Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease LITERATURE REVIEW ON THE CORRELATION BETWEEN ABNORMALITIES IN EYE MOVEMENT AND THE PRESENCE OF ALZHEIMER DISEASE

Abstract

Alzheimer's Disease (AD) is a major societal and financial burden. The current diagnostic tools rely on invasive and expensive tests, most notably MRI and PET scan.Additionally, clinicians rely on neuropsychiatric assessments, which are also affected by the age and background of a person. Therefore, the search for biomarkers of AD has been an area of emphasis. This literature review of various biomarkers identifies a non-invasive and inexpensive adjunct tool, which is easy to implement. Also, the paper includes a mean strength of the proposed biomarker based on literature involving various biological components and the strength of various relations between the components using Hardy Weinberg's mathematical model. A novel techno-clinical paradigm is proposed based on eye saccade as an affordable and easy to use adjunct diagnostic tool for early detection and ongoing monitoring of progression of AD.

Full text

International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 –8991, ISSN(e): 2321 –9009
Volume-8, Issue-3, Jul.-2020, http://iraj.in
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
84
LITERATURE REVIEW ON THE CORRELATION BETWEEN
ABNORMALITIES IN EYE MOVEMENT AND THE PRESENCE OF
ALZHEIMER DISEASE
1HARSH PANCHAL, 2ANIKET DE, 3CHIBUZO AGBAKWURUONYIKE, 4YING JIANG, 5PAYAM
KAMJOO
1,2,3,4,5Esurgi Inc., USA
E-mail: 1hp6267@gmail.com, 2aniketde9@gmail.com, 3drfranklinchibuzo@yahoo.com, 4jiangying19@outlook.com,
5payam@myesurgi.com
Abstract - Alzheimer's Disease (AD) is a major societal and financial burden. The current diagnostic tools rely on invasive
and expensive tests, most notably MRI and PET scan.Additionally, clinicians rely on neuropsychiatric assessments, which
are also affected by the age and background of a person. Therefore, the search for biomarkers of AD has been an area of
emphasis. This literature review of various biomarkers identifies a non-invasive and inexpensive adjunct tool, which is easy
to implement. Also, the paper includes a mean strength of the proposed biomarker based on literature involving various
biological components and the strength of various relations between the components using Hardy Weinberg's mathematical
model. A novel techno-clinical paradigm is proposed based on eye saccade as an affordable and easy to use adjunct
diagnostic tool for early detection and ongoing monitoring of progression of AD.
Keywords - Alzheimer’s Disease, Biomarkers, Early Detection, Real-Time Monitoring, Screening Tool, Saccade.
I. INTRODUCTION
Nearly 50 million individuals worldwide suffer from
Alzheimer's or related dementia. AD poses a major
public health burden globally being the 6th leading
cause of death in the U.S.A. In the U.S. alone, the
prevalence had risen by 0.5 million in 2019 when
compared with the number in 2009 [1]. To provide
care to AD and other dementia patients Americans
invested 290 billion dollars including $195 billion in
Medicare and Medicaid payments, along with 16
million people providing unpaid care in 2019 which
amounted to the sum of $234 billion. Deaths from
AD have risen by 145 percent between 2000 and
2017. For people 65 or older, where the incidence of
AD was estimated 97%; found in about 2 of every
1000 people, the risk of developing AD doubles
every five years [2].
There is currently no available definitive treatment
for AD, however, the current state strategy for
investigators of AD solutions is to improve early
detection and ongoing monitoring of the disease
progression, which will promote early initiation of
interventions that may delay the disease progression
that is projected to impact public health [3]. Though
definitive diagnosis for AD requires histopathology,
since brain tissue samples required for
histopathological diagnosis are not done on live
patients, a clinical diagnosis has remained the best
substitute.
Clinical screening modalities for AD are an interplay
of assessments that take into account the spectrum of
the cognitive and functional status of the patient.
Patients who test positive for the cognitive and
functional deficit during screening such as the Mini-
mental State Examination (MMSE) or the Montreal
Cognitive Assessment (MoCA), then undergo clinical
diagnostic neuroimaging such as MRI or PET scans
and CSF tests according to the AD diagnostic criteria
[4]. Cognitive screening results, as well as the
diagnostic neuroimaging and CSF results, play a
crucial role in defining the clinical stages of AD
dementia [5]. Environmental and socio-cultural
context has also been considered to play a role in the
diagnosis of AD, though these factors are less
objective [6].
