic models of neurodegeneration: 1) constant-rate model (blue straight line with x-axis of time after the onset of disease), 2) constant-risk model (red exponential line with x-axis of time), 3) variable-risk model (red exponential line with x-axis of cumulative risk), and 4) heterogeneity (+variable risk) model (green stretched exponential decay line with x-axis of cumulative risk). (B) Time courses of intraocular pressure (IOP) in animals with glaucoma. Closed point and thick line, the glaucomatous eye (G); open point and dashed line, control (contralateral side) eye. (C). The shapes of the points specify each of the animals: animal #1 (▲△); #2 (∎□); #3 (⋄♦); #4 (▼∇); and #5 (●○). (C) Time course of quantitative values of fractional anisotropy (FA) in the optic nerves of glaucomatous eye (G-ON), control (C-ON, contralateral side), and in those in normal animals (N-ON). Constant-rate model and constant-risk model are also fit to the G-ON data. See also Table 1. (D) A plot of quantitative FA values (in y-axis) across cumulative risk (∫r(t)dt, in Eq. 2) in the variable-risk model (solid line). (E) Time course of relative FA values (rFA) in the glaucomatous optic nerve expressed as a ratio to the control optic nerve (G) and a ratio, left-to-right, in normal animals (N). Constant-rate and constant-risk models are also fit to the ratio of G. (F) A plot of rFA values in the glaucomatous optic nerve (y-axis) and cumulative risk (x-axis) in glaucomatous animals (G) and normal animals (N). The glaucomatous FA values are fit by the variable-risk model (solid line: fitted curve). (G) A plot of predicted neurodegeneration (line) and actual rFA values (points) in each animal of #1-5. The prediction of rFA were calculated based on the initial value (N ₀ =1) and optimized values (r ₀ = 0.0019, β = 0.057) in the variable-risk model. (H) Results of the voxel-based analysis of FA images with cumulative IOP as a regressor. A significant cluster (P < 0.05, corrected for multiple comparison) is shown in blue. ON, optic nerve; OT, optic tract; and OR, optic radiation. See Additional file 2: Table S2 for a list of all significant regions.