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Journal Alzheimer
Journal Alzheimer
Retinal Imaging
Abstract Introduction: The aim of this study was to investigate retinal thickness as a biomarker for identi-
fying patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).
Methods: The retinal thickness, utilizing the spectral domain optical coherence tomography, was
compared among 73 patients with AD, 51 patients with MCI, 67 cognitive normal control (NC) subjects.
Results: The retinal thickness of ganglion cell complex and peripapillary retinal nerve fiber layer
decreased in both AD and MCI patients, in comparison with NC subjects (AD vs. NC, P , .01;
MCI vs. NC, P , .01). The inner retinal layers in macular area in MCI exhibited significant thinning
compared with NC (P , .001). Remarkable association was found between the retinal thickness and
brain volume (P , .05). Better correlation was seen between the inner perifovea retinal thickness and
the hippocampal and entorhinal cortex volume (r: 0.427–0.644, P , .01).
Discussion: The retinal thickness, especially the inner retinal layer thickness, is a potentially early
AD marker indicating neurodegeneration.
Ó 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
Keywords: Alzheimer’s disease; Mild cognitive impairment; Retinal thickness; Brain atrophy; Biomarker
been widely used in clinical practice. The retina is embryon- research nurse who collected demographic information, a
ically derived from the cranial portion of the neural tube and medical and neurologic history, and a risk factor profile.
can be used to noninvasively assess the central nervous sys- The interview also had the study candidate answer a short
tem. During 1986-1987, Hinton and Sadun [6,7] provided set of questions concerning their memory. (2) A neurologic
evidence that visual dysfunction and optic-nerve degenera- evaluation performed by a physician. The evaluation
tion occurred during the early stage of AD. Spectral domain included a medical history review and a complete neuro-
optical coherence tomography (SD-OCT) is a newly devel- logic examination. (3) Neuropsychological testing. All
oped sophisticated imaging technique that can be used to the participants underwent global cognitive screening and
rapidly obtain objective and reliable measurements of the were administered the Mini-Mental State Examination
retinal layers with an axial resolution of 5 mm. Recently, (MMSE). Patients with mild AD or MCI completed a
several studies that used OCT found that the thickness of comprehensive battery of tests that covered 4 main do-
the retinal nerve fiber layer (RNFL) [8–11], and also the mains: (1) memory (delayed recall from the Auditory Ver-
ganglion cell layer [12,13], was reduced in patients with bal Learning Test, Logic Memory Test); (2) executive
AD when compared with healthy subjects. Therefore, function/attention (Trail Making Test, Stroop Color Word
RNFL and macular measurements have been proposed as Test, Symbol Digit Modalities Test); (3) language (Boston
surrogate markers that can be used for identifying and Naming Test, Verbal Fluency Test); (4) visuospatial skills
monitoring AD. Because early detection of AD should (Rey-Osterrieth Complex Figure Test, Clock Drawing
allow physicians to identify patients who might benefit Test). Normative data and detailed descriptions of these
from therapy before experiencing the onset of apparent tests were reported elsewhere [26,27]. AD and MCI were
cognitive impairment [14], more attention had been paid to diagnosed based on NIA/AA 2011 criteria. Operationally,
the prodromal or preclinical stage of AD. MCI was defined as (1) Scored 1.5 standard deviations
Mild cognitive impairment (MCI) is defined as a status below the norms for age and education-specific cutoffs
between normal aging and dementia [15]. MCI can evolve in at least one neuropsychological domain; (2) without
into AD, with an annual progression rate of 4w23% noticeable functional impairment in daily life. The NC
[16–19]. Among the various MCI subtypes, amnestic MCI subjects had no cognitive complaint or any evidence of
(aMCI) is most likely to progress to AD dementia [20,21]. a neurologic disorder. The control subjects were ascer-
However, unlike the OCT studies of AD, retinal structural tained as cognitively normal according to a neuropsycho-
changes in patients with MCI have remained a subject logical assessment.
