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Alzheimer’s
disease (AD) is a neurodegenerative illness that involves the formation of beta
amyloid plaques, and tau clumps, leading to irreversible changes in the brain.
Studies have identified the correlation between particular alterations in the
physiology of the eye and early stages of AD, more specifically reduction in
the retinal nerve fibre layer (RNFL) thickness. Such changes can be quantitatively
measured through the use of specific ocular imaging techniques such as the
optical coherence tomography (OCT), and its different versions, all of which specialize
in taking cross-section images of the retina. The aim of this review is to highlight
the specific changes in RNFL in AD patients without visual impairment, as well
as the use of OCT as an accessible, and non-invasive method for AD assessment. In
general, research studies have shown that the average RNFL thickness of a
healthy individual is of ~75 µm; however, AD patients showed a decrease of approximately 10 µm, particularly
in the superior quadrant of the RNFL. Other areas of research have shown that various neurodegenerative
diseases, such as Parkinson’s disease, multiple sclerosis, and glaucoma, lead
to similar effects on the RNFL. Since AD is the most common form of dementia, advances
in the area of early diagnosis have become an important target in research,
which could result beneficial for further treatment of current and future patients
with the disease. Defining specific biomarkers could allow the clinicians to
decide the more appropriate approach to treat the patient, or even if there is
a possibility of administrating a preventive treatment. Future studies should
focus on defining the precise parameters under which biomarkers in the eye, like
RNFL thickness, can provide information on the progress of a neurodegenerative
disease such as AD.

Key words: Alzheimer’s disease, biomarker, neurodegeneration, eye, retinal fibre
layer, optical coherence tomography.

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Background

Alzheimer’s
disease (AD) is the most common type of dementia and currently affects 564,00
Canadians. Due to the increasing longevity of the population, this number will
elevate to 937,000 in the following 15 years, therefore making it one of the
most important topics in scientific research (Alzheimer Society of Canada, 2016;
Evans et al., 1989). The neuropathology of this disease involves the formation
of senile plaques that contain amyloid beta (Ab)
and intraneuronal fibrillary tangles, which result
in progressive cognitive impairment, and affected learning and executive
functions (Glenner, 2990; Harman, 2006; Kirbas et al., 2013; Tomlinson et al.,
1968, 1970). In fact, there is a correlation between the plaque count and
degree of dementia, which can be assessed through psychological tests that
indicate a relationship between the pathological lesions caused by the
aggregates, and the clinical symptoms of the illness (Blessed et al., 1968). Unfortunately,
the cognitive decline caused by AD arises after significant, irreversible
neurodegeneration has occurred, making it of great urgency to find a technique
to detect AD at an early stage (Frost et al., 2010). Thanks to the recognition
of the public health importance, AD has gained interest that has led to
extensive research regarding the symptoms, pathology, and treatment of the
disease. However, the search of a non-invasive technique that allows its
diagnosis before reaching an advanced stage is still in the works.

Extensive neuroscientific research has shown that certain brain areas including
the entorrhinal cortex, and the hippocampus, show pathological changes in early
stages of AD (Katzman & Saitoh, 1991). Further evidence suggests that the
eye is also affected in AD patients, some of who have reported visual
impairment potentially caused by the neurodegeneration of the retinal nerve
fibre layer (RNFL), and the optic nerve  (Berisha et al., 2009; Ohno-Matsui, 2011). Since the
RNFL is nonmyelinated until it enters the lamina cribrosa, it is a great
indicator of neurodegeneration, neuroprotection, and regeneration. These changes can be quantitatively measured in a non-invasive manner
through the use
of imaging techniques such as optical coherence tomography (OCT; Fercher, 1996).
Moreover, the comparison between OCT images of AD patients, and healthy
controls is a promising approach to identify a defined range of retinal axonal
loss that could be used as an indicator of AD.

Kirbas et al. (2013) opted
to thoroughly study the use of spectral domain OCT (SD-OCT) as a potential
instrument to detect degeneration of the RNFL in AD. This version of the OCT
offers imaging at higher speed and scan depth, thus making it more sensible to
changes in the RNFL (Yaqoob, 2005).The authors compared the measurements of AD
patients who were recently diagnosed with the disease, were untreated, and had
not expressed visual impairment, with the ones of healthy controls. The
analysis of the data indicated a decrease in RNFL thickness, especially in the
superior quadrant, in AD patients. This suggests that SD-OCT might be a useful
biomarker to understand the course of the illness, as well as to evaluate
potential treatment modalities. This review will present additional studies
that suggest the use of indicators in the eye to assess AD; support the use of OCT
as an instrument to clinically assess the disease; as well as their findings
concerning RNFL in specific.

