Characterization of Inner Retinal Hyperreflective Alterations in Early Cognitive Impairment on Adaptive Optics Scanning Laser Ophthalmoscopy

Abstract

PURPOSE. To examine inner retinal hyperreflective features on adaptive optics scanning laser ophthalmoscopy (AOSLO) in individuals with early cognitive impairment. METHODS. In this prospective, cross-sectional study, we enrolled 12 participants with either amnestic mild cognitive impairment (aMCI, n ¼ 10) or early dementia due to Alzheimer's disease (eAD, n ¼ 2) and 12 age-, sex-, and race-matched cognitively normal controls. All participants completed AOSLO imaging of the inner retina. AOSLO montages of the peripapillary area were graded for hyperreflective features including granular membranes, mottled membranes, and nummular features. Regions of interest on AOSLO were compared qualitatively to corresponding optical coherence tomography (OCT) cross sections. OCT was also used to analyze peripapillary retinal nerve fiber layer (RNFL) thickness. RESULTS. Cognitively impaired individuals had a significantly higher number of granular membranes with a larger overall area compared to controls. The proportion of cognitively impaired individuals with two or more granular membranes was 41.7% compared to none in the control group. Granular membrane area was also inversely correlated with cognitive performance on the Montreal Cognitive Assessment. There was no difference between the two groups in terms of other membrane types or RNFL thickness. CONCLUSIONS. Individuals with early cognitive impairment related to Alzheimer's show hyperreflective granular membranes on high-resolution imaging, which we hypothesize to be manifestations of inner retinal gliosis. The presence of these subtle hyperreflective membranes may obscure underlying RNFL thinning in these eyes on OCT imaging. The distinctive phenotype of granular membranes surrounding the optic nerve on AOSLO may represent a new potential biomarker of early Alzheimer's.

Optical Coherence Tomography in Patients with Alzheimer’s Disease: What Can It Tell Us?

“…Sixty-one (86%) studies used a form of neurocognitive testing (eg Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), etc. ), 17–34 , 36–44 , 46 , 47 , 49–80 56 (79%) relied on clinical diagnosis by experts based on criteria such as the DSM-IV or NINCDS-ADRDA, 18 , 20 , 21 , 24 , 26–34 , 36 , 39 , 41–44 , 46–52 , 54–57 , 62–64 , 66–88 29 (41%) utilized neuroimaging techniques (eg magnetic resonance imaging (MRI), computed tomography (CT) scan, or PET), 18 , 19 , 21–23 , 25 , 29–31 , 33 , 34 , 37 , 39–41 , 44 , 46 , 48 , 49 , 51 , 53 , 56 , 57 , 60 , 61 , 66 , 68 , 75 , 79 and 13 (18%) used immunohistochemical staining for biomarkers tau and amyloid. 21–23 , 25 , 31 , 32 , 34 , 35 , 37 , 39 , 50 , 51 , 61 …”

“… 29 , 57 , 83 However, there is great variability among these studies, perhaps due to their sample sizes and the broad definitions of MCI for which there are multiple subtypes (eg amnestic and non-amnestic MCI). Studies including only amnestic MCI are more relevant to the study of AD, 28 , 39 , 44 , 51 , 52 , 57 , 65 , 75 , 76 , 81 but a number of the studies did not specify which subtype of MCI was included. 24 , 26 , 27 , 29 , 30 , 37 , 41 , 42 , 46–48 , 54 , 56 , 78 , 83 Further exploration of these imaging tools as screening measures for pre-clinical neurodegenerative changes is warranted, especially in larger cohorts of amnestic MCI patients.…”

“…For example, four of eight studies evaluating RNFL thickness in aMCI demonstrated RNFL thinning in aMCI patients compared to healthy controls, 57 , 65 , 76 , 81 but the remaining four studies found no statistically significant differences. 28 , 39 , 51 , 75 Some of the studies showing no differences were potentially underpowered 28 or had significant demographic variation between groups, 39 limiting the conclusions that could be drawn. Overall, it is not clear whether aMCI patients are consistently similar to AD patients in OCT/OCTA findings based on the current literature.…”

“…[21][22][23]25,31,32,34,35,37,39,50,51,61 Studies also differed in terms of the subject groups they included for comparison. The vast majority of studies compared patients with AD to healthy controls, while 25 studies 24,[26][27][28][29][30]37,39,41,42,44,[46][47][48]51,52,54,56,57,65,75,76,78,81,83 included an additional subset of patients with a diagnosis of MCI or subjective cognitive decline for comparison. Four studies also included subjects with preclinical AD, 32,35,40,53 defined as cognitively normal individuals who are positive for established AD biomarkers.…”

Afferent and Efferent Visual Markers of Alzheimer’s Disease: A Review and Update in Early Stage Disease

“…Some studies have also reported macular thickening in moderate stage AD (Salobrar-García et al, 2019 ). These findings may be a result of inflammatory changes triggered by amyloid deposition or development of granular membranes secondary to retinal gliosis (Zhang et al, 2019a ). Although the timeline of these changes is unclear, the proposed dynamic nature of the retina may partially explain negative OCT studies, which examine retinal thickness across pre-set areas.…”