of controversy [13,22,23]. Recently, den Haan et al. [24] Subjects who satisfied any of the following criteria were
performed a meta-analysis to assess retinal layer thickness excluded from the study: (1) Personal or family history of
in patients with AD or MCI. Those data showed that psychiatric disorders, dementia associated with Lewy body
RNFL thickness was moderately reduced in patients dementia, frontotemporal dementia, vascular dementia, Par-
with MCI when compared with RNFL thickness in kinson’s disease, or multiple sclerosis, among others; (2)
healthy control subjects. By contrast, other case-control History of glaucoma or increased intraocular pressure
studies and meta-analyses [25] have found no significant (IOP), retinal detachment, severe myopia, optic neuropathy,
difference between the OCT measurements in aMCI or other optic nerve disorders. Retinal vascular disease, early
and normal control (NC) subjects. age-related macular degeneration, ocular trauma, cataract
In this study, we used SD-OCT to investigate retinal that prevented an ocular and OCT examination, and other
thickness by measuring the following indexes in subjects ocular diseases (e.g., cornea disease or uveitis, etc); (3) His-
with AD or MCI as well as NC: peripapillary retinal nerve tory of alcohol abuse, carbon monoxide poisoning, hypothy-
fiber layer (p-RNFL) thickness, ganglion cell complex roidism, or other serious chronic medical conditions; (4)
(GCC) thickness, and segmentation of macular thickness. Severe cognitive impairment that made the participant un-
By analyzing the cognitive and imaging data, we further able to cooperate during the eye examination.
explored the degree to which retinal measurements corre-
lated with cognitive performance and imaging markers.
2.2. Eye examinations
The time interval between the clinical assessment and eye
2. Materials and methods examination was 1w90 days. All subjects underwent the
following eye examinations: visual acuity, IOP using noncon-
2.1. Subjects
tact tonometry, slit-lamp examination of the anterior segment,
The patients were enrolled from the Memory Clinic in ophthalmoscope examination of the posterior segment, and
Huashan Hospital from June 2017 to March 2018. Cogni- fundus photography (Version 1.5.0.0, NIDEK Co., Ltd).
tively NC subjects were recruited from a community-based Because the retinal changes that occur in glaucoma can
aging cohort—Shanghai Aging Study. resemble those that occur in AD, we excluded patients
Each participant completed an in-person evaluation that with glaucoma to avoid a possible confounding bias. Sub-
included three main components: (1) an interview by a jects with any of the following conditions were excluded
R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414 407
from the study: (1) a random IOP .22 mm Hg; (2) slit-lamp a sequence of MPRAGE T1WI. The voxel size was 1 !
examination revealed a suspicious angle closure; (3) 1 ! 1 mm. The FreeSurfer (http://surfer.nmr.mgh.harvard.
fundus photography combined with a fundus examination edu) Analysis software package was used to analyze and
revealed the following changes in the optic papilla: (a) visualize structural neuroimaging data obtained from
narrowing of the existential disk edge; (b) parapapillary cross-sectional or longitudinal views. The procedures used
hemorrhage; (c) rim widths that did not comply with for MRI structural analysis were as follows: (1) OsiriX
inferior superior nasal temporal principles. (http://www.osirix-viewer.com) software was used to view
the obtained brain MRI structure and exclude data produced
by obvious lesions and imaging artifacts; (2) FreeSurfer soft-
2.3. Optical coherence tomography imaging
ware was used to analyze the brain MRI structure screened
OCT images were obtained with an Optovue AngioVue by recon-all instructions; (3) tKmedit and tKsurfer were
System (software RTVue version 2017.1.0.155, Optovue used to check the division partition of white-gray matter af-
Inc., Fremont, CA, USA), and an ophthalmic evaluation ter checking recon-all.log to exclude any errors; (4) Aseg-
was performed on the same day. The OCT images were ob- stats2table and aparcstats2table were used to extract data
tained under conditions of normal room daylight, and no cy- for the relevant structure.
cloplegic eye drop was administered. The following
procedures were selected for use in our study: cross-line 2.5. Standard protocol approvals, registrations, and
testing, optic nerve head and 3D disc examinations, GCC patient consent
evaluation, and retinal mapping. The retina consists of ten
layers; from the inside out, it comprises the internal limiting The study protocol was approved by the Institutional Re-
membrane (ILM), nerve fiber layer (NFL), ganglion cell view Board of Huashan Hospital. Written informed consent
layer, inner plexiform layer (IPL), inner nuclear layer was obtained from each study participant and/or the legal
(INL), outer plexiform layer, outer nuclear layer, outer representative.
