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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



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.
International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 8991, ISSN(e): 2321 9009
Volume-8, Issue-3, Jul.-2020,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
1,2,3,4,5Esurgi Inc., USA
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.
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
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,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
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.
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,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
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.
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].
International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 8991, ISSN(e): 2321 9009
Volume-8, Issue-3, Jul.-2020,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
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
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
High (1): If multiple experimental studies
concluded a strong relationship supported by
any proof of concept or analysis result.
Associated components
Table 2. Components association
International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 8991, ISSN(e): 2321 9009
Volume-8, Issue-3, Jul.-2020,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
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.
[1] Alzheimer’s Association, 2009 Alzheimer’s Disease Facts
and Figures, Alzheimer’s & Dementia, Volume 5, Issue 3.
[2] Alzheimer’s Association. 2020 Alzheimer’s Disease Facts
and Figures. Alzheimers Dement 2020;16(3):391.
[3] Brookmeyer R, Gray S, Kawas C. Projections of
Alzheimer's disease in the United States and the public health
impact of delaying disease onset. Am J Public Health.”
[4] McKhann GM, Knopman DS, Chertkow H, et al. The
diagnosis of dementia due to Alzheimer's disease:
recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines
for Alzheimer's disease. Alzheimers Dement.
[5] Alzheimer’s Association, Alzheimers-Demential. Stages of
[6] Boenink, Marianne et al. “Assessing the sociocultural
impacts of emerging molecular technologies for the early
diagnosis of Alzheimer's disease.” International journal of
Alzheimer's disease vol. 2011 (2011): 184298.
[7] Gerardo Fernández, Pablo Mandolesi, Nora P. Rotstein,
Oscar Colombo, Osvaldo Agamennoni, Luis E. Politi; Eye
Movement Alterations During Reading in Patients With Early
Alzheimer Disease. Invest. Ophthalmol. Vis.
Sci. 2013;54(13):8345-8352.
International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 8991, ISSN(e): 2321 9009
Volume-8, Issue-3, Jul.-2020,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
[8] Armstrong, Richard A. "Alzheimer's Disease And The
Eye". Journal Of Optometry, vol 2, no. 3, 2009, pp. 103-
111. Elsevier BV,.
[9] Molitor, Robert J. et al. "Eye Movements In Alzheimer's
Disease". Journal Of Alzheimer's Disease, vol 44, no. 1,
2015, pp. 1-12. IOS Press,
[10] Jamadar, Sharna D. et al. "Behavioral And Neural Plasticity
Of Ocular Motor Control: Changes In Performance And Fmri
Activity Following Antisaccade Training". Frontiers In
Human Neuroscience, vol 9, 2015. Frontiers Media SA,
[11] Beason-Held, Lori L et al. “Changes in brain function occur
years before the onset of cognitive impairment.” The Journal
of neuroscience: the official journal of the Society for
Neuroscience vol. 33,46 (2013): 18008-14.
[12] Srivastava, Anshul et al. “The Relationship between Saccades
and Locomotion.” Journal of movement disorders vol. 11,3
(2018): 93-106. doi:10.14802/jmd.18018
[13] Wilcockson, Thomas D W et al. “Abnormalities of saccadic
eye movements in dementia due to Alzheimer's disease and
mild cognitive impairment.” Aging vol. 11,15 (2019): 5389-
[14] Terao, Yasuo et al. “What do eye movements tell us about
patients with neurological disorders? - An introduction to
saccade recording in the clinical setting.” Proceedings of the
Japan Academy. Series B, Physical and biological sciences
vol. 93,10 (2017): 772-801. doi:10.2183/pjab.93.049
[15] Lewczuk, Piotr et al. "Tau Protein Phosphorylated At
Threonine 181 In CSF As A Neurochemical Biomarker In
Alzheimer's Disease: Original Data And Review Of The
Literature". Journal Of Molecular Neuroscience, vol 23, no.
1-2, 2004, pp. 115-122. Springer Science And Business
Media LLC, doi:10.1385/jmn:23:1-2:115.
