Alzheimer Disease: OCT Retinal and Choroidal Thickness
João Paulo Cunha
1,2
and António Castanheira-Dinis
3,4
1
Department of Ophthalmology, Central Lisbon Hospital Center, Lisbon, Portugal
2
NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
3
Department of Ophthalmology, Northern Lisbon Hospital Center, Lisbon, Portugal
4
Visual Sciences Study Center, Faculty of Medicine, Lisbon University, Lisbon, Portugal
Keywords: Alzheimer Disease, Optical Coherence Tomography, Retinal Layers, Choroidal Thickness.
Abstract: The aim of this study is to compare macular retinal layers and choroidal thicknesses of patients with
Alzheimer’s disease (AD) with those of patients without other known ophthalmological pathology, using
spectral domain optical coherence tomography. Multiple linear regression analysis was applied to assess the
effects of age, gender, spherical equivalent, visual acuity, intraocular pressure, axial length and mean
arterial pressure on macular retinal layers thickness. Fifty eyes of 50 patients (mean age 73.10; SD=5.36
years) with a diagnosis of mild AD and 152 eyes of 152 patients without AD (mean age 71.03; SD=4.62
years) were included. There was a thinning in the peripheral ring of the ganglion cell layer (GCL) in the AD
group (S6 p < 0.001; T6 and N6 p = 0.001). In the superior sectors of the inner plexiform layer (IPL),
differences between the two groups also remained statistically significant after Bonferroni correction (S3 p
= 0.001 and S6 p < 0.001). In the outer layers we did not observe differences statistically significant for AD
group. These layers’ thicknesses were associated with statistical significance with gender (in inner and outer
nuclear layers), age and choroidal thickness (CT) (in photoreceptor layer). In the AD patients group, CT was
significantly thinner than in the first group of patients without AD, in all 13 locations (p<0.001), and age
was relevant factor. Patients with AD showed a significant reduction in retinal layers and choroidal
thickness. The thinnest macular measurements were found mostly in the inner layers, GCL and IPL, at
superior sectors (pericentral and peripheral rings). This thinning may reflect a retinal characteristic of AD,
related with both primary retinal lesion and transsynaptic retrograde degeneration and the choroidal thinning
probably reflects the importance of vascular factors in the pathogenesis of this disease.
1 INTRODUCTION
Alzheimer’s disease (AD) is the most common form
of dementia and is a long-term progressive
neurodegenerative disorder with great social impact.
(
Association Alzheimer’s Dementia1, 2012). The earliest
AD pathological change in the central nervous
system (CNS) is the accumulation of amyloid β
(Aβ), derived from abnormal processing of amyloid
precursor protein (APP). (
Perl DP, 2010). This
process can begin a decade before the onset of the
clinical syndrome of dementia. Visual symptoms
occur frequently among the earliest complaints in
AD patients, contributing to further impairment in
the quality of life. (Burns A et al, 2009; Querfurth
HW, Laferla FM, 2010) However, the results of
visual tests are dependent on the patient’s
understanding, memorization and compliance to the
rules and the test instructions, which depends on the
cognitive status of each patient.
Visual defects in AD patients were initially
thought to be solely due to parietal and primary
visual cortex pathology. However, increasing
evidence has demonstrated that anterior visual
pathway degeneration also plays a role. Hinton et al.
first provided histopathological evidence of optic
neuropathy and degeneration of retinal ganglion
cells (RGC) in patients with AD, with reduced
number of RGCs and reduced retinal nerve fiber
layer (RNFL) thickness (Hinton DR et al., 1986).
Later post-mortem studies showed that degeneration
of the ganglion cell layer (GCL) occurs
preferentially in superior and inferior sectors, as well
as in the central retina, in particular the temporal
foveal region (Blancs JC, Torigoe Y et al., 1996;
(Blancs JC, Schmidt SY et al., 1996).
Cunha J. and Castanheira-Dinis A.
