By Marc Dinkin, MD
Director of Neuro-Ophthalmology; Associate Professor, Departments of Ophthalmology and Neurology, Weill Cornell Medical College
Dr. Dinkin reports he is a consultant for Serenity Medical, Inc.
Optical coherence tomography (OCT) is an innovative imaging device that measures thickness of retinal nerve fiber layers and ganglion cells. Thinning of these layers is associated with current and future risk of dementia.
Mutlu U, Colijn JM, Ikram MA, et al. Association of retinal neurodegeneration on optical coherence tomography with dementia: A population based study. JAMA Neurol 2018; Jun 25. doi:10.1001/jamaneurol.2018.1563. [Epub ahead of print].
Ko F, Muthy ZA, Gallacher J, et al. Association of retinal nerve fiber layer thinning with current and future cognitive decline. A study using optical coherence tomography. JAMA Neurol 2018; Jun 25. doi:10.1001/jamaneurol.2018.1578. [Epub ahead of print].
Over the last two decades, a growing body of evidence has demonstrated thinning of certain retinal layers in association with Alzheimer’s disease (AD) and dementia. Optical coherence tomography (OCT) uses low coherent light much like an ultrasound to visualize the retina in three dimensions with a resolution of < 10 microns, allowing analysis of each segmented layer. Using this technology, the retinal nerve fiber layer (RNFL), which contains the fibers of the optic nerve as they course along the inner retina, and the ganglion cell layer (GCL), which contains their parent neurons, both have been found to be thinner in AD patients than controls. These observations have been complimented by pathological studies that have demonstrated the presence of amyloid plaques in retinas of AD patients, suggesting that the disease directly affects retinal neurons. However, it has remained unclear as to whether such changes in the retina would precede the onset of clinical symptoms, thus providing a screening tool that would allow identification of patients for early interventions and treatment trials.
This question was addressed by two recent studies in JAMA Neurology. In the first, Mutlu and colleagues prospectively followed patients older than 45 years of age from the Rotterdam study with spectral OCT between 2007-2012, and evaluated them for dementia using the Mini-Mental State Examination and Geriatric Mental State Organic Level at baseline and subsequent visits. The authors found that GCL thickness, but not RNFL thickness, was associated with the prevalence of dementia at baseline. However, RNFL thickness at baseline, but not GCL thickness, was associated with the risk of developing dementia or AD over the course of the study.
In a second study, Ko and colleagues analyzed cognitive function prospectively in a British cohort of 32,038 patients between 2009 and 2013, and found an association between RNFL thinning at baseline and future cognitive impairment. Specifically, those within the lowest quintile for RNFL thickness at baseline were 11% more likely to fail at least one of four cognitive tests at baseline, while those within the lower two quintiles were twice as likely to fail one of the cognitive tests during the follow-up period.
COMMENTARY
Together, these two studies provide evidence that RNFL thickness in older adults, in the absence of any other ocular or neurological disease, can help predict one’s risk of future cognitive decline, dementia, and AD. It remains unclear as to whether the observed atrophy is due to direct damage by AD to the retina and optic nerve or is simply a consequence of retrograde trans-synaptic degeneration (RTSD), a phenomenon of secondary atrophy of pregeniculate visual pathways due to post-geniculate degeneration that only recently has been shown to occur in adults. A subanalysis of those patients in the studies who later developed posterior cortical atrophy could address this: If the degree of RNFL thinning is greater in these patients, a contribution by RTSD would be suggested, since post-geniculate pathways are affected predominantly in those patients.
Regardless of the exact mechanism of retinal atrophy, the data suggest that GCL thinning is a better biomarker for current dementia, while RNFL thinning is superior as a predictor of future dementia. Of course, the lack of association of RNFL with prevalent dementia in this study is curious, since it is apparently already thinned prior to clinical symptoms, but this finding may reflect the fact that patients with dementia are older than those in the preclinical stage, and age-matched controls might have thinner RNFL for other age-related reasons.
As a practical matter, it would be challenging to use RNFL assessment to predict risk of AD, given the number of relatively common conditions that can affect it, including glaucoma, high myopia, congenital optic anomalies, and a long list of retinal and neurological conditions. Nevertheless, these findings suggest that once such confounding conditions are excluded, RNFL thickness, in association with other biomarkers, may allow identification of those at greater risk of dementia, thus permitting therapeutic intervention to slow down or arrest its course.