limiting membrane, photoreceptor, and retinal pigment
epithelium. The cross-line test was administered to exclude 2.6. Data analysis and statistics
maculopathy. The optic nerve head and 3D disc assessments
All data were analyzed using IBM SPSS Statistics for
were performed to analyze the thickness of the p-RNFL. The
Windows, Version 21 (IBM Corp., Armonk, NY, USA).
retinal map divided the macular region of the retina into the
Values for continuous variables are expressed as the mean
inner retina and the outer retina, with the inner retina extend-
and standard deviation (SD), and values for categorical vari-
ing from the ILM to the IPL and the outer retina extending
ables are expressed as a number and frequency (%). Histo-
from the INL to the retinal pigment epithelium. The retinal
grams and Q-Q plots were used to test data for a normal
map analysis circles had diameters of 1 mm, 3 mm, and
distribution. Normally distributed data were analyzed by
5 mm, respectively. The GCC included layers from the
one way ANOVA, non-normally distributed data were
ILM to the IPL, and had a diameter of 7 mm. Therefore,
analyzed with the Mann-Whitney U test, and binary vari-
the inner retina was equivalent to the core area of the
ables were analyzed with Fisher’s exact test. Between-
GCC. All measurements were taken by the same ophthal-
group comparisons were performed using post hoc analysis.
mologist to ensure operative coherence among the subjects.
We performed a Bonferroni correction by dividing the crit-
Images were reviewed by two ophthalmologists indepen-
ical P value (a) by the number of comparisons being
dently, and only those with good quality were included (im-
made. We used a generalized linear model to assess the
age clarity . 6). The values for all parameters were
cross-sectional associations (beta estimates [b], standard er-
automatically calculated by the system’s software. The
ror [SE]) of the AD group, aMCI group, and NC group based
ophthalmologist who collected OCT data performed any
on retinal measurements. All models were adjusted for age,
manual corrections needed to obtain accurate results in the
sex, hypertension, and diabetes. Pearson’s coefficient was
optic nerve head and 3D disc scans for the p-RNFL.
used to correlate parameters of the Angio-OCT with cogni-
Both eyes were examined for each subject; however, only
tive scores and MRI volume measurements. All P values
data for the right eye of each subject was included in our sta-
and 95% CIs were estimated in a two-tailed manner. Differ-
tistical analysis, to avoid bias caused by an association be-
ences with a P value , .05 were considered to be statistically
tween the eyes of each subject [28]. The left eye was
significant.
selected if the right eye was ineligible.
3. Results
2.4. Neuroimaging data acquisition and imaging analysis
3.1. Clinical and demographic characteristics of the study
The time interval between the OCT examination and MRI
participants
scan was 6 months. Neuroimaging was performed via stan-
dard procedures to ensure uniform data collection. The scan The clinical and demographic characteristics and MMSE
was conducted in a Siemens 3.0 T MAGNETOM Verio with scores of participants in the AD, MCI, and NC groups are
408 R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414
Fig. 1. SD-OCT image of the typical GCC and RNFL analysis figures of a 68-year-old patient with AD, a 65-year-old patient with MCI, and a 72-year-old NC
subject. The software automatically compared the measured thickness to the age-matched database, generating the map and a significance color-coded to match
thickness. The left line was GCC analysis, and the right line was p-RNFL analysis. The green zone means within the normal range (P 5 5%–95%), the yellow
zone means borderline values (1% , P , 5%), the red zone means outside the normal range (P , 1%). Abbreviations: AD, Alzheimer’s disease; GCC, ganglion
cell complex; MCI, mild cognitive impairment; RNFL, retinal nerve fiber layer; NC, normal control; SD-OCT, spectral domain optical coherence tomography.
for confounding factors [13]. A recent meta-analysis significant difference between the MCI and AD groups,
found that RNFL thickness was significantly (inversely) suggesting that the reduction in p-RNFL thickness
related to cognitive scores [25]. The inconsistent results might be a relatively early pathological event in the
in these studies can be attributed to high degrees of continuous process of AD, and probably occurs before
variability in the study inclusion/exclusion criteria, cogni- clinical dementia becomes evident.
tive testing scales, and the rigor of adjustment for con- Here, we utilized the GCC as an indicator of the retinal
founding factors. Unlike previous studies [23,32], our ganglion cell (RGC) layer, because the RGC layer is the
study showed that the p-RNFL in both MCI and AD main component of the GCC. The GCC refers to the com-
patients was thinner when compared with the p-RNFL plex of the macular fovea, 7 mm from the ILM to the IPL.
