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Potential Applications of Spectral-Domain Optical Coherence Tomography

(SD-OCT) in the Study of Alzheimer's Disease

Article · March 2014

DOI: 10.1177/201010581402300112

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REVIEW

Potential Applications of Spectral-Domain Optical Coherence

Tomography (SD-OCT) in the Study of Alzheimer’s Disease
Yi-Lin Ong1, Yi-Ting Ong1,2, BSc, Mohammad Kamran Ikram1,2,3, MD PhD, Christopher Li Hsian Chen3, FRCP,
Tien Yin Wong1,2,4, MD PhD, Carol Yim-lui Cheung1,2,4, PhD
1
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
2
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore,
Singapore
3
Memory Ageing and Cognition Centre, National University Health System, Singapore
4
Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore

ABSTRACT

Alzheimer’s Disease (AD) is the most common subtype of dementia. As the prevalence of dementia is projected
to increase, the burden of the disease on society is expected to become increasingly significant. The link between
eye pathology and neurodegenerative diseases has been established in multiple studies. In particular, optic nerve
parameters associated with neuronal loss in AD include retinal ganglion cells (RGC). Retinal ganglion cells are
similar to neurons in the cerebral cortex, and have been correlated to neurodegeneration in AD. Ocular imaging
techniques such as optical coherence tomography (OCT) have provided a rapid and non-invasive method for
quantifying optic nerve parameters in vivo. Spectral domain (SD)-OCT has shown good potential in the study of
the optic nerve in AD as it enables more comprehensive assessment of RGCs. Earlier generation OCT techniques
only assess the retinal nerve fibre layer, which consists of RGC axons. Spectral domain-OCT offers ultra-high scan
speed and image resolution, enabling improved sampling of retinal layers. Retinal layers such as the ganglion
cell-inner plexiform layer (GC-IPL), which contain the dendrites and nuclei of RGCs, can be assessed with SD-
OCT. This article presents a review of literature associating eye pathology with AD, and explores the potential
of SD-OCT in future AD studies. Spectral domain-OCT has the potential to draw more links between optic nerve
pathology and neurodegeneration.

Keywords: Alzheimer’s Disease, Imaging, Spectral domain optical coherence tomography, Neurodegeneration,
Retinal ganglion cell.

INTRODUCTION (AD) is the most common subtype of dementia,

Dementia is of growing medical, social and
economic concern globally, afflicting an estimated
35.6 million people worldwide in 2010, with figures
projected to rise to 65.7 million by 2030 and 115.4
million by 20501. In Singapore, dementia is a rising
public health issue as Singapore has a rapidly ageing
population, with the proportion of elderly (aged 65
and above) estimated to increase from 7% in 1999
to 19-20% by 20302,3. As such, the prevalence of
dementia in Singapore is expected to increase from
0.65% in 2010 to 3.6% in 20504. Alzheimer’s Disease
accounting for approximately 60% of cases5,6. With
an increasing prevalence of dementia in Singapore,
the burden of disease on our healthcare service,
society and economy is likely to be significant.
An increasing number of studies have begun to draw
the link between neurodegenerative diseases and
eye pathology, suggesting that studying the visual
system may shed more light on neurodegenerative
diseases. The retina and optic nerve share the same
embryological origin as the brain areas responsible