[16] NORDBERG, AGNETA. "In Vivo Detection Of
Neurotransmitter Changes In Alzheimer's Disease". Annals
Of The New York Academy Of Sciences, vol 695, no. 1,
1993, pp. 27-33. Wiley, doi:10.1111/j.1749-
[17] Hu, K., Harper, D., Shea, S. et al. Noninvasive fractal
biomarker of clock neurotransmitter disturbance in humans
with dementia. Sci Rep 3, 2229 (2013).
[18] Smyth, Matthew D. et al. "Decreased Levels Of C1q In
Cerebrospinal Fluid Of Living Alzheimer Patients Correlate
With Disease State". Neurobiology Of Aging, vol 15, no. 5,
1994, pp. 609-614. Elsevier BV.
[19] Terai, K et al. "Neurons Express Proteins Of The Classical
Complement Pathway In Alzheimer Disease". Brain
Research, vol 769, no. 2, 1997, pp. 385-390. Elsevier BV.
[20] Yasojima, Koji et al. "Up-Regulated Production And
Activation Of The Complement System In Alzheimer's
Disease Brain". The American Journal Of Pathology, vol 154,
no. 3, 1999, pp. 927-936. Elsevier BV.
[21] Denk, Johannes et al. "Microrna Profiling Of CSF Reveals
Potential Biomarkers To Detect Alzheimer's Disease". PLOS
ONE, vol 10, no. 5, 2015, p. e0126423. Public Library Of
Science (Plos), doi:10.1371/journal.pone.0126423.
[22] Dominy, Stephen S. et al. "PorphyromonasGingivalis in
Alzheimer’s Disease Brains: Evidence For Disease Causation
And Treatment With Small-Molecule Inhibitors". Science
Advances, vol 5, no. 1, 2019, p. eaau3333. American
Association For The Advancement Of Science (AAAS),
[23] Hershey, L. A. et al. "Saccadic Latency Measurements In
Dementia". Archives Of Neurology, vol 40, no. 9, 1983, pp.
592-593. American Medical Association (AMA),
[24] Schewe, H J et al. “Abnormality in saccadic eye movement in
dementia.” European psychiatry: the journal of the
Association of European Psychiatrists vol. 14,1 (1999): 52-3.
[25] Shafiq-Antonacci, Ruxsana et al. “Spectrum of saccade
system function in Alzheimer disease.” Archives of
neurology vol. 60,9 (2003): 1272-8.
[26] Yang, Qing et al. “Specific saccade deficits in patients with
Alzheimer's disease at mild to moderate stage and in patients
with amnestic mild cognitive impairment.” Age (Dordrecht,
Netherlands) vol. 35,4 (2013): 1287-98. doi:10.1007/s11357-
[27] Currie, J et al. “Validation of a clinical antisaccadic eye
movement test in the assessment of dementia.” Archives of
neurology vol. 48,6 (1991): 644-8.
[28] Garbutt, Siobhan et al. “Oculomotor function in
frontotemporal lobar degeneration, related disorders and
Alzheimer's disease.” Brain: a journal of neurology vol.
131,Pt 5 (2008): 1268-81. doi:10.1093/brain/awn047.
[29] Antoniades, C A, and C Kennard. “Ocular motor
abnormalities in neurodegenerative disorders.” Eye (London,
England) vol. 29,2 (2015): 200-7. doi:10.1038/eye.2014.276
[30] Petersen, Ronald C. “Early diagnosis of Alzheimer's disease:
is MCI too late?.” Current Alzheimer research vol. 6,4
(2009): 324-30. doi:10.2174/156720509788929237.
[31] Bittencourt, Juliana et al. “Saccadic eye movement
applications for psychiatric disorders.” Neuropsychiatric
disease and treatment vol. 9 (2013): 1393-409.
[32] Sperling, Reisa A et al. “Toward defining the preclinical
stages of Alzheimer's disease: recommendations from the
National Institute on Aging-Alzheimer's Association
workgroups on diagnostic guidelines for Alzheimer's
disease.” Alzheimer's & dementia: the journal of the
Alzheimer's Association vol. 7,3 (2011): 280-92.
[33] Ewers, Michael et al. “Prediction of conversion from mild
cognitive impairment to Alzheimer's disease dementia based
upon biomarkers and neuropsychological test performance.”