Cognitive tests such as MMSE form the initial basis
of an assessment of dementia-associated diseases
such as AD including Mild Cognitive Impairment
(MCI) as well as severe AD. However, its major
shortcoming is that it does not clearly differentiate
AD from non-AD dementia. This has sparked
continued research on other more objective screening
modalities that can support cognitive assessments
during the initial workups for AD before the
recommendation of more invasive diagnostic tests
such as the neuroimaging and the CSF. This
supportive screen modality should be able to
demonstrate some AD-specific characteristics
especially during the early stages of AD.
Several studies have demonstrated a pattern of eye
movement changes that occur in MCI and AD
patients which has opened an opportunity for
potential screening and monitoring. It is imperative to
have an overview of the scientific premise on which
eye movement changes can serve as an important
clinical tool in the early screening of AD. The four
basic eye movements are smooth pursuit, vergence,
vestibuloocular and saccades. Of these eye
movements, the saccades have been shown
consistently to change among MCI and AD patients
and these changes may have started to occur in the
preclinical stages of AD before the time that overt

International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 –8991, ISSN(e): 2321 –9009
Volume-8, Issue-3, Jul.-2020, http://iraj.in
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
85
observable cognitive changes are seen in the clinical
stages of AD [7], [8].
Normal saccade generation, control, and their
corrective anti-saccade modifications occur via a
complex neurological circuit through the brain which
involves multiple regions in the cortex, brainstem and
the cerebellum including- frontal eye field, parietal
eye field, supplementary eye field, substantia nigra
pars reticulata, reticular formation dorsolateral
prefrontal cortex and the oculomotor neuron which
transmits all the neural commands from these regions
to move the eye [9], [10].
Neuropathological studies of AD have shown that the
disease process affects different areas of the
neocortex with the entorhinal and hippocampal
cortical areas mostly implicated. These cortical
pathological changes occur long before the
appearance of clinical signs and symptoms that
constitute the criteria for the diagnosis of the clinical
stage of the AD [11]. Parts of the neocortex such as
the frontal, parietal, occipital, and temporal cortices
are affected during these early pathological changes,
and the neuropathological changes in these areas are
implicated in eye movement dysfunctions seen in AD
patients. Though no studies have demonstrated the
exact point and when the neural-circuitry break had
occurred in the complex oculomotor pathways
involved in the eye movement dysfunction, many
studies have observed eye movement changes before
the appearance of overt symptomatic cognitive
deficits among MCI and AD patients [12]. Thus, eye
movement abnormalities occur as early as the
preclinical phase of AD [13].
It has been demonstrated that the changes in these
basic eye movements do not occur in isolation but are
cognitively controlled and this is suggested to be the
reason why there is a correlation between these eye
movement changes especially the saccadic latency,
peak velocity, anti-saccade error rates and the clinical
stages of AD by MMSE [14]. Thus, saccadic eye
movement changes seen in AD patients have the
potential for monitoring AD progression. This article
aims to identify biomarkers candidates that are
associated with AD, identify biomarkers that can be
used in early detection and ongoing monitoring of
progression of AD, assess the strength of the
associated biomarkers, and recommend a future path
in AD solution as an adjunct screening and
monitoring tool.
II. REVIEW OF RESEARCH STUDIES
2.1. Current state of identified AD biomarkers
Though studies have identified several biomarkers in
the AD pathogenesis, a few are clinically significant.
Yet, realistic technology does not exist to implement
all these biomarkers in clinical settings.
 Abnormal proteins: The neurofibrillary
tangles (NFT) of tau proteins and the
amyloid plaques have been one of the most
consistent biomarkers associated with AD
which is still currently used in the diagnostic
evaluation of AD. AD patients are
associated with a significant elevation of
phosphorylated tau proteins in their CSF
[15].Amyloid plaques that are deposited in
the neurons of the CNS can be detected on
MRI and PET scans. Residues of beta-
amyloid peptides are significantly detected
in the CSF of AD patients [16], [17].
 Neurotransmitter alterations: Low levels
of acetylcholine (Ach), serotonin,
norepinephrine (NE), dopamine (DOPA),
and GABA have been associated with AD.
The most significant reduction of
neurotransmitters was seen in the levels of
acetylcholine and this was due to a more
than 50% decrease in the activity of the
Choline Acetyltransferase (CAT) in AD
patients [18].
