Glaucoma progression associated with altered cerebral spinal fluid levels of amyloid beta and tau proteins

Several studies have revealed links between Alzheimer’s disease (AD) and glaucoma. This report describes a glaucoma patient with medically controlled intraocular pressure (IOP) who experienced disease progression concomitantly with the onset of mild cognitive impairment (MCI) and positivity for cerebral spinal fluid (CSF) markers of AD. In 2005 a 69-year-old man presented with reduced visual acuity in the left eye. He had no history of hypertension, diabetes, cerebrovascular problems or cognitive impairment, but the family history was positive for glaucoma. Best-corrected visual acuity in the right eye was 0.1 logMAR; the left eye could barely perceive light. IOPs were 25 mmHg (right eye) and 28 mmHg (left eye). Exam of the anterior chamber with the gonioscopic lens revealed an open irodocorneal angle. Visual field testing (Humphrey sita standard 30–2) of the right eye revealed stage 4 glaucoma (Brusini Glaucoma Staging System 2, GSS2) (Fig. 1). The optic nerve head of the right eye presented advanced cupping with total loss of superior, inferior and temporal disc tissue and with nasal displacement of the blood vessels (Fig. 2a). In the left eye, all the neural rim was destroyed, and the optic nerve head appeared white and deeply excavated (Fig. 2b). Advanced open-angle glaucoma was diagnosed and treatment started with timolol 0.5% BID and travoprost (both eyes). Follow-up visits every 6 months for 4 years revealed IOPs < 16 mmHg and no change in the visual fields. Between February and October 2009, he developed progressive visual loss in the right eye (0.7 logMAR), and worsening of the visual field to GSS2 stage 5 (Fig. 1) although the IOP was 14 mmHg. Because his wife reported concomitant onset of memory deficits, the Mental Deterioration Battery was performed and MCI was diagnosed. Routine blood work including B12 and folate levels, screening for vasculitis (erythrocyte sedimentation rate (ESR), C-reactive protein, antinuclear antibodies, rheumatoid factor) and syphilis serology were normal. Blood pressure monitoring for episodes of systemic hypotension, electrocardiogram and epiaortic ultrasonography were also unremarcable. Magnetic resonance imaging with gadolinium found normal-appearing visual pathways. CSF markers of neurodegenerative dementia were assessed with commercial ELISAs (Innogenetics, Ghent, Belgium). The results were consistent with AD: decreased amyloid beta (Ab)1–42 (226 pg/mL) and elevated levels of total and phosphorylated tau (t-tau and p-tau) (655 and 105 pg/mL, respectively). An increased incidence of primary open-angle glaucoma has been reported among AD patients, and a Japanese population study found that almost all such cases are the normal-tension form, which suggests the involvement of causative factors unrelated to IOP. Glaucoma also seems to progress more rapidly in AD patients than in other groups. In addition, in rats with experimental ocular hypertension, activation of caspase 3 in the retinal ganglion cells has been shown to cause cleavages of the amyloid precursor protein that generate Ab and other neurotoxic species. This is consistent with reports that blocking the effects of Ab prevents retinal ganglion cell apoptosis. Recent evidence indicates that altered CSF circulatory dynamics can reduce the clearance of both Ab and tau, and decreased Ab and increased tand p-tau levels in the CSF have been shown to predict progression from cognitive normality to MCI or AD-type dementia and from MCI to AD. Cut-off values were 550 (95% CI 531–570) ng/L for Ab, 375 (325–405) ng/L for t-tau and 52 (48–56) ng/L for p-tau. Our experience with the patient described here suggests that in advanced glaucoma, the onset of cognitive impairment may be associated with progression to end-stage glaucoma, regardless of IOP levels. Apart from predicting imminent dementia, the altered CSF levels of Ab and tau proteins observed in this case might also reflect increased risk for progression of glaucoma to the stage of visual loss. It is also possible that altered CSF circulatory dynamics in this case reduced neurotoxin clearance along optic nerves in the subarachnoid space and that deposits/aggregates of tau and/or other toxic molecules may have contributed to the glaucoma progression (see Killer et al. 2008). This seems to be the first report of severe glaucoma progression associated with CSF alterations indicative of AD, and it requires confirmation in large studies.