Neurobiology of aging vol. 33,7 (2012):1203-14.
[34] Arevalo-Rodriguez, Ingrid et al. “Mini-Mental State
Examination (MMSE) for the detection of Alzheimer's
disease and other dementias in people with mild cognitive
impairment (MCI).” The Cochrane database of systematic
reviews vol. 2015,3 CD010783. 5 Mar. 2015,
[35] de Leon, M J et al. “Imaging and CSF studies in the
preclinical diagnosis of Alzheimer's disease.” Annals of the
New York Academy of Sciences vol. 1097 (2007): 114-45.
[36] Ritter, Kerstin et al. “Multimodal prediction of conversion to
Alzheimer's disease based on incomplete biomarkers.”
Alzheimer's & dementia (Amsterdam, Netherlands) vol. 1,2
206-15. 30 Apr. 2015, doi:10.1016/j.dadm.2015.01.006
[37] O'Caoimh, Rónán et al. “Screening for Mild Cognitive
Impairment: Comparison of "MCI Specific" Screening
Instruments.” Journal of Alzheimer's disease : JAD vol. 51,2
(2016): 619-29. doi:10.3233/JAD-150881.
[38] Ismail, Zahinoor et al. “Brief cognitive screening
instruments: an update.” International journal of geriatric
psychiatry vol. 25,2 (2010): 111-20. doi:10.1002/gps.2306.
[39] Bonnie Slavych, Pros and Cons of Various Screening Tools
for Dementia. Ashawire. May 2019.
[40] Hwang AB, Boes S, Nyffeler T, Schuepfer G
(2019) Validity of screening instruments for the detection of
dementia and mild cognitive impairment in hospital
inpatients: A systematic review of diagnostic accuracy
studies. PLOS ONE 14(7): e0219569.
[41] Shanakerr, Population Genetics: the Hardy-Weinberg
Principle. Biology 1510 Biological Principles, (2016).
[42] Steve Selbst, Reimbursement Benchmarking: Weighted
Averages and the Importance of Codes. September 01, 2015.
[43] Hampel, Harald et al. “The cholinergic system in the
pathophysiology and treatment of Alzheimer's disease.” Brain
: a journal of neurology vol. 141,7 (2018): 1917-1933.
[44] Connell, Charlotte J W et al. “Fatigue-related impairments in
oculomotor control are prevented by norepinephrine-
dopamine reuptake inhibition.” Scientific reports vol. 7
42726. 15 Feb. 2017, doi:10.1038/srep42726
International Journal of Advances in Science Engineering and Technology, ISSN(p): 2321 8991, ISSN(e): 2321 9009
Volume-8, Issue-3, Jul.-2020,
Literature Review on the Correlation between Abnormalities in Eye Movement and the Presence of Alzheimer Disease
[45] Hampel, Harald et al. “The cholinergic system in the
pathophysiology and treatment of Alzheimer's disease.”
Brain: a journal of neurology vol. 141,7 (2018): 1917-1933.
[46] Márquez-Ruiz, Javier, and Miguel Escudero. “Eye
movements and abducens motoneuron behavior after
cholinergic activation of the nucleus reticularis
pontiscaudalis.” Sleep vol. 33,11 (2010): 1517-27.
[47] Pan, Xiongfeng et al. “Dopamine and Dopamine Receptors in
Alzheimer's Disease: A Systematic Review and Network
Meta-Analysis.” Frontiers in aging neuroscience vol. 11 175.
11 Jul. 2019, doi:10.3389/fnagi.2019.00175
[48] Pinkhardt, E.H., Jürgens, R., Lulé, D. et al. Eye movement
impairments in Parkinson's disease: possible role of
extradopaminergic mechanisms. BMC Neurol 12, 5 (2012).
[49] Blier, P. “Crosstalk between the norepinephrine and serotonin
systems and its role in the antidepressant response.” Journal
of psychiatry & neuroscience: JPN vol. 26 Suppl,Suppl
(2001): S3-10.
[50] Kalinin, Sergey et al. “Noradrenaline deficiency in brain
increases beta-amyloid plaque burden in an animal model of
Alzheimer's disease.” Neurobiology of aging vol. 28,8
(2007): 1206-14. doi:10.1016/j.neurobiolaging.2006.06.003.