74 Proceedings of Singapore Healthcare  Volume 23  Number 1  2014


for cognitive function7,8. Homology between
retinal and brain microvasculature is such that
changes in cerebral vasculature can be reflected in
the retinal vasculature7, with retinal microvascular
abnormalities shown to be associated with
cognitive impairment9,10. Ocular manifestations of
neuropathology have been observed to precede
brain pathological changes in many central nervous
system (CNS) disorders, suggesting a means of
early diagnosis.
In the study of neurodegenerative diseases
and the eye, retinal ganglion cells (RGCs) are
of particular interest as they are neuronal cells.
Early neuropathological studies have drawn a
link between RGC and AD, showing RGC loss in
AD patients11. Other optic nerve manifestations
in AD have been found in later studies, such
as reduction in retinal nerve fibre layer (RNFL)
thickness and RGC loss12–15. Aside from AD, ocular
manifestations can also be seen in other CNS
disorders. Some examples include RNFL thinning
and optic nerve neurodegeneration in stroke16,
RGC degeneration and RNFL thinning in multiple
sclerosis17,18, as well as swelling of photoreceptors
and RNFL thinning in Parkinson’s Disease19–23.
Hence, the optic nerve has emerged as a possible
tool for observing neurodegenerative processes
occurring in the brain. Using newly derived ocular
imaging techniques, optic nerve parameters can be
quantified in detail. This would allow observation
of both the physiological and functional impact
of dementia on the visual system, allowing further
insight into the pathophysiology of cerebral
neurodegenerative processes.
Of the variety of ocular imaging techniques now
available, optical coherence tomography (OCT) has
emerged to the forefront with its high speed, high
resolution, and capability to analyze the retina and
optic nerve in vivo. The recent development of the
spectral-domain OCT (SD-OCT) has considerable
advantages over earlier generation time-domain
OCT (TD-OCT). The SD-OCT is able to identify intra-
retinal layers such as the RGC layer, enabling the
quantification of more detail in the retina and optic
nerve that are useful in studying AD. In this article,
we discuss the potential of the SD-OCT as a tool to
observe neurodegeneration in AD.
OCULAR MANIFESTATIONS OF AD
Alzheimer’s Disease is a neurodegenerative disease
that is commonly associated with memory and
Proceedings of Singapore Healthcare  Volume 23  Number 1  2014
SD-OCT in Alzheimer’s Disease
cognitive defects, including short-term memory
deterioration, impaired cognitive function and
reduced emotional control6,24. In AD, some of
the observed neuropathologic changes include
atrophy of the hippocampus, deposition of
amyloid plaques and neurofibrillary tangles in
the neocortex, hippocampus, amygdala and basal
nucleus of Meynert25,26.
Early studies of the brain have started to draw close
links between the visual system and the brain.
Amyloid-beta plaques were found to be present
in the visual association cortex of AD patients and
even cognitively intact persons diagnosed with
preclinical AD27–30. Furthermore, neurofibrillary
tangles tend to be located in the visual association
areas28–30. Thus, it has been hypothesised that AD
pathology may originate in the visual association
area instead of the hippocampus, suggesting that
visual function loss may serve as an early indication
of AD. However, of all the components of the visual
system, research has mainly focused on the link
between the retina and AD.
A number of pathological changes in the retina,
optic disc and optic nerve have been found to
be associated with AD. Retinal ganglion cells
are responsible for consolidating information
from the photoreceptors and surrounding cells,
before passing on visual information received
to the brain via the optic nerve. Although RGC
depletion is typically associated with loss of vision
in glaucoma31–35, since RGCs are similar to neurons
in the cerebral cortex, RGC degeneration is also
expected to be present in other neurodegenerative
diseases such as AD36,37. Post mortem studies by
Hinton et al11 first reported histopathological
evidence of widespread axonal degeneration
in the RGC layer and RNFL of the optic nerve
in AD patients. Retinal ganglion cell loss in AD
patients has been linked to deterioration of visual
function. Additionally, mouse models show that
RGC dendritic degeneration may possibly be a
sensitive marker for neural damage in AD38. While
the RGC layer shows good potential in assessing
neurodegeneration in AD, this has not been fully
exploited due to lack of high-resolution imaging of
the retinal layers.
In vivo observations of optic neuropathy may be
useful in early identification of AD and assessment
of neurodegeneration. Advancing from
