[New insights into the pathogenesis of glaucomatous optic neuropathy and refinement of the objective assessment of its functional damage].

Glaucomatous optic neuropathy is a primary pathological condition responsible for visual dysfunction due to glaucoma. However, how intraocular pressure and other risk factors lead to glaucomatous optic neuropathy is not fully understood. Given that static or kinetic visual field tests for evaluating visual dysfunction in glaucomatous optic neuropathy are a subjective assessments based on a psychophysical principle, the development of a tool for objective assessment of the visual field is needed. In this study, we attempt to elucidate the pathophysiology of glaucomatous optic neuropathy and to refine a modality for the objective assessment of the visual dysfunction due to it. Aquaporin (AQP) water channels are located primarily in the plasma membrane. These proteins form either a homo- or hetero-tetramer and allow water to cross the plasma membrane bi-directionally. The transmembrane water movement through AQPs is critically involved in the maintenance of normal neuronal activity. Among the 13 isoforms indentified so far, AQP-4 is known to be expressed in the retrobulbar portion of the optic nerve. However, the optic nerve head, the primary pathological site of glaucomatous optic neuropathy, reportedly does not express AQP-4. We found that in control rats, astrocytes throughout the optic nerve express AQP-9. The chronic elevation of intraocular pressure due to cauterization of three episcleral veins substantially reduced both gene expression and immunoreactivity of AQP-9, whereas it did not change the AQP-4 gene or protein expression in the retrobulbar portion of the optic nerve. These findings are implicated in the chronic elevation of intraocular pressure in astrocytes. Similar findings were also observed in the eyes of a monkey with angle-laser-induced ocular hypertension and of a human with primary open-angle glaucoma. AQP-9 was also expressed in the cell bodies of retinal ganglion cells in control rats and its expression was significantly reduced in the eyes of rats with ocular hypertension. Recently, the astrocyte-to-neuron lactate shuttle hypothesis has been proposed. This hypothesis suggests that lactate generated by glucose during glycolysis in astrocytes is used by neurons as an energy substrate. Given that AQP-9 belongs to an aquaglyceroporin subfamily and allows solutes other than water (e.g., lactate) to cross the plasma membrane, chronic ocular hypertension may perturb this physiological passage of lactate. Thus, lactate as the energy substrate may be unable to be transported from astrocytes to retinal ganglion cells at the cell bodies and axons due to the reduction of AQP-9 expression by astrocytes at the optic nerve head and retinal ganglion cells. The multifocal visual evoked potential (mfVEP) is an objective visual field test, which enables the recording of cortical potential corresponding to 60 local retinal areas simultaneously. Evidence is accumulating that the signal-to-noise ratio (SNR) has been enhanced by recording mfVEPs from multiple channels at the same time. However, previous studies evaluated the mfVEPs mostly in Caucasians. It has not yet been proven whether this strategy is applicable to Japanese people who have a skull frame that may be different from that of Caucasians. We calculated the relative position of the calcarine landmark for electrode placement during the mfVEP recording, from brain MRI images of 200 individuals, which were found to be 1 cm lower than those reported in Caucasians with a statistical significance. Then, we recorded mfVEPs from 110 normal controls using three channels and conducted receiver-operating characteristic (ROC) curve analysis of the overlap of SNR distribution at signal and noise windows. We found that a combination of one horizontal channel straddling the inion with either one of the two perpendicular vertical channels yielded the largest area under the ROC curve (AUC). Next, we showed that the SNR-AUC exhibited a similar diagnostic performance to, and a significant correlation with, a total deviation of the Humphrey visual field in 56 eyes with mild to moderate glaucomatous damage, which exhibited a mean deviation of -15 dB or less, and in 62 control eyes. In contrast, a topographical agreement in defining abnormal locations based on probability plots between the Humphrey visual field and mfVEP testing was moderate. The SNR-AUC may be used as a global index, analogous to the mean deviation of the Humphrey visual field, to quantify diffuse functional loss due to glaucomatous optic neuropathy, in contrast to the previously proposed cluster analysis of the mfVEP probability plots, which is a strategy more suitable to diagnosing local sensitivity loss.