[51] Vizi E.S. (1974) Interaction between Adrenergic and
Cholinergic Systems: Presynaptic Inhibitory Effect of
Noradrenaline on Acetylcholine Release. In: Csillik B.,
Kappers J.A. (eds) Neurovegetative Transmission
Mechanisms. Journal of Neural Transmission, vol 11.
Springer, Vienna
[52] Fraser, Deborah A et al. “C1q differentially modulates
phagocytosis and cytokine responses during ingestion of
apoptotic cells by human monocytes, macrophages, and
dendritic cells.” Journal of immunology (Baltimore, Md.:
1950) vol. 183,10 (2009): 6175-85.
[53] Carly Vandergriendt, “What’s the Difference Between
Dopamine and Serotonin?” Healthline, Dec 2018.
[54] Fujimura, S et al. “Effects of GABA on noradrenaline release
and vasoconstriction induced by renal nerve stimulation in
isolated perfused rat kidney.” British journal of
pharmacology vol. 127,1 (1999): 109-14.
[55] Deng, Maoxian et al. “MicroRNAs 29b and 181a down-
regulate the expression of the norepinephrine transporter and
glucocorticoid receptors in PC12 cells.” Journal of
neurochemistry vol. 139,2 (2016): 197-207.
[56] Cella Henry Arnaud, Finding a path between amyloid-β and
tau. C&EN Volume 98, Issue 4. Jan 2020.
[57] Vizi, S E et al. “Inhiitory effect of dopamine on acetylcholine
release from caudat nucleus.” Polish journal of pharmacology
and pharmacy vol.29,3 (1977): 201-11.
[58] Seo, Dongju et al “Role of Serotonin and Dopamine System
Interactions in the Neurobiology of Impulsive Aggression
and its Comorbidity with other Clinical Disorders.”
Aggression and violent behavior vol. 13,5 (2008): 383-395.
[59] Ch Beck, G., Brinkkoetter, P., Hanusch, C. et al. Clinical
review: Immunomodulatory effects of dopamine in general
inflammation.Crit Care 8, 485 (2004).
[60] Lewohl JM, Nunez YO, Dodd PR, Tiwari GR, Harris RA,
Mayfield RD (November 2011). "Up-regulation of
microRNAs in brain of human alcoholics". Alcoholism,
Clinical and Experimental Research. 35 (11): 192837.
[61] Koppel, Jeremy & Jimenez, Heidy & Adrien, Leslie &
Chang, Eric & Malhotra, Anil & Davies, Peter. (2018).
Increased tau phosphorylation follows impeded dopamine
clearance in a P301L and novel P301L/COMT‐deleted (DM)
tau mouse model. Journal of Neurochemistry. 148.
[62] Hoerbelt, Paul et al. “Dopamine directly modulates GABAA
receptors.” The Journal of neuroscience: the official journal
of the Society for Neuroscience vol. 35,8 (2015): 3525-36.
[63] Feuerstein, T J et al. “Modulation of cortical acetylcholine
release by serotonin: the role of substance P interneurons.”
Naunyn-Schmiedeberg's archives of pharmacology vol. 354,5
(1996): 618-26. doi:10.1007/bf00170837.
[64] Reale, Marcella et al. “Relation between pro-inflammatory
cytokines and acetylcholine levels in relapsing-remitting
multiple sclerosis patients.” International journal of
molecular sciences vol. 13,10 12656-64. 3 Oct. 2012,
[65] Singh, Jameel et al. “Role of complement component C1q in
the onset of preeclampsia in mice.” Hypertension (Dallas,
Tex.: 1979) vol. 58,4 (2011): 716-24.
[66] Nadorp, Bettina, and HermonaSoreq. “Predicted overlapping
microRNA regulators of acetylcholine packaging and
degradation in neuroinflammation-related disorders.”
Frontiers in molecular neuroscience vol. 7 9. 10 Feb. 2014,
[67] Rubio, Alicia et al. “Effect of acetylcholine on tau
phosphorylation in human neuroblastoma cells.” Journal of
molecular neuroscience: MN vol. 30,1-2 (2006): 185-8.
