Progress in Retinal and Eye Research 83 (2021) 100938

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Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/preteyeres

Past, present and future role of retinal imaging in

neurodegenerative disease
Amir H. Kashani a, g, 1, *, Samuel Asanad b, 1, Jane W. Chan c, 1, Maxwell B. Singer a, 1,
Jiong Zhang d, 1, Mona Sharifi d, 1, Maziyar M. Khansari d, 1, Farzan Abdolahi a, 1, Yonggang Shi d, 1,
Alessandro Biffi e, 1, Helena Chui f, 1, John M. Ringman f, 1
a
USC Roski Eye Institute and Department of Ophthalmology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
b
Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
c
Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA, USA
d
USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
e
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
f
Department of Neurology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
g
USC Ginsburg Institute for Biomedical Therapeutics, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Retinal imaging technology is rapidly advancing and can provide ever-increasing amounts of information about the
Retina structure, function and molecular composition of retinal tissue in humans in vivo. Most importantly, this information
Imaging can be obtained rapidly, non-invasively and in many cases using Food and Drug Administration-approved devices
Alzheimer’s disease
that are commercially available. Technologies such as optical coherence tomography have dramatically changed
Parkinson’s disease
our understanding of retinal disease and in many cases have significantly improved their clinical management.
Huntington’s disease
Cerebral small vessel disease Since the retina is an extension of the brain and shares a common embryological origin with the central nervous
system, there has also been intense interest in leveraging the expanding armamentarium of retinal imaging tech­
nology to understand, diagnose and monitor neurological diseases. This is particularly appealing because of the high
spatial resolution, relatively low-cost and wide availability of retinal imaging modalities such as fundus photog­
raphy or OCT compared to brain imaging modalities such as magnetic resonance imaging or positron emission
tomography. The purpose of this article is to review and synthesize current research about retinal imaging in
neurodegenerative disease by providing examples from the literature and elaborating on limitations, challenges and
future directions. We begin by providing a general background of the most relevant retinal imaging modalities to
ensure that the reader has a foundation on which to understand the clinical studies that are subsequently discussed.
We then review the application and results of retinal imaging methodologies to several prevalent neurodegener­
ative diseases where extensive work has been done including sporadic late onset Alzheimer’s Disease, Parkinson’s
Disease and Huntington’s Disease. We also discuss Autosomal Dominant Alzheimer’s Disease and cerebrovascular
small vessel disease, where the application of retinal imaging holds promise but data is currently scarce. Although
cerebrovascular disease is not generally considered a neurodegenerative process, it is both a confounder and
contributor to neurodegenerative disease processes that requires more attention. Finally, we discuss ongoing efforts
to overcome the limitations in the field and unmet clinical and scientific needs.

unique opportunity to study CNS pathology because of the shared

1. Introduction embryological origins, structure and physiology with the retina. Over
the last several decades, many investigators have attempted to leverage
The retina is the only portion of the central nervous system (CNS) the optical accessibility of the retina to better understand, diagnose and
that is optically accessible for high-resolution imaging. This presents a even treat neurodegenerative diseases including sporadic late onset

* Corresponding author. Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
E-mail address: akashan1@jhmi.edu (A.H. Kashani).
1
Percentage of work contributed by each author in the production of the manuscript is as follows: Amir H Kashani: 35%, Samuel Asanad: 15%, John Ringman: 5%,
Alessandro Bissi: 5%, Yonggang Shi: 5%, Helena Chui: 5%, Jane Chen: 5%, Jiong Zhang: 5%, Mona Sharifi: 5%, Maziar Khansari: 5%, Maxwell Singer: 5%, Farzan
Abdolahi: 5%.

https://doi.org/10.1016/j.preteyeres.2020.100938
Received 21 August 2020; Received in revised form 11 December 2020; Accepted 17 December 2020
Available online 15 January 2021
1350-9462/© 2021 Elsevier Ltd. All rights reserved.
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