Alzheimer Disease: OCT Retinal and Choroidal Thickness.
DOI: 10.5220/0006328704070413
Copyright
c
2017 by SCITEPRESS Science and Technology Publications, Lda. All rights reserved
Initial in vivo non-invasive studies of optic
neuropathy in patients with AD using fundus
photographs showed RNFL abnormalities, as well as
macular changes and optic nerve head abnormalities
(increased cup-to-disc ratio and decreased
neurorretinal rim). (Tsai CS et al., 1991; Hedges TR
et al., 1996; Kromer R et al., 2013).
In addition, in vivo studies have shown reduced
macular thickness and volume in patients with AD
(Iseri PK et al., 2006) reporting macular changes in
the ganglion cell complex (GCC), comprising the
GCL and the inner plexiform layer (IPL) (Mochos
MM et al., 2012 Marziani E et al., 2013; Ascaso FJ
at el., 2014; Garcia-Martin ES et al., 2014; Cheung
CYL et al., 2015).
The aim of this study is to identify the retinal and
choroidal macular regions more affected and the
layers where the retinal thinning is more
pronounced, considering potential confounding
variables such as age, gender, spherical equivalent,
best corrected visual acuity (BCVA), axial length,
intraocular pressure (IOP) and mean arterial pressure
(MAP).
2 MATERIALS AND METHODS
2.1 Subjects Groups
This cross-sectional study was conducted at the
Ophthalmology and Neurology Departments of the
Central Hospital Lisbon Center (CHLC), between
2014 and 2016. Consecutive AD patients sent by the
Neurology Department for ophthalmological
screening were observed for inclusion/exclusion
criteria. The inclusion criteria were AD patients with
age between 65 and 78 years old with normotensive
eyes and ability to understand the study.
Exclusion criteria were: refractive error > 5
diopters (D) or/and axial length > 25 mm in the
studied eye; known diagnosis of diabetes; retinal
diseases; glaucoma or ocular hypertension; uveitis;
neurodegenerative diseases; significant media
opacities that precluded fundus imaging. Other
relevant known neurologic pathology, such as
neurodegenerative diseases, other types of dementia,
previous stroke or uncertain or indeterminate
diagnosis were also excluded.
Patient's informed consent was obtained before
participation in this study. The principles of the
Declaration of Helsinki were respected and the study
was approved by our institutional Ethics Committee.
Fifty patients with AD (AD group) and 152
patients without AD (control group) were recruited
from the Neurology department of CHLC.
2.2 Study Procedures
After a pre-screening visit where demographic,
background history, full ophthalmological
examination with visual acuity, anterior segment
examination, tonometry, indirect ophthalmoscopy
and ultrasonic biometry were recorded, patients were
assigned to a specific study visit where the following
methodology was taken: Goldmann applanation
tonometry and spectral domain optical coherence
tomography. One eye of each subject was randomly
selected.
2.2.1 Visual Acuity
BCVA for each eye was measured using Snellen
charts and converted to the logarithm of the
minimum angle of resolution (logMAR).
2.2.2 Intraocular Pressure
IOP was measured before pupillary dilation with
Goldmann applanation tonometry and a mean of 3
measurements was taken.
2.2.3 Spectral Domain Optical Coherence
Tomography Imaging
All eyes were examined with SD-OCT (Spectralis
Heidelberg Engineering, Germany, software version
6.0) at the same time of the day from 2 PM to 4 PM.
For macular measurements, subjects were studied
using the “fast macular volume” preset, consisting of
a 25-line horizontal raster scan covering 20° × 20°,
centered on the fovea (consisting of 25 high-
resolution scans). In the same session, enhanced
depth imaging scans (EDI) were also performed to
improve the quality of choroidal imaging according
to the previously reported method (Spaide et al.,
2008).