 Inflammatory cytokines (cyto):
Accumulation of NFT and amyloid plaques
in AD patients have been the trigger of these
cytokine productions. High levels of
inflammatory cytokines in CSF have been
implicated [19], [20].
 Complement proteins (Cmpl): Many
studies show significant low levels of
complement proteins in the CSF of AD
patients [21].
 MicroRNAs: AD patients demonstrated a
significant increase in microRNA in their
plasma and CSF. The levels of the
microRNA showed a linear correlation with
plaque score [22], [23].
 Gingipains: The level of gingipains showed
a linear correlation with the levels of
abnormal tau proteins associated with AD,
though it is unclear whether gingipain
associated neurolysis in AD patients have a
secondary association due [24].
Most of the above-mentioned biomarkers associated
with AD are analyzed either with the CSF sample or
in very limited situations with the blood sample and
therefore will require some level of an invasive
technique. In contrast, eye movement changes that
have been linked with most of the neurodegenerative
disorders can be elicited by physical examination or
non-invasive technique. More directly, in AD
patients, specific patterns of saccadic eye movement
changes have demonstrated a significant association
with AD. Patients with AD have increased saccade
latency [25]. They also showed a reduced peak
velocity of the saccades [26]. A decline in attention
instead of a pure motor deficit was responsible for the
abnormalities associated with the generation of
saccades in AD patients [27]. The two most
consistent impairments in saccades that have emerged
from AD research are an increased frequency of

International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 –8991, ISSN(e): 2321 –9009
Volume-8, Issue-3, Jul.-2020, http://iraj.in
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
86
saccadic intrusions during fixation of a visual target,
and errors in the antisaccade process [28], [29].
The antisaccade process can assess the functionality
of the dorsolateral prefrontal cortex (DLPFC) which
is noted to be impaired in AD. Thus, providing a link
between physical findings such as the antisaccade
pattern and structural changes such as affectation of
the DLPFC in AD patients. Therefore, antisaccades
can be used as a tool for monitoring the progression
of AD [30]. AD patients showed marked impairment
in the antisaccade task which reflects the inhibitory
functions. As a result, the antisaccades can be used to
measure the executive function in AD patients.
Antisaccade error rates correlate with dementia
severity in AD. Though considered as a biomarker in
novel stages of research, high frequency of saccadic
intrusions, saccadic latency, and the antisaccade error
rate patterns have shown to be the most consistent
components of saccadic abnormalities registered in
AD patients[31].
2.2. Need: Early detection and monitoring
There is a need to identify patients who go on to
develop AD in preclinical stages. The
neuropathological research has demonstrated that
there is a stage of AD during which patients are
asymptomatic with normal cognition on clinical
assessment but has some depositions of
neurofibrillary tangles and neuritic plaques in the
brain with patterns that are different from normal
aging but closely related to pathological aging known
as the preclinical stage of AD [32]. MCI is still
regarded as the initial stage of symptomatic cognitive
decline without a functional decline in activities of
daily living.
The paradigm of the current research targets three
major diagnostic pathways which are biofluid,
neuropsychological assessments, and neuroimaging.
The main biofluid biomarker is CSF assay for
qualitative and quantitative analysis of
phosphorylated Tau protein (p-tau), t-tau protein,
beta-amyloid peptide (Aβ1-42); for neuropsychological
testing, MMSE and MoCA tests are frequently used
and for neuro-imaging, fluoro-deoxy-glucose-
positron emission tomography (FDG-PET) scan is
most significant for analyzing plaques in the brain
especially in the entorhinal and hippocampal cortical
regions [33]-[35]. Also, some studies have included
genetic components such as ApoE4 carriers. Overall,
the predictive strength and sensitivity of a multimodal
approach that takes into account all of these three
pathways, as well as a genetic component in detecting
MCI and conversion to AD, are higher than utilizing
a single pathway [36].
The neuropsychiatric test pathways such as using
MMSE and MoCA are among the safest, convenient
and the cheapest among the above-mentioned
pathways. Through this pathway, when used as a
single modality approach, it serves only as a sensitive
screening test for the detection of MCI but is less
predictive for MCI conversion to AD and therefore is
weak as a single tool for monitoring progression of
MCI towards possible AD [37]. Nonetheless, MMSE
and MoCA have remained the current state widely
used clinical screening tool for MCI and AD [38].