List of abbreviations IPL Inner Plexiform Layer

INL Inner Nuclear Layer
CNS Central Nervous System ONL Outer Nuclear Layer
LOAD Late Onset Alzheimer’s Disease OPL Outer Plexiform Layer
ADAD Autosomal Dominant Alzheimer’s Disease GCIPL Ganglion Cell Layer + Inner Plexiform Layer
HD Huntington’s Disease GCC Retinal Ganglion Cell Complex (mRNFL + GCL + IPL)
PD Parkinson’s Disease PCA Posterior Cortical Atrophy
AD Alzheimer’s Disease NMO Neuromyelitis Optica
FTD Frontotemporal Dementia MOG Myelin Oligodendrocyte Glycoprotein
CSVD Cerebral Small Vessel Disease mRGC Melanopsin containing RGC
MS Multiple Sclerosis CSF Cerebrospinal Fluid
OCT Optical Coherence Tomography VCID Vascular Cognitive Impairment and Dementia
OCTA Optical Coherence Tomography Angiography FAZ Foveal Avascular Zone
PET Positron Emission Tomography ffERG Full Field ERG
MRI Magnetic Resonance Imaging SRL Superficial Retinal Layer
RGC Retinal Ganglion Cells DRL Deep Retinal Layer
LGN Lateral Geniculate Nucleus MoCA Montreal Cognitive Assessment
BRB Blood Retinal Barrier MMSE Mini-Mental Status Exam
BBB Blood Brain Barrier CAG Cytosine-adenine-guanine
RNFL Retinal Nerve Fiber Layer Htt huntington protein
pRNFL Peripapillary RNFL HC Healthy Control
mRNFL Macular RNFL VA Visual Acuity
αsyn Alpha-Synuclein DFE Dilated Fundus Examination
Aβ Beta-Amyloid IOP Intraocular Pressure
ptau Hyperphosphorylated Tau PSEN1 Presenilin 1
CFP Color Fundus Photography PSEN2 Presenilin 2
FAF Fundus Autofluorescence APP Amyloid Precursor Protein
FOV Field-of-View TDP43 Transactive Response DNA Binding Domain Protein 43
RPE Retinal Pigment Epithelium ALS Amyotrophic Lateral Sclerosis
HRI Hyperspectral Retinal Imaging CAA Cerebral Amyloid Angiopathy
FLIO Fluorescence Lifetime Imaging Ophthalmoscopy WMH White Matter Hyperintensity
ERG Electroretinography CMB Cerebral Microbleeds
mfERG Multifocal ERG HTNA Hypertension Associated Angiopathy
PERG Pattern ERG CADASIL Cerebral autosomal dominant arteriopathy with
VEP Visual Evoke Potentials subcortical infarcts and leukoencephalopathy
ON Optic Neuritis

Alzheimer’s Disease (LOAD), Huntington’s Disease (HD), Parkinson’s
Disease (PD), Multiple Sclerosis (MS), cerebral small vessel disease
(CSVD) and Frontotemporal Dementia (FTD). In many cases these
studies have demonstrated significant associations of retinal thickness
and function with disease severity and have provided tantalizing pos­
sibilities for disease assessment.
The development of imaging techniques such as optical coherence
tomography (OCT) and optical coherence tomography angiography
(OCTA) have reinvigorated the search for retinal changes that are
associated with neurodegenerative disease. Although clear clinical ap­
plications are needed, there are several reasons to continue the search
for in vivo retinal changes in neurodegenerative disease. First, diagnosis
of many neurodegenerative diseases requires significant time, resources
and cost. For example, positron emission tomography (PET) and mag­
netic resonance imaging (MRI) are commonly used in the evaluation of
intracranial pathology but both are time-intensive, not universally
available and come at significant cost. In addition, neither has the spatial
resolution to detect sub-millimeter changes in tissue pathology with
clinically useful reproducibility. In contrast, in vivo OCT imaging of the
retina provides near histologic level resolution of neurosensory tissue
and the recent advent of OCTA provides similar information about
retinal blood vessels, including capillaries. Therefore, there exists the
possibility that in vivo retinal imaging can provide useful biomarkers of
neurodegenerative disease much earlier in the disease process than
conventional neuroimaging methods or clinical examination. It is un­
likely and impractical to think that retinal imaging will be the sole or
even primary diagnostic criteria for any neurodegenerative process, but
there are at least three scenarios in which it might prove useful. First, in
vivo retinal findings in human subjects with neurodegenerative diseases
may provide new insight into the underlying disease pathophysiology.
Second, in vivo retinal imaging may be a relatively low-cost and widely
available screening tool for assessing risk for certain neurodegenerative
disease if appropriate biomarkers are identified. This would be a valu­
able tool in recruiting appropriate populations for clinical trials and for
more resource intensive testing such as brain imaging. Lastly, under the
most ideal circumstances, in vivo retinal imaging may be a useful pri­
mary or secondary endpoint in clinical trials.
In this article, we discuss the literature on the most prevalent and
well-described neurodegenerative diseases with retinal manifestations
and examine how rapidly evolving retinal imaging modalities can be
leveraged to advance our understanding of these diseases. While there
are currently few clinical indications for retinal imaging in neurode­
generative diseases, the opportunity clearly exists and future advances
in our understanding of the diseases and imaging methods may enable
such indications. By consolidating the knowledge about retinal imaging
findings in this comprehensive review we hope to provide a very useful
resource for ophthalmologists, neurologists, researchers and students to
understand the current state-of-the-art and advance the field in new
directions. It is important to mention that many neurodegenerative
diseases have extraretinal ophthalmic manifestations (e.g. oculomotor
abnormalities) that have been well-described in the neuro-
ophthalmologic literature and which we will not discuss here. We also