histopathological studies, fundus photography was
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later used in retinal studies of AD. A study conducted
by Tsai et al39 found a significant correlation
between cup-to-disc ratio, cup volume and disc
rim area with Alzheimer’s Disease Assessment Scale
(ADAS) scores and duration of disease. However,
the method of optic nerve head (ONH) analysis in
this study has certain disadvantages, as it is manual
and highly subjective to each individual observer.
The use of automated image processing programs
to analyse the ONH would be more effective in
addressing these limitations.
ASSESSMENT OF THE OPTIC NERVE IN
AD USING ADVANCED OCULAR IMAGING
TECHNOLOGY
Studies on ocular manifestations of AD have been
conducted with various imaging techniques.
Currently, commercially available ocular imaging
techniques include OCT, confocal scanning laser
ophthalmoscopy (CSLO) using the Heidelberg
Retinal Tomograph (HRT) and scanning laser
polarimetry (SLP) using the GDx Variable Corneal
Compensator (VCC)40. These imaging technologies
allow the cross-sectional imaging of the retina and
ONH in vivo, allowing quantitative analysis of the
RNFL, ONH and macula.
Optical coherence tomography is an optical
imaging technique that performs high resolution
tomographic imaging of biological tissues41,
providing a non-invasive biopsy of retinal tissue
morphology. Optical coherence tomography
technology utilises a low-coherence light source
near the infra-red spectrum to penetrate biological
tissue, forming an image of the tissue based on the
backscattering of light or the time taken for the
light to travel back to the lens, with varying signal
intensities. Axial scans are continuously taken of
the tissue to obtain a complete cross-sectional
image of the tissue.
Optical coherence tomography has been widely
used clinically in glaucoma and retinal disease
detection, such as macular edema and age-
related macular degeneration42. Previous studies
using the TD-OCT14,15,43–46, CSLO47 and SLP48 have
found optic nerve changes in AD when compared
against age-matched controls. Some of these
imaging studies have found significant reduction
in RNFL and macular thickness15,43, as well as
optic nerve damage in AD patients compared to
healthy controls11,14,43,44. Several studies have found
significant RNFL thickness reduction in the superior
76 Proceedings of Singapore Healthcare  Volume 23  Number 1  2014
and inferior quadrants14,46, while others have
found significant reductions in all quadrants15,43
(superior, nasal, inferior, temporal). A similar trend
was also observed in patients with mild cognitive
impairment (MCI), defined as slight impairment in
cognitive function greater than expected for an
individual’s age but with no notable interference
with daily activities49,50, generally considered
as a preclinical stage to AD. Patients with MCI
were found to have RNFL thinning in the inferior
quadrant46, suggesting that changes in the optic
nerve pathology may occur in early stages of AD.
Of the ocular imaging techniques available, TD-OCT
has been most widely utilised to assess optic nerve
degeneration in AD. While the TD-OCT has shown
promising results in assessing RNFL reduction in
AD, it has certain limitations, such as the resolution
of TD-OCT scans being insufficient to demarcate
and quantify the RGC layer reliably. As a result,
many studies have yet to tap into the potential
of the RGC layer as a tool to assess neuronal loss
in AD.
SD-OCT
Recent advancement in OCT technology has
gradually shifted the focus from TD-OCT to SD-
OCT, which offers improved performance. The main
difference between both systems is the movement
of the reference mirror. In TD-OCT, the reference
mirror is displaced and scanned mechanically over
a distance to obtain depth scans. This reference
mirror is immobilised in the SD-OCT. Spectral
domain-OCT employs a different detection scheme
from the TD-OCT, using a single spectrometer with
a dispersive element such as diffraction grating.
This allows broadband interference to be acquired
using a broadband source. The single spectral
measurement detected then undergoes Fourier
transformation, which allows axial depth scans to
be obtained without mechanically scanning the
reference mirror, thus increasing scan speed51.
The signal-to-noise ratio of SD-OCT is also
independent of both bandwidth and scan depth,
giving it improved sensitivity over TD-OCT52. In
SD-OCT, higher spatial resolution is achievable
with increased source bandwidth, which is not
possible in TD-OCT, as increased source bandwidth
would decrease signal-to-noise ratio51 and reduce
sensitivity. The SD-OCT can achieve a higher axial
scan rate with greater scan depth, which is highly
desired in OCT systems.

