Alzheimer Disease: OCT Retinal and Choroidal Thickness

João Paulo Cunha

1,2

and António Castanheira-Dinis

3,4

Department of Ophthalmology, Central Lisbon Hospital Center, Lisbon, Portugal

NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal

Department of Ophthalmology, Northern Lisbon Hospital Center, Lisbon, Portugal

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

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

Table 1: Demographic and clinical characteristics of the patients by group.

Alzheimer Group

(n=50)

Control Group 1

(n=152)

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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