2
A.H. Kashani et al.
do not attempt to review the vast body of literature from informative
animal models of neurodegenerative disease so that we can focus on the
already vast number of applications of retinal imaging in human
neurodegenerative disease in this manuscript.
2. Rationale for retinal imaging in neurodegenerative disease
2.1. Embryology
The retina and optic nerve are derived from the neuroectoderm
around 23 days of gestation when they invaginate from the dienceph­
alon (Cameron et al., 2017). Therefore the retina shares a common
cellular origin with brain tissue and is considered part of the CNS.
Retinal neurons have many structural and functional similarities to
other neurons in the brain. Retinal ganglion cells (RGC) have axons that
extend to the lateral geniculate nucleus (LGN) via a nerve fiber tract
complete with an oligodendrocytic myelin sheath. Retinal neurons are
generally excitable and have synaptic interconnections mediated by
neurotransmitters including acetylcholine, dopamine, glutamate,
glycine, and gaba-aminobutyric acid (Gregg et al., 2013). This similarity
led to investigation of the pupillary response to dilute tropicamide, a
cholinergic antagonist, as a diagnostic test for LOAD, a disease in which
CNS cholinergic tone is widely depressed (Scinto et al., 1994; Kardon
1998; Iijima et al., 2003). Similar to other axonal pathways, damage to
the optic nerve causes retrograde and anterograde degeneration of the
axons, associated cell bodies and target tissues. For example, atrophy of
the retina is inversely associated with brain weight in persons with MS
(Green et al., 2010). A broad range of biophysical, pathological, clinical
and epidemiologic studies demonstrate that retinal blood vessels share
many similarities with cerebral vessels and undergo similar pathologic
changes implicated in cerebral small vessel disease (CSVD) (Zamir
1976a,b; Sherman 1981; Cogan and Kuwabara 1984; Törnquist and Alm
1986; Frank et al., 1990; Ravalico et al., 1996; Trost et al., 2016). Retinal
and cerebral blood vessels share significant similarity in capillary
branching angles and organization (Cogan and Kuwabara 1984),
carrier-mediated transport functions of blood-retina barrier (BRB) and
blood brain barrier (BBB) (Törnquist and Alm 1986), structural features
of capillaries and tight junctions (Trost et al., 2016), and
pericyte-to-endothelial cell ratio (Frank et al., 1990). In addition to these
similarities in health, there are many retinal manifestations of CNS
disease as we will discuss below.
2.2. Pathophysiological mechanisms of retinal degeneration in
neurodegenerative disease
Given the embryological and physiological similarity between the
neurosensory retina, retinal vasculature and brain, there are at least two
plausible pathophysiological mechanisms by which neurodegenerative
changes may manifest in the retina. One plausible mechanism is that the
underlying neurodegenerative process concurrently occurs in retinal
tissue as well as in the brain. Abnormal intracellular and extracellular
deposition of proteins such as tau, alpha-synuclein (αsyn), and beta-
amyloid (Aβ) among others are present in several neurodegenerative
disorders and are also found in the aging retina (Löffler et al., 1995;
Leger et al., 2011). There is also evidence that Aβ, tau and αsyn accu­
mulate in the retina of subjects with AD (Koronyo-Hamaoui et al., 2011)
and PD (Bodis-Wollner et al., 2014), respectively, and may therefore
mediate the same neurotoxicity in RGCs as in other CNS tissue. In one
study, atrophy of specific classes of RGCs was shown to be associated
with disturbance of the sleep-wake cycle in persons with AD (La Morgia,
Ross-Cisneros et al., 2016).
A second plausible mechanism is that neurodegenerative changes in
the CNS cause some form of retrograde degeneration of ganglion cell
axons and associated cell bodies located in the retina (Peng et al., 2020).
There is some evidence that diencephalic and brainstem visual centers
such as the LGN and superior colliculus manifest senile plaques and
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Progress in Retinal and Eye Research 83 (2021) 100938
neurofibrillary tangles (Leuba and Saini 1995) although the topographic
distribution of these changes does not consistently correspond with the
patterns of degeneration observed in the retinal nerve fiber layer
(RNFL). Analogous evidence exists from case reports of occipital lesions
in humans (Meier et al., 2015; Goto et al., 2016). Histopathologic
analysis of the visual system in primates with occipital lesions also re­
veals evidence of transsynaptic degeneration of RGCs (Cowey et al.,
2011). Localized defects in the RNFL are also significantly associated
with acute and chronic stroke independent of systemic vascular risk
factors such as hypertension and diabetes mellitus (Wang et al., 2014).
RNFL defects are also significantly associated with infarcts and white
matter lesions on MRI in large population-based studies (Kim et al.,
2011; Mauschitz et al., 2018). In subjects with PD, the laterality of
retinal findings seems to correlate with the more affected hemisphere
suggesting a neuroanatomic link (Pilat et al., 2016).