in cognitively normal elderly individuals, even after Our study demonstrated an absolute 5 mm decrease in
adjusting for the confounding factors of age, gender, GCC thickness in the MCI group when compared with
diabetes, and hypertension. Moreover, there was no the control group. Snyder et al. [33] studied preclinical
410 R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414
Fig. 2. Peripapillary retinal nerve fiber layer thickness and ganglion cell complex thickness. ** MCI versus NC, P , .01, ## AD versus NC, P , .01, AD versus
MCI, P ..05. Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; NC, normal control; SD, standard deviation; RNFL, retinal nerve fiber
layer; GCC, ganglion cell complex; Avg, average; superior, superior hemisphere; inferior, inferior hemisphere. Data reported as mean and SD with P values
from one-way ANOVA.
AD and found evidence of tissue loss in the IPL during a ness was observed in both the inner and outer perifoveal
continued period of disease progression. The patients with layer. Meanwhile, in the MCI group, only the inner retina
MCI in our study showed a significant reduction in mean exhibited significant thinning, when compared with the
overall GCC thickness and reductions in the GCC thick- inner retina of cognitively healthy, elderly control sub-
ness in all four quadrants. This indicated that the ganglion jects. This finding is consistent with that in an earlier
cells and their axons in the retina had changed not only study, which showed that although the disease caused a
during the AD stage but also during the MCI stage. general decrease in RNFL foveal thickness, only the inner
The human retina contains more than 1 million RGCs. retinal layers exhibited significant thinning when
Approximately, 50% of RGCs are concentrated within compared with those of healthy subjects [35]. The thin-
4.5 mm of fovea [34], and unlike a population of RNFL ning of the outer layer indicates tissue loss extending
cells, there is almost no variation in the RGC population from the INL to the outer nuclear layer and suggests
within the parafoveal area [34]. Thus a quantitative eval- retrograde synaptic degeneration.
uation of RGC structure in the parafoveal area may be The retina is an extension of nerve cells in the brain,
more sensitive and reliable. The Optovue AngioVue Sys- and our study indicates that retinal measurements, and
tem automatically segments the macular retina into re- especially the thickness of the inner layer of the retina,
gions of full, inner, and outer macula. The retina is a more sensitive marker of early neurodegeneration
contains three types of neurons: RGCs, bipolar cells, than other segmental retinal indexes, such as outer retina
and optic cells. The inner retina extends from the ILM thickness. We also analyzed how retinal changes corre-
to the IPL, and the outer retina extends from the INL to lated with cognitive performance and MRI volumetric
the retinal pigment epithelium. Thus the inner retina con- measurements. No correlation was found between RNFL
sists of small-sized ganglion cells, and the outer retina thinning and cognitive performance. However, retinal
mainly includes two other types of neurons and the axons. layer thickness, and especially the thickness of the inner
Our results showed that the retinal layers in the macular retinal layer, was strongly correlated with volumetric
area were differentially affected in the AD and MCI measurements made by MRI imaging. Few studies have
groups: in patients with AD, a general decrement in thick- described the relation between retinal layers and MRI
R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414 411
Table 2
Retina map: segmentation analysis (perifovea area)
P value
Retinal thickness AD (N 5 42) MCI (N 5 48) NC (N 5 45) AD versus NC MCI versus NC
Inner average perifovea 107.79(6.19) 108.23(7.39) 113.36(6.00) ,.001* ,.001*
Inner superior perifovea 107.60(5.54) 107.63(6.59) 113.22(5.77) ,.001* ,.001*
Inner inferior perifovea 104.21(7.47) 105.65(7.96) 108.91(6.80) .004* .036y
Inner nasal perifovea 118.12(9.92) 118.10(10.68) 125.04(8.50) .001* .001*
Inner tempo perifovea 101(5.81) 101.83(8.17) 106.27(6.07) ,.001* .002*
Outer average perifovea 167.21(6.78) 171.79(8.72) 173.24(8.78) .001* .394
Outer superior perifovea 170.10(8.06) 173.79(9.31) 175.87(8.80) .003* .256
Outer inferior perifovea 161.24(6.82) 165.54(8.27) 167.53(9.14) ,.001* .242
Outer nasal perifovea 173.05(8.05) 177(11.69) 178.78(11.95) .015y .429
Outer tempo perifovea 164.55(7.59) 170.48(9.23) 171.73(9.39) ,.001* .494
The retina contains ten layers: internal limiting membrane (ILM), nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nu-
clear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), outer limiting membrane (OLM), photoreceptor, retinal pigment epithelium (RPE).