Fig. 1. Rapid three-dimensional scan of the optic disc cube using SD-OCT allows comprehensive morphology of the ONH and retina to
be visualised.
Spectral domain-OCT offers ultra-high scan speed
and image resolution, providing depth resolution
to a few microns, allowing improved sampling
of retinal tissue layers and three-dimensional
mapping53–55 (Fig. 1). Spectral domain-OCT can
produce a 6 mm by 6 mm scan of the optic disc
in 1.48 seconds with its improved scan speed.
Three-dimensional models of the ONH can also be
obtained, allowing better visualisation of retinal
pathology and quantification of parameters such
as RNFL thickness and neuroretinal rim area. In
addition, improved axial resolution enables more
reliable measurement and visualisation of detailed
intra-retinal layers.
Spectral domain-OCT techniques have not been
widely used in the study of AD, but a few studies
which have started to employ the use of SD-OCT
to access RNFL and RNFL+GCL thickness in case-
control studies have shown promising results.
Kirbas et al56 has reported significantly reduced
average RNFL thickness in patients at early stages
of AD, with selective thinning in the superior
quadrant, compared to healthy controls. Marziani
et al57 has likewise reported reduced RNFL and
RNFL+GCL thickness in AD patients, as compared
to cognitively normal controls matched for age
and sex. Such findings are consistent with previous
TD-OCT studies. Currently, we are unable to derive
conclusive differences between the findings of
studies using SD-OCT and TD-OCT due to the
lack of sufficient data from AD studies using SD-
Proceedings of Singapore Healthcare  Volume 23  Number 1  2014
SD-OCT in Alzheimer’s Disease
OCT. Additionally, these studies have not used the
high-resolution imaging of the SD-OCT to assess
the ganglion cell-inner plexiform layer (GC-IPL)
independently of the RNFL, which has potential as
a more sensitive indication of neuronal loss in AD.
RNFL ANALYSIS USING SD-OCT
Figure 2 shows evidence of RNFL thinning observed
in AD patients, using Carl Zeiss Meditec CirrusTM HD-
OCT. Image analysis and quantitative optic nerve
parameters were obtained by the built-in review
software. The software carries out automated
segmentation of the RNFL, quantifying the RNFL
thickness map (6 mm by 6 mm) and average
RNFL thickness, thickness per quadrant (superior,
temporal, inferior, nasal) and per 12-clock-hours
along the calculation circle (3.14 mm diameter), as
well as a series of ONH parameters (e.g. optic disc
area, neuroretinal rim area and cup-to-disc ratio).
The software also allows the comparison of RNFL
thickness against a normative database present
within the software, highlighting abnormalities if
RNFL thickness is lower than the fifth percentile
of the normative population. Abnormal RNFL
thickness is highlighted in yellow if the reading
is lower than the fifth percentile of the normative
population, and highlighted in red if it is lower
than the first percentile. Readings within the 95th
percentile of the population are considered normal
and coloured green.
Based on the RNFL analysis report from an
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Review