Though they can barely be considered as objective
screening tools, their scoring can be flawed with
several biases including interpretation, educational
level of the patient and cultural factors [39]. These
cognitive screening tests are also less specific as a
single tool since they can generally screen for other
dementia subtypes [40]. Frequent spinal tap for CSF
analysis can cause life-threatening complications
such as a spinal epidural abscess or epidural
hematoma. Frequent neuroimaging with PET scan
will expose patients to ionizing radiation.
In summary, these complex procedures are very
expensive and life-threatening for patients to keep up
with. Though one can argue that these multimodal
diagnostic pathways could be safely used once for
early detection of MCI and prediction for the
conversion of MCI to AD due to the above-
mentioned side effects, however, since AD is a
progressive disorder and therefore requires both early
detection and monitoring with the goal of attempting
to intervene early and delay the process from the
early stages, then there is still a need for a monitoring
tool that is sensitive as well as specific.
III. RESULTS AND DISCUSSION
3.1. Analysis
To determine the existence of the relationship
between AD and abnormalities in saccadic eye
movement, we took into consideration various
significant components that indirectly link the
changes associated with AD and the impact on the
eye movement attributes. In other words, though
there are studies linking AD and saccadic changes,
there are also additional studies linking AD and
neurotransmitter changes, and studies linking
neurotransmitter changes and changes in saccadic eye
patterns. A 1:1 relationship among the significant
components impacting the relationship was made.
The relationship strength is defined by the legends
below table no. 1. Using a sum of all the prominent
components and taking a percentage out of the total,
it showcases how strongly each component is related
to another, bringing us to the mean strength of
67.64% as a whole.
A mathematical model was used to determine the
existence of the changes in the AD stage and
abnormalities in saccadic eye movement. An analysis
akin to Hardy-Weinberg law was used here as the
evidence-based ordinal association. Using the
principle of Hardy-Weinberg law that was used for
population genetics, we looked at several variables,
including biomarkers, that have relationships with
AD, with a focus saccade [41].

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Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
87
Table 1. A 1:1 relationship between components
Where the indirect relationship might support the
primary relationship, the formula of Hardy-Weinberg
Law was used. Here, x±y=z, which means that the
indirect relationship might be equally, less, or
stronger than the primary relationship. Here, x and y
stand for the relationship between components. For
example, in table no. 2, serial no. 1, x = relationship
between changes in AD and NE, y = relationship
between changes in NE and changes in saccadic eye
movement, and z = relationship between changes in
AD and changes in saccadic eye movement.
Making an assumption where z, the outcome of the
primary relationship does exhibit a relationship and x,
y and z are not equal to zero. Also, an isolated system
is considered where the relationship is not affected by
any other external factors. Making a hypothesis
where z can be either greater than or less than 0, if
squaring on both sides of x+y=z, itcan conclude that z
is always ≥0. Considering the expected result to be
z=1 (strong relation), the bond of AD to Saccade
using Hardy Weinberg's equation is x2+y2±2xy≥1. In
fig.1., a graph of the equation along with the points
considering legends are showcased. The blue points
fall within the graph while the red points fall outside
the graph. Other outcomes are also showcased in the
graph where an increase in one component leads to a
decrease in another component as -x or -y shown as *
in the table no.1. Even if the relationship is inverse,
the impact should be almost similar, and the Hardy
Weinberg law supports such situations by squaring
the negative components and considering a
comparatively lower value.
A similar concept was followed for an indirect
relationship with 3 links, which makes use of the
extended Hardy Weinberg's law where x+y+w≥z.
Although, a graph of this would be 4D which is not
feasible to plot, so the output was calculated using
x2+y2+w2±2xy±2yw±2wx in the table only. The result
is calculated using a weighted average: an increase in
the number of indirect components, the strength of
the primary bond decreases[42]. Components having
either a low or no relationship were excluded in the
analysis due to limited studies.
 None (0): If no articles or studies are found
or if it demonstrated that there is no
relationship.
 Low (0.33): If any article suggested a
relationship between two components
without experimental results, or if there is an
indirect relationship.
 Medium (0.5): If the conclusion of the
article is based on a preliminary
experimental study showcasing a
relationship.
 High (1): If multiple experimental studies
concluded a strong relationship supported by
any proof of concept or analysis result.
Sr.
no.