The new Spectralis automatic segmentation
software was used to obtain individual retinal layer
thickness measurements including: RNFL, GCL,
IPL, inner nuclear layer (INL), outer plexiform layer
(OPL), outer nuclear layer (ONL), retinal pigment
epithelium (RPE) and photoreceptor layer (PR).
The thickness values were calculated for the nine
Early Treatment Diabetic Retinopathy Study
(ETDRS) sectors/regions (Grading diabetic
retinopathy from stereoscopic color fundus
photographs--an extension of the modified Airlie
House classification. ETDRS report number 10.
Early Treatment Diabetic Retinopathy Study
Research Group.’ (1991). This ETDRS plots consist
in three concentric rings of 1, 3 and 6 mm diameter
centered at the fovea and two outer rings subdivided
in 4 sectors. Each sector was designated the fovea or
central sector (C), the pericentral ring (ETDRS
sectors: S3, T3, I3 and N3) and the peripheral ring
(ETDRS sectors: S6, T6, I6 and N6).
The OCT images were obtained by one
ophthalmologist (A.S.) and were assessed by other
two ophthalmologists (J.P.C. and R.P.), masked to
the patients’ diagnosis, who verified the automatic
segmentation and the automatic position of the
ETDRS grid, correcting when necessary. Choroidal
thickness (CT) was measured manually from the
hyperreflective line, corresponding to the retinal
pigment epithelium (RPE, to the hyporreflective
line, corresponding to the sclerochoroidal interface,
as previously described. (Tavares Ferreira J et al.,
2016).
2.2.4 Mean Arterial Pressure
Blood pressure was measured in the seated position
by an automatic sphygmomanometer and systolic
and diastolic blood pressure (SBP and DBP) were
recorded. Mean arterial pressure (MAP) was
calculated using the following formula:
MAP = DBP + 1/3 (SBP – DBP).
2.2.5 Statistical Analysis
Demographics and clinical characteristics of patients
were described with frequencies (percentages) and
with mean (SD: standard deviation) or with median
and interquartile range (IQR: 25th percentile-75th
percentile), as appropriate. Nonparametric Chi-
Square test and Mann-Whitney tests were applied.
Linear regression models were used to identify
the variables which may explain the variability of
macular retinal layers thicknesses. The variables
group, gender, age, IOP, axial length, spherical
equivalent, MAP, and BCVA were considered in
this analysis. Variables with a p-value <0.25 in the
univariable analysis were selected as candidates for
the multivariable models. Multivariable regression
models regarding PR layer in sectors C, S3, I3, N3,
and T3, also considered the variable CT subfoveal,
1000 superior, inferior, nasal, and temporal of the
fovea, respectively. Normality assumption of the
residuals was verified using Kolmogorov–Smirnov
goodness-of-fit test with Lilliefors correction. A
level of significance α=0.05 was considered. Data
were analysed using the Statistical Package for the
Social Sciences for Windows (IBM Corp. Released
2013. IBM SPSS Statistics for Windows, Version
22.0. Armonk, NY: IBM Corp.)
3 RESULTS
3.1 Patient Demographics and Clinical
Characteristics
A total of 50 AD patients (16 males) were included
in the AD group and 152 patients without AD (55
males) were included in the control group.
Concerning gender, no significant differences were
found between AD and control groups (32.0% vs
36.2%; p=0.591). The mean age was 73.1 (SD=5.36)
years in AD group and 71.0 (SD=4.62) years in
control group (p=0.011).
The demographic, clinical and ophthalmologic
characteristics of the 2 groups, including BCVA,
IOP, spherical equivalent, axial length, MAP,
therapy with diuretics and antihypertensive
medication are summarized and compared in Table
1.
Table 1: Demographic and clinical characteristics of the patients by group.