Fig. 2. Retina nerve fibre layer (RNFL) analysis report of an AD patient reflecting varying parameters including topological display of
RNFL, deviation from normative data and thickness analysis by quadrant; figures in yellow and red (see online version of article) indicate
RNFL thickness (average, quadrant or clock hours) to be lower than fifth and first percentile of normative population respectively. RNFL
thinning is apparent in multiple quadrants, as well as in the average RNFL of both eyes.

AD patient (Fig. 2), Retinal nerve fibre layer GC-IPL ANALYSIS

abnormalities can be observed in both eyes.
The average RNFL thickness of the right eye is
highlighted in yellow and that of the left eye is
red, indicating that the average RNFL thickness of
each eye is lower than the fifth and first percentile
of the normative population respectively. Detailed
analysis of the RNFL quadrants shows that RNFL
thinning is apparent in the superior quadrant of
the right eye, and the superior, nasal and inferior
quadrants of the left eye. These findings remain
consistent with earlier TD-OCT studies, which
have generally associated RNFL thinning with
neurodegeneration in AD.
One of the main advantages of the SD-OCT over
the TD-OCT is the increased axial resolution, which
provides clearer and more reliable identification
and quantification of intra-retinal layers. Some of
the retinal layers of interest include the ganglion
cell and inner plexiform layers54 (Fig. 3), which
could not be reliably identified and clearly
demarcated using the TD-OCT. The ganglion cell
layer is located near the surface of the retina and
consists of the nuclei of RGCs. The inner plexiform
layer is located below the ganglion cell layer, and
contains the dendrites of RGC. In past studies, the
reduced resolution of the TD-OCT could only allow

78 Proceedings of Singapore Healthcare  Volume 23  Number 1  2014


Fig. 3. Clear demarcation of detailed retinal layers including the nerve fibre layer, ganglion cell layer and inner plexiform layers using
the SD-OCT.
the quantification of the RNFL, which only consists
of the axons of RGCs. With the improved resolution
of the SD-OCT, assessment of the GC-IPL can be
carried out in addition to RNFL analysis. This allows
a full assessment of the RGC density present in the
retina and hence provides a more comprehensive
picture of retinal neuronal loss.
Figure 4 shows evidence of GC-IPL thinning in an AD
patient. In the GC-IPL analysis, the review software
of the SD-OCT detects the macula region and lays
a grid over it, carrying out automatic segmentation
of the macula into six sectors. The quantification
of the GC-IPL layer is carried out at the macula
where the RGC population is the densest, with
approximately 50% of the RGCs located in this
region. The grid is centred at the fovea, at which
RGCs are absent, and quantification of the layer is
done on the surrounding macula region. Similar
to the RNFL analysis, the average thickness of the
GC-IPL layer is measured in microns, as well as the
thickness per sector. Abnormalities in thickness are
highlighted in red and yellow. Based on the GC-
IPL analysis of the AD patient (Fig. 4), thinning of
the GC-IPL is apparent based on the yellow- and
red-coloured sectors of the macula of both eyes,
which indicate deviation from the normative data.
Proceedings of Singapore Healthcare  Volume 23  Number 1  2014
SD-OCT in Alzheimer’s Disease
In addition, the average GC-IPL thickness of the left
eye is also thinner than the fifth percentile of the
normative population.
FUTURE DIRECTIONS
Spectral domain-OCT offers a significant advantage
in ophthalmology studies over the TD-OCT,
allowing the study of additional retinal parameters
such as RGCs, which could be more sensitive than
current parameters used in AD retinal studies.
Spectral domain-OCT has shown promising results
based on RNFL and GC-IPL analyses, identifying the
presence of RGC and optic nerve damage in AD.
More recently, SD-OCT technology has been used
in studies of other CNS and neurodegenerative
disorders such as Parkinson’s disease58–60 and
multiple sclerosis61, to evaluate retinal parameters
including RNFL thickness, inner retinal layer
thickness and macular thickness. There is definitely
potential for this technology to be used in further
studies of neurodegenerative diseases.
Furthermore, SD-OCT enables clearer identification
and demarcation of retinal layers with the improved
scan resolution. This function allows follow-up of
modifications in retinal pathology of patients to be
tracked, an improvement from TD-OCT. Past studies
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Fig. 4. Ganglion cell-inner plexiform layer (GC-IPL) analysis report of an AD patient reflecting GC-IPL thickness maps, deviation from
normative data and sector maps; figures in yellow and red (see online version of article) indicate GC-IPL thickness (average or sector)
to be lower than fifth and first percentile of normative population respectively. GC-IPL thinning is apparent in multiple sectors of both
eyes.