Associated components
Strength
(%)
1
AD
NE
Saccade
200
2
AD
Ach
Saccade
200
3
AD
DOPA
Saccade
50
4
AD
Serotonin
NE
Saccade
300
5
AD
Amyloid
plaques
NE
Saccade
300
6
AD
Ach
NE
Saccade
300
7
AD
Cmpl
NE
Saccade
300
8
AD
DOPA
NE
Saccade
33.33
9
AD
GABA
NE
Saccade
208.33
10
AD
MicroRNA
NE
Saccade
133.33
11
AD
Tau
proteins
NE
Saccade
208.33
12
AD
Ach
DOPA
Saccade
208.33
13
AD
Serotonin
DOPA
Saccade
208.33
14
AD
Cyto
DOPA
Saccade
33.33
15
AD
MicroRNA
DOPA
Saccade
133.33
16
AD
Tau
proteins
DOPA
Saccade
133.33
17
AD
GABA
DOPA
Saccade
8.33
18
AD
Serotonin
Ach
Saccade
300
19
AD
Cyto
Ach
Saccade
33.33
20
AD
Cmpl
Ach
Saccade
208.33
21
AD
MicroRNA
Ach
Saccade
208.33
22
AD
Tau
proteins
Ach
Saccade
208.33
23
AD
GABA
Ach
Saccade
133.33
Table 2. Components association

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Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
88
It can be seen that many relationships in the above
table showcase more than 100% of strength, meaning
that the points fall outside the graph of x2+y2±2xy or
x2+y2+w2±2xy±2yw±2wx, thus suggesting the
existence of a relationship between changes in AD
and abnormalities in saccadic eye movement.
Fig. 1. Graph of Hardy Weinberg law
3.2. Conclusion
None of the currently used biomarkers and diagnostic
gold-standards associated with AD can be elicited by
physical examination or non-invasive technique.
There is a requirement for an objective screening tool
that can support neuropsychiatric assessments such as
MMSE as a multimodal screening strategy for early
detection of preclinical stages of the AD. MMSE
alone as a screening test is not purely objective and
can be biased. Early detection is still of utmost
importance to achieve the goal of early intervention
which can delay the progression of mild stages of AD
to severe stages of AD. A non-invasive monitoring
tool that can record real-time eye movement patterns
occurring in MCI and AD patients can help select
qualified candidates who may require more invasive
diagnostic tests.
Numerous studies and the mathematical model
analysis presented here also demonstrates that there
exists an association between the existence of AD and
the changes in saccadic eye movement, making the
eye movement a significant biomarker.
3.3. Future directions
Developing a novel device based on this science can
help perform screening in preclinical stages for MCI
and its progression through AD. This future novel
device will potentially support the Neuropsychiatric
tests i.e. MMSE and MoCA as an adjunct screening
tool. It can also serve as a monitoring tool for
registering progressive changes in patients with MCI
and help predict the conversion of MCI to AD. This
device will be operating on the level of physical
assessment and can serve as a bridging screening and
monitoring tool between the neuropsychiatric testing
pathway and the neuro-imaging biomarker by
eliciting physical changes as a good representation of
anatomical changes in the brain. Though this may not
have the predictive strength as the multimodal
approach discussed above with regards to
neuroimaging and CSF biomarkers, it is expected
based on the scientific premise to have more
predictive strength when used with neuropsychiatric
test than the single approach with only
neuropsychiatric test and yet less harmful to patients
than CSF-derived biomarkers or neuroimaging.
Patients who register eye movement patterns
suggestive of preclinical AD indications, MCI
conversion to AD, or progression of AD in real-time,
can then be exposed to more invasive FDG-PET and
CSF analysis if required. Thus, monitoring eye
movement changes satisfies the need for an adjunct
tool to support a more robust neuropsychological test
pathway and it should be able to elicit early physical
changes that can be used to screen for MCI and
monitor its progression. The MMSE or MoCA can
form a multimodal approach at the physical
assessment level which can increase the predictive
strength of assessing MCI conversion to AD.
Saccades cannot be used in AD patients who may
also have primary or secondary visual disorders that
can prevent subjects from performing eye tracking
such as complete blindness; though AD causes a
visuospatial problem that is linked to dementia. The
visuospatial problem secondary to AD is the reason
for the loss of orientation.
Recent advances in technology can enable us to
identify and quantify eye movement abnormalities,
inexpensively, safely, and noninvasively, and on an
ongoing basis. Utilizing the saccadic frequency and
latency, and the antisaccade error rate patterns of
patients who are at risk of developing AD (pre-
clinical stage), as well as patients who already have
AD, are future possibilities for early detection and
monitoring of AD patients, respectively.
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