The retina map divide the macular region retina into inner retina and outer retina, inner retina is from ILM to IPL and outer retina is from INL to RPE.
Data reported as mean and SD.
The bold values indicate the statistical significance.
Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; NC, normal control; SD, standard deviation; Avg, average; superior, superior
quadrant; inferior, inferior quadrant; nasal, nasal quadrant; tempo, temporal quadrant.
*P , .01.
y
P , .05.
features. One such study found an association between is that a degenerative change in the retina represents an
decreased gray-matter volume and disrupted white- earlier pathological change, and precedes a decline in
matter microstructure and retinal layer thickness, but cognitive function.
only in NC subjects [36]. Another study in cognitively Under the latest ATN marker framework, we propose
healthy subjects showed that the medial temporal lobe that measurements of retinal thickness be included in
was related to both RNFL thickness and total macular the “N” category, which reflects neurodegeneration or
thickness [37]. In patients with AD, retinal thickness neuronal injury. Further studies are needed to determine
was reported to be correlated with parietal cortical atro- whether retina thinning represents a specific Alz-
phy [38], most likely because of age-related changes [39]. heimer’s-related pathogenic process, or is just indicative
Atrophy of the medial temporal lobe (including the of a general change that underlies various neurodegenera-
hippocampus, entorhinal cortex, temporal lobe volume, tive diseases.
etc.) predicts the conversion of MCI to AD [40,41]. The present study has some limitations. Owing to the
We analyzed correlations between the p-RNFL, GCC, cross-sectional nature of the study, we could not
macular thickness, and the brain volume. Significant
associations were found between p-RNFL thickness,
full perifovea (Ø 5 5 mm) thickness, and MRI volume
measurements. A further segmentation analysis Table 3
revealed an even stronger association between inner Multivariate analysis of retinal thickness: full and segmental measures
perifovea retinal thickness and the hippocampal and AD versus NC MCI versus NC
entorhinal cortex volume, which once again suggested Retinal thickness b SE P value b SE P value
the inner layer of the retina to be an imaging-relevant
Average p-RNFL 28.826 1.377 ,.001* 28.598 1.506 ,.001*
biomarker.
Average GCC 26.316 1.825 ,.001* 24.631 1.766 ,.001*
This study included only patients with mild to moderate Inner average 26.316 1.825 ,.001* 24.631 1.766 .001*
AD, and the mean MMSE score was 19.67 6 4.58. Patients perifovea
with severe AD were not able to follow instructions and Outer average 25.050 1.934 .002* 21.638 1.871 .477
successfully complete an OCT evaluation, which made perifovea
OCT testing unreliable in that population. It is possible Generalized linear model was used to evaluate the relation between
that changes in the RNFL are more apparent in patients retinal measures and cognitive diagnosis, which was adjusted for con-
with severe dementia; if so, this could explain why we founders of sex, age, medical history of hypertension and diabetes.
The scale parameter was estimated by maximum likelihood.
found no differences in the mean p-RNFL and GCC mea-
The bold values indicate the statistical significance.
surements in the MCI and AD groups. It could also explain Abbreviations: RNFL, retinal nerve fiber layer; GCC, ganglion cell com-
why we failed to find an association between cognitive plex.
scores and RNFL thickness. However, another possibility *P , .01.
412 R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414
Fig. 3. Correlation analysis between SD-OCT measures and brain volume. The parameter was estimated using Pearson’s correlation coefficients. Abbrevia-
tions: HIPPO, brain volume of hippocampus; ENTOR, brain volume of entorhinal cortex; L 5 left; R 5 right; SD-OCT, spectral domain optical coherence
tomography. **P , .01.
substantiate the chronological of changes that occurred in less than those in the two patient groups. The mean ages
the RNFL. The NC group might have included a few sub- in the AD, MCI, and NC groups, were 71.40 years,
jects with subtle cognitive impairment. Although not sta- 71.67 years, and 68.91 years, respectively. A previous
tistically significant, the mean age in the NC group was study conducted with nonglaucomatous Asian subjects
R. Tao et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 405-414 413
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