using OCT imaging mainly had small sample
sizes and were cross-sectional in design14,15,43–46,
but longitudinal studies are essential in order to
assess the aetiological, diagnostic and predictive
value of retinal changes for AD. With a tracking
function, longitudinal studies tracking the changes
in retinal parameters over time can be carried out,
allowing the predictive ability of retinal changes
in AD development to be assessed. The rapid scan
acquisition speed of SD-OCT also allows better
patient cooperation from patients with MCI or
dementia.
Constant advancement in OCT techniques can
improve the quality of ocular imaging in AD,
providing new qualitative and quantitative data
that may provide new information for assessing
neurodegeneration in AD. The development of the
swept source OCT (SS-OCT) addresses some of the
limitations of the SD-OCT, including the reduced
signal strength and image quality in patients with
ocular opacities. SS-OCT and SD-OCT, which are
classified as Fourier domain OCT techniques, have
higher scans speeds than the TD-OCT as the need
for mechanical depth scanning is eliminated62.
Depth scans, or axial scans, can be calculated using
a Fourier-transform of the spectra, thus improving
scan speeds of both SS-OCT and SD-OCT. Hence,

80 Proceedings of Singapore Healthcare  Volume 23  Number 1  2014


the SS-OCT maintains the same advantage of
scan speed over TD-OCT, allowing more effective
retinal imaging of dementia patients, who have
shorter attention spans and higher tendency
for nystagmus63.
Swept source-OCT also has an improved signal-
to-noise ratio as compared to TD-OCT64, providing
scans of higher resolution. SD-OCT utilises a
broadband light source, while the SS-OCT “sweeps”
a narrow band laser through a broad optical
bandwidth, obtaining time-encoded spectral
information. Hence, the setup of the SS-OCT is
simpler as it uses a single photodiode detector
instead of the spectrometer needed to detect the
spectral information in SD-OCT65. With the absence
of the spectrometer, the SS-OCT has higher
detection efficiency as the spectrometer grating
losses are eliminated66. In addition, the SS-OCT
has further advantages over the SD-OCT, including
increased sensitivity with imaging depth, reduced
fringe washout and longer imaging range66.
Additionally, it allows higher penetration into the
ONH and choroid as well as lowered sensitivity to
ocular opacities67–70. This is essential in assessing
parameters in dementia patients, who tend to be
older and more likely to have more ocular opacities.
Adaptive optics (AO) is another form of technology
that can be used in combination with OCT by
providing improved lateral scan resolution.
Adaptive optics technology measures ocular
aberrations in real-time using a wavefront sensor
and corrects for these errors with a wavefront
corrector71. This complements the high axial
resolution of OCT scans, improving overall
scan resolution. In addition to improved lateral
resolution, AO reduces speckle size and increases
sensitivity to weak reflections71. Using AO-OCT
systems, volume images of retinal structures
including retinal nerve fibre bundles, retinal
capillaries, cone photoreceptors, microstructures in
the ganglion cell layer and the lamina cribrosa71 can
be obtained in detail. By using AO-OCT techniques,
more qualitative and quantitative parameters of
the retina can be investigated in greater detail.
The development of the SD-OCT offers a high-
resolution, high-speed imaging technique
that has shown potential in improving the
understanding of dementia. Aside from applying
this technique in the diagnosis of retinal diseases,
Proceedings of Singapore Healthcare  Volume 23  Number 1  2014
SD-OCT in Alzheimer’s Disease
it may also enhance the understanding of the
role of retinal involvement in neurodegenerative
disease progression.
In summary, the use of SD-OCT or future OCT
techniques may be potentially useful in assessing
neuronal loss in AD, allowing evaluation of disease
progression even in preclinical stages, as well as
evaluating treatment in clinical trials.
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