Alzheimer Group
(n=50)
Control Group 1
(n=152)
p
Age (years) 73.1 (5.36) 71.0 (4.62) <0.001
Male gender n (%) 16 (32) 55 (36)
BCVA (logMAR) 0.121 (0.153) 0.040 (0.073) <0.001
IOP – Goldmann (mmHg) 15.52 (2.62) 14.72 (2.51) 0.66
Spherical Equivalent (D) 0.995 (1.43) 0.700 (1.64) 0.344
Axial length (mm) 22.44 (0.91) 22.49 (0.99) 0.668
Mean Arterial Pressure (mmHg)
98.91
(94.67-103.33)
97.87
(93.75-101.25)
0.287
Therapy 0.058
Results are expressed as mean (SD) or median (IQR), as appropriate; Best Corrected Visual Acuity (BCVA); Intra-Ocular Pressure
(IOP).
3.2 OCT Measurements - Macular
Retinal Thickness
In multivariable linear regression models
considering factors such as age, gender, visual
acuity, IOP, spherical equivalent, axial length, MAP,
therapy and antihypertensive medication we have
observed a thinning of the GCL for AD group in
three of the four pericentral sectors (S3 p= 0.016; T3
p= 0.050 and N3 p= 0.043) and in three of the four
peripheral sectors (S6 p < 0.001; T6 p= 0.001 and
N6 p= 0.001). In fact, the mean values of GCL
decreased between 2.29 and 3.28 µm in AD group
when compared with control group, and for each ten
years increase of life, the mean values of the layers
also decreased between 1.28 and 2.71 µm.
In the IPL, all sectors excepting the central and
N6, had thinner thicknesses with statistical
significance for AD group (S3 p= 0.001; T3 p=
0.003; I3 p= 0.005; N3 p= 0.018; S6 p < 0.001; T6
p= 0.015 and N6 p= 0.010). Results showed that the
mean values of IPL decreased between 1.23 and
2.61 µm in AD group, and for each ten years
increase of life, the mean values of the layers also
decreased between 1.02 and 1.48 µm.
After Bonferroni correction, the sectors still
statistically thinner in the inner layers for AD group
were localized in the GCL peripheral sectors S6, T6
and N6, and in the superior sectors S3 and S6 of the
IPL.
For the other layers other than GCL and IPL for
multivariable regression models results regarding
RNFL, INL, ONL, RPE and PR layers), results of
the multivariable regression models after
Bonferroni correction, showed a mean thickening of
1.49 µm at T3 sector in the RNFL for AD group; a
mean thickening of 5.22 µm at C sector in the INL
for male gender; a mean thickening of 5.82 µm at I3
sector in the ONL for male gender and a mean
thinning of 3.11 µm at C sector in the PR for each
10 years increase of life. Additionally, the
pericentral sectors of PR layer had a positive
association with choroidal thickness after Bonferroni
correction
3.3 EDI-OCT Measurements –
Choroidal Thickness
In all 13 locations the differences were statistically
significant (p<0.001).
In the multivariable regression models, after
adjusting for age, spherical equivalent, BCVA, IOP,
axial length and MAP we identified significant
differences in CT between the groups in all 13
locations. In all locations, except at 500 and 1000
μm superior and 1000 μm inferior of the fovea,
independently from the group, age was negatively
associated with CT with a mean decrease between
15.5 and 28.4, for each 10 additional years.
Spherical equivalent was also associated with CT in
four locations, namely 1000 μm nasal, 1500 μm
nasal, 1500 μm superior and 1500 μm inferior of the
fovea. For each increase of 1 D in spherical
equivalent value, the CT was thicker in ADG with
increases between 5.3 and 7.2 μm.
4 DISCUSSION
Diagnosis of AD can be made with high accuracy by
using clinical, neuropsychological, and imaging
assessments. Fortunately, in ophthalmology, we
have the possibility to measure neuronal layers in a
non-invasive way with OCT technology.