[68] Bianchi, C., Tanganelli, S., Marzola, G. et al. GABA
induced changes in acetylcholine release from slices of
guinea-pig brain.Naunyn-Schmiedeberg's Arch. Pharmacol.
318, 253258 (1982).
ResearchGate has not been able to resolve any citations for this publication.
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Background: There is increasing evidence that people in the early stages of Alzheimer's disease (AD) have subtle impairments in cognitive inhibition that can be detected by using relatively simple eye-tracking paradigms, but these subtle impairments are often missed by traditional cognitive assessments. People with mild cognitive impairment (MCI) are at an increased likelihood of dementia due to AD. No study has yet investigated and contrasted the MCI subtypes in relation to eye movement performance. Methods: In this work we explore whether eye-tracking impairments can distinguish between patients with the amnesic and the non-amnesic variants of MCI. Participants were 68 people with dementia due to AD, 42 had a diagnosis of aMCI, and 47 had a diagnosis of naMCI, and 92 age-matched cognitively healthy controls. Results: The findings revealed that eye-tracking can distinguish between the two forms of MCI. Conclusions: The work provides further support for eye-tracking as a useful diagnostic biomarker in the assessment of dementia.
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Introduction: As the population ages, Alzheimer's disease and other subtypes of dementia are becoming increasingly prevalent. However, in recent years, diagnosis has often been delayed or not made at all. Thus, improving the rate of diagnosis has become an integral part of national dementia strategies. Although screening for dementia remains controversial, the case is strong for screening for dementia and other forms of cognitive impairment in hospital inpatients. For this reason, the objective of this systematic review was to provide clinicians, who wish to implement screening, an up-to-date choice of cognitive tests with the most extensive evidence base for the use in elective hospital inpatients. Methods: For this systematic review, PubMed, PsycINFO and Cochrane Library were searched by using a multi-concept search strategy. The databases were accessed on April 10, 2019. All cross-sectional studies that utilized brief, multi-domain cognitive tests as index test and a reference standard diagnosis of dementia or mild cognitive impairment as comparator were included. Only studies conducted in the hospital setting, sampling from unselected, elective inpatients older than 64 were considered. Results: Six studies met the inclusion criteria, with a total of 2112 participants. Diagnostic accuracy data for the Six-Item Cognitive Impairment Test, Cognitive Performance Scale, Clock-Drawing Test, Mini-Mental Status Examination, and Time & Change test were extracted and descriptively analyzed. Clinical and methodological heterogeneity between the studies precluded performing a meta-analysis. Discussion: This review found only a small number of instruments and was not able to recommend a single best instrument for use in a hospital setting. Although it was not possible to estimate the pooled operating characteristics, the included description of instrument characteristics, the descriptive analysis of performance measures, and the critical evaluation of the reporting studies may contribute to clinician's choice of the screening instrument that fits best their purpose.
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Background: The dopaminergic system has been associated with the progression of Alzheimer's disease. But previous studies found inconsistent results regarding the relationship between Alzheimer's disease and dopamine when looking at dopamine receptor concentrations. Objective: The aim of this review was to synthesize, using a random-effects model of meta-analysis, the link between the dopaminergic system and Alzheimer's disease. Methods: A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42018110798). Electronic databases of PubMed, Embase, Web of Science, and Psyc-ARTICLES were searched up to December 2018 for studies that examined dopamine and dopamine receptors in relation to Alzheimer's disease. Standardized mean differences (SMD) were calculated to assess group differences in the levels of dopaminergic neurometabolites. Results: Seventeen studies met the eligibility criteria. Collectively, they included 512 patients and 500 healthy controls. There were significantly lower levels of dopamine in patients with Alzheimer's disease compared with controls (SMD = −1.56, 95% CI: −2.64 to −0.49). In addition, dopamine 1 receptor (SMD = −5.05, 95% CI: −6.14 to −3.97) and dopamine 2 receptor (SMD = −1.13, 95% CI: −1.52 to −0.74) levels were decreased in patients with Alzheimer's disease compared with controls. The results of network meta-analysis indicated that the rank of correlation with Alzheimer's disease from highest to lowest was dopamine (0.74), dopamine 2 receptor (0.49), dopamine 3 receptor (0.46), dopamine 4 receptor (0.33), dopamine 5 receptor (0.31), and dopamine 1 receptor (0.64). Conclusions: Overall, decreased levels of dopaminergic neurotransmitters were linked with the pathophysiology of Alzheimer's disease. Nonetheless, there is a clear need for more prospective studies to validate these hypotheses.