Major Results

Kirbas et al. (2013) used SD-OCT images to analyze
RNFL thickness in untreated AD patients without visual impairment, and compared
the results with healthy controls. In addition, patients were also administered
a Mini-Mental State Examination (MMSE) which served to ensure that the patients
were in an early stage of AD. In this study all of the optic
nerve quadrants were analyzed, but the only significant results were those for
the superior quadrant (76 ± 6.7 mm vs 105 ± 4.8 mm; P = 0.001), as well as the overall average RNFL thickness (65 ± 6.2 mm vs
75 ± 3.8 mm; P = 0.001). Furthermore, there was no
correlation between MMSE scores and OCT measurements. In brief, there was a
noticeable decrease in the total RNFL thickness of AD patients compared with
healthy controls; this was mainly because of thinning of the superior quadrant
(see Figure 1). These results comply with prior findings that have described degeneration of the retina due to AD,
which has been identified both through clinical, and pathological techniques. Furthermore,
this indicates that decreased RNFL thickness of the superior quadrant could be
used as an indicator of AD.

The
eye as a biomarker. The eye is the only organ where both vascular and
neural tissue can be imaged through non-invasive techniques. In addition to its
accessibility for imaging, there have been several reports regarding AD
affecting the eye; therefore make it a window to brain pathology, and a great
candidate to be a biomarker for AD (Frost et al., 2010; Lim et al., 2016). Some
of the main findings show significant narrowing of the retinal veins (see
Figure 2), and a significantly reduced venous blood flow rate compared with control
subjects (Berisha et al., 2007; Ohno-Matsui, 2011). Other studies have
identified a significant decrease in the number of ganglion cells in the retina
of AD patients; hence representing sensory-system degeneration due to the
disease (Hinton et al., 1986). 

RNFL. There is neuroscientific evidence that associates
the RNFL with changes in scores that assess episodic memory, meaning that
changes in RNFL thickness could reflect a higher risk of developing cognitive
impairment (Mendez-Gómez et al., 2017).

Therefore, RNFL measurements have been extensively
used in research to assess neurodegeneration (Jones-Odeh, 2015; Satue et al.,
2010). Several studies have demonstrated significant thinning of the superior
quadrant of the RNFL in patients with AD compared with control subjects, which
has been calculated by some researcher to be around 10 to 11 ?m (Berisha et al., 2007;
Keslet et al., 2011; Ohno-Matsui, 2011).

Conclusions/Discussion

Researchers have demonstrated a significant thinning
of the RNFL in AD patients who have not expressed visual impairment. Similar
results have been found in other studies; however, the efficiency and
sensitivity of the SD-OCT have allowed identifying that the majority of these
changes affect the superior quadrant, where there was decrease of approximately
10 µm, compared to healthy controls. An accessible biomarker, such as the change
in RNFL thickness, gives clinicians the opportunity to provide neuroprotective
therapies during early stages of the disease, and may be of use for further
research on new treatments.

A plausible
explanation for the thinning of the RNFL in AD is death of retinal ganglion
cell axons, and retrograde degeneration due to further loss of cortical
neurons. The damage to these cells could be caused by the neurotoxicity of the
Ab
aggregates formed during AD. Scientific findings have shown that AD affects the
eye, and more specifically produces quantifiable retinal abnormalities that
include a specific pattern of RNFL decrease, narrow veins, and deficient blood
flow in retinal veins, all of which can be potential biomarkers for the disease
at its earlier stages, which
can impact the increasing numbers of patients with AD.

Critical Analysis

Kirbas et al.
(2013) showed consistent results to what has been shown in other studies: a
significant decrease in the RNFL thickness of AD patients, and that of healthy
subjects; all done through cross-sectional studies. Nonetheless, a longitudinal
approach could be beneficial to follow the changes in individual patients from
the time they are diagnosed. Furthermore, Kirbas and his group mention that they
evaluated patients who had not received any medications because these could
potentially stabilize, and slow down the progression of the disease. However, they
could further benefit from the follow up of patients after they have received treatment.

Future Directions

Future
studies should do SD-OCT studies that follow up patients starting at the time
they were diagnosed, and through their treatment. Furthermore, this technique
could also be used to analyze RNFL thickness of individuals in later stages of
AD, who could potentially be visually impaired. Data of patients who are in
later stages of AD should show an even thinner RNFL due to advanced
neurodegeneration. Whereas in follow-up SD-OCTs of untreated patients that
start receiving treatment researchers should expect to see progressive thinning
at a slow rate, which is probably not as severe as that of patients who were
undiagnosed until further development of the disease. Thorough analysis of
these groups could help define specific parameters that may differentiate
retinal pathology in early AD versus late AD. Nevertheless, no significant progression
in the deterioration of the RNFL as AD develops, could indicate that the
thinning of the RNFL is unique to early AD, and that it is not necessarily
caused by the increasing amount of plaque, but rather by other reasons than the
pathobiology of the disease. The outcome of these experiments can help find a
method to accurately timely diagnose AD; determine specific changes in the RNFL
as the disease progresses; and obtain detailed data that can contribute to the
research of current and future treatments.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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