Since 2001, peripapillary RNFL thinning has
been demonstrated with time domain TD-OCT and
spectral-domain SD-OCT studies (Parisi). However,
differences have been reported regarding which
retinal quadrants are most affected. More recent
OCT studies have reported also macular changes in
ganglion cell complex (GCC), comprising the
ganglion cell layer (GCL) and inner plexiform layer
(IPL) (Mochos MM et al., 2012 Marziani E et al.,
2013; Ascaso FJ at el., 2014; Garcia-Martin ES et
al., 2014; Cheung CYL et al., 2015).
In addition, one study using SD-OCT showed a
diffuse reduction of the RNFL and GCL combined
in AD (Marziani E et al., 2013), although the authors
were not able to determinate which layer was most
affected by AD. Other studies have demonstrated
IPL thinning in AD patients (Ascaso FJ et al., 2014;
Ong YL et al., 2014; Cheung CY et al., 2014). This
reduction of ganglion cell complex thickness (GC-
IPL and RNFL layers) in AD occurs to a larger
extent than that accounted for age-related GC-IPL
loss alone (about 0.3 µm/year) (Cheung CY et al.,
2014). Macular GC-IPL thinning may be a more
sensitive marker of earlier neurodegeneration in
Mild Cognition impairment (MCI) and AD than
evaluation of the RT. ()
Whether or not an association exists between
retinal changes and severity of dementia also
remains a controversial issue. While most studies
concluded that OCT can be used to detect early
abnormalities in AD, the majority reported no
statistically significant differences between MCI and
AD patient groups Oktem EO et al., 2014; Paquet C
et al., 2007; Kesler A et al., 2011). Only one TD-
OCT study reported correlation between MMSE
scores and macular volume (Iseri PK et al., 2006).
Two meta-analyses by K.L. Thomson et al. and
G. Coppola et al. also tried to determine the utility of
OCT as a tool for evaluating disease progression,
and prognostic significance of GC-IPL and RNFL
thickness, but their conclusions failed to determine
an association between RNFL and the clinical
severity of dementia (Thomson KL et al., 2015;
Coppola G et al., 2015). A recent SD-OCT study
found that reduced grey matter volumes of occipital
and temporal lobes were associated with thinning of
the GC-IPL and peripapillary RNFL in individuals
without dementia (Ong YT et al., 2015). Since those
cortical regions are an early site of deposition of
senile plaques and NFTs, the findings by Y.-T. Ong
and co-workers raises the possibility that GC-IPL
thinning may reflect neurodegenerative changes in
the brain, even before the clinical onset of dementia.
In our study, we used SD-OCT to compare
retinal thickness in mild AD patients with a large
control group. In the multivariable analysis, after
adjustment for age, gender, BCVA, IOP, axial
length, spherical equivalent and MAP, the GCL and
the IPL were thinner especially in superior sectors.
This thinning of the superior macular sectors in AD
patients would explain the predominantly inferior
visual field defects previously described in AD
(Kesler A et al., 2011; Lu Y et al., 2010; Berisha F
et al., 2007; Kirbas S et al., 2013; Bambo MP et al.,
2015) and probably associated to the increased risk
of falls in these patients.
The sensitivity of pericentral sectors between 1-3
mm from the fovea, in SD-OCT, was already
reported by our group of research as the macular
sector is more affected in neuro-ophthalmological
diseases (Costa L et al., 2015) and can provide a
clue for the probable neuro-ophthalmological
etiology of some OCT findings.
When we analysed the different areas of the
macula of both groups, we observed a normal
distribution of each layer thickness, with a thicker
nasal quadrant than temporal and a thicker superior
than inferior quadrant. The multivariable analysis
considering retinal thickness as the dependent
variable support the importance of AD in the
thinning of superior sectors of GCL and IPL, nearly
eliminating the classically described superior-
inferior asymmetry. The higher statistical
significance in the upper sectors allows, in some
way, to differentiate the diagnosis of glaucomatous
optic neuropathy from another possible AD related
neuropathy. Also, Armstrong (Armstrong RA, 1996)
found a greater density of senile plaques and
neurofibrillary tangles in the cuneal gyrus than in the
lingual gyrus, suggesting the explanation for the
predominantly inferior field defects reported by
Trick et al. in AD (Trick GL et al., 1995). Like in
others studies, the increasing age is responsible for
changes in retinal layer thickness, as studied by Ooto
et al. (Ooto S et al., 2011). Demirkaya et al
postulated a lose of 2.06 µm of pericentral GCL and
of 0.92 µm of peripheral IPL over a period of 20
years, probably due to a diffuse loss of neural tissue
(Demirkaya et al., 2013).