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Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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Fatigue-induced reductions in saccade velocity have been reported following acute, prolonged exercise. Interestingly, the detrimental impact of fatigue on oculomotor control can be prevented by a moderate dose of caffeine. This effect may be related to central catecholamine upregulation via caffeine’s action as an adenosine antagonist. To test this hypothesis, we compared the protective effect of caffeine on oculomotor control post-exercise to that of a norepinephrine-dopamine reuptake inhibitor. Within a placebo-controlled crossover design, 12 cyclists consumed placebo, caffeine or a norepinephrine-dopamine reuptake inhibitor (bupropion) during 180 minutes of stationary cycling. Saccades, smooth pursuit and optokinetic nystagmus were measured using infrared oculography. Exercise fatigue was associated with an 8 ± 11% reduction in the peak velocity of prosaccades, and a 10 ± 11% decrement in antisaccade peak velocity. Optokinetic nystagmus quick phases decreased in velocity by 15 ± 17%. These differences were statistically significant (p < 0.05). Norepinephrine-dopamine reuptake inhibition and caffeine prevented fatigue-related decrements in eye movement velocity. Pursuit eye movements and visual attention were unaffected. These findings show that norepinephrine-dopamine reuptake inhibition protects oculomotor function during exercise fatigue. Caffeine’s fatigue-reversing effects on eye movements appear to be mediated, at least in part, via modulation of central catecholamines.
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MicroRNAs are short non-coding RNAs that provide global regulation of gene expression at the post-transcriptional level. Such regulation has been found to play a role in stress-induced epigenetic responses in the brain. The norepinephrine transporter (NET) and glucocorticoid receptors are closely related to the homeostatic integration and regulation after stress. Our previous studies demonstrated that NET mRNA and protein levels in rats are regulated by chronic stress and by administration of corticosterone, which is mediated through glucocorticoid receptors. Whether miRNAs are intermediaries in the regulation of these proteins remains to be elucidated. The present study was undertaken to determine possible regulatory effects of miRNAs on the expression of NET and glucocorticoid receptors in the noradrenergic neuronal cell line. Using computational target prediction, we identified several candidate miRNAs potentially targeting NET and glucocorticoid receptors. Western blot results showed that overexpression of miR-181a and miR-29b significantly repressed protein levels of NET, which is accompanied by a reduced [3H] NE uptake, and glucocorticoid receptors in PC12 cells. Luciferase reporter assays verified that both miR-181a and miR-29b bind the 3’UTR of mRNA of NET and glucocorticoid receptors. Furthermore, exposure of PC12 cells to corticosterone markedly reduced the endogenous levels of miR-29b, which was not reversed by the application of glucocorticoid receptor antagonist mifepristone. These observations indicate that miR-181a and miR-29b can function as the negative regulators of NET and glucocorticoid receptor translation in vitro. This regulatory effect may be related to stress-induced upregulation of the noradrenergic phenotype, a phenomenon observed in stress models and depressive patients. This article is protected by copyright. All rights reserved.
Non-invasive and readily implemented in the clinical setting, eye movement studies have been conducted extensively not only in healthy human subjects but also in patients with neurological disorders. The purpose of saccade studies is to "read out" the pathophysiology underlying neurological disorders from the saccade records, referring to known primate physiology. In the current review, we provide an overview of studies in which we attempted to elucidate the patterns of saccade abnormalities in over 250 patients with neurological disorders, including cerebellar ataxia and brainstem pathology due to neurodegenerative disorders, and what they tell about the pathophysiology of patients with neurological disorders. We also discuss how interventions, such as deep brain stimulation, affect saccade performance and provide further insights into the workings of the oculomotor system in humans. Finally, we argue that it is important to understand the functional significance and behavioral correlate of saccade abnormalities in daily life, which could require eye tracking methodologies to be performed in settings similar to daily life.