The principle role of the choroid is to supply
oxygen to the outer retina up to the level of the inner
nuclear membrane and, therefore, the neurosensory
retina in the foveal avascular zone derives blood
from the choroid. Vascular choroidal changes can
therefore occur in patients with vascular risk factors
as AD.
In vivo studies have demonstrated that CT varies
topographically within the posterior pole and is
inversely correlated with age. It decreases
approximately 16 μm for each decade of life. A
study reviewed 54 eyes and demonstrated that CT
was thinnest nasally and thickest subfoveally.
Additionally, choroidal thickness was found to be
highly correlated with age, axial length, and
refraction, emphasizing the importance of
controlling for these variables when studying any
patient population. More interestingly, choroidal
thickness varied on a diurnal basis by as much as 33
µm (ranging from 8 to 65) in one study, suggesting
that it can be a highly variable measure of choroidal
vasculature and further emphasizing the need to
develop novel approaches to reliably assess
choroidal vascular health in vivo.
Patients with AD have an altered microvascular
network in the retina (narrower retinal venules and a
sparser and more tortuous retinal vessels) compared
with matched controls. The accumulation of Aß and
development of neurofibrillary tangles (NFTs) cause
neurotoxicity, neuronal and synaptic loss, and
vascular angiopathy. The role of choroidal
vasculature in the pathogenesis of AD is unknown,
but the results in this study of choroidal thinning in
patients with AD when compared with controls
support previous results of others studies. When we
analysed the pattern of CT in the control and AD
groups, both had a normal distribution of CT, with a
thicker superior quadrant than the inferior and a
thicker temporal than nasal quadrant.
The models of multifactorial linear regression for
the dependent variable choroidal thickness support
the importance of Alzheimer disease as a risk factor
for choroidal atrophy besides aging.
Our study had some limitations. The first one
concerned to the different age distribution of the two
groups. However, to overcome this drawback, all the
regression models were adjusted by age which has
been proved to be very important in some inner and
outer layers. CT measurements were done manually,
however, the measurements were done by 3
independent persons and this manual technique
already been proved to have a high intra-observer
and inter-observer reproducibility. Secondly, the
hydration status, that may affect the CT, was not
taken into account. To this extent, we try to decrease
any circadian variability by performing the
measurements at the same time of the day and in the
same location and environment. Also, the automatic
segmentation and centration of ETDRS grid could
have resulted in imprecise measurements, although it
was confirmed by 2 independent persons.
5 CONCLUSIONS
Patients with AD showed a significant thinning in
pericentral and peripheral sectors of the inner layers.
The thinnest macular measurements were found
mostly in the inner layers and superior sectors. After
Bonferroni correction, the most affected regions
were localized in the GCL S6, T6 and N6, and in the
IPL S3 and S6. These OCT findings in AD support
the direct retinal involvement but also suggest the
contribution of transynaptic retinal degeneration in
the physiopathology of retinal and visual
dysfunction in AD. Patients with AD showed a
choroidal thinning that was statistically significant in
the 13 locations studied at 1.5 mm centered on the
fovea. This thinning may reflect the importance of
choroidal vascular factor in the pathogenesis of this
disease and may aid in the diagnoses of
“Alzheimer’s choroidopathy” not related with age.
However, further studies are needed to clarify
some questions that remain to be answered before
considering OCT a useful clinical tool for early
detection of dementia and assessment of disease
progression in AD.
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