Lastly, it is likely that a combination of concurrent and sequential
degeneration is present in variable amounts depending on the specific
pathological process and its duration. We should note that these two
mechanisms described above are therefore not mutually exclusive.
3. Imaging methodologies
There are numerous methods of imaging the retina ranging from
relatively simple color photography to functional imaging of retinal
electrical activity. This wealth of imaging technology combined with the
optical accessibility of the retina has been one of the main motivations in
exploring the role of retinal pathology in neurodegenerative diseases.
Broadly speaking these imaging modalities can be divided into those
that demonstrate structural features of the retina and those that measure
some aspect of retinal function. Structural features include size of retinal
vessels, retinal lesions and thickness of retinal layers. Functional fea­
tures of the retina that are quantified by imaging methods include
retinal light sensitivity, blood flow and electrical activity. Below we
enumerate and describe the key modalities that have been used to study
retinal changes in neurodegenerative diseases. In the subsequent sec­
tions we discuss the applications of these imaging modalities in disease-
specific contexts. It is important to note that most of these modalities are
approved for clinical use in ophthalmology practices by the Food and
Drug Administration (FDA). Therefore they provide readily available
and clinically feasible tools for assessing retinal pathology in clinical
trials and health care settings.
3.1. Structural imaging
The most widely used and well-accepted modalities in retinal im­
aging provide some measure of retinal structure whether that is the
qualitative physical appearance of the retina or a quantitative measure
such as thickness. The sections below are not meant to be exhaustive
reviews of the imaging methodologies. Rather, these sections are meant
to provide an overview of the methods so that the relevance to neuro­
degenerative diseases discussed in subsequent sections can be more
easily understood.
3.1.1. Fundus photography
3.1.1.1. Color fundus imaging. Color fundus photography (CFP) repre­
sents the most common and widely used retinal imaging modality
(Yannuzzi et al., 2004; Panwar et al., 2016). CFP was traditionally
performed with film but is now available in true color and pseudocolor
digital format as well as multi-wavelength scanning laser ophthalmos­
copy. These cameras acquire information with relatively low spectral
resolution (red, green and blue color channels) but with high spatial
resolution approaching dozens of microns. Most fundus cameras require
pharmacologic pupillary dilation (mydriasis) which can be a barrier to
use in non-ophthalmic settings. Non-mydriatic cameras are becoming
A.H. Kashani et al.
more widely available but often have decreased resolution or
field-of-view (FOV).
It is important to note that there can be significant artifactual vari­
ations in the spectral patterns (color) of the normal retina using pseu­
docolor digital systems. The color of retinal lesions can be significantly
altered by the laser calibration of the camera and media properties of the
eye. Therefore, depending on the lesion of interest, some cameras may
be more suitable than others. One of the most important variables in CFP
is the FOV which can range from 30 degrees of the retinal surface to
more than 100◦ (Panwar et al., 2016). Digital montages of 30–50 degree
FOV are also possible to allow for evaluation of peripheral retinal
findings (Fig. 1). Common uses of CFP include identifying retinal lesions
(e.g. RNFL defects), measuring retinal vascular caliber (e.g. central
retinal artery and vein equivalents) and evaluating optic disc appear­
ance (e.g. pallor) in the posterior pole. Modern devices allow for im­
aging of almost the entire retina and are often referred to as “widefield”
(FOV approximately 90◦ ) or “ultra-widefield” (FOV greater than 90◦ )
devices Fig. 2 to contrast with those devices that have more restricted
fields (ranging between 30 and 50◦ ; Fig. 1). Widefield imaging has
particularly useful applications in identifying peripheral retinal pa­
thology that is difficult to describe and capture with conventional im­
aging (Kashani et al., 2014a,b). Therefore, one important parameter
when considering CFP is that the FOV may exclude relevant pathology
especially if it is located in the peripheral retina.
3.1.1.2. Fundus autofluorescence imaging. One form of fundus imaging
takes advantage of the natural autofluorescent characteristics of the
retina and retinal pigment epithelium (RPE). The retina has intrinsic
autofluorescence when stimulated by light at several wavelength ranges
that is commonly referred to as fundus autofluorescence (FAF) (Sparrow
et al., 2020). The FAF properties of the retina are studied at “short
wavelength” and “long wavelength” ranges (Kellner et al., 2010). FAF is
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Progress in Retinal and Eye Research 83 (2021) 100938
primarily thought to be a property of the RPE and not the neurosensory
retina itself, at least in normal subjects. In addition, FAF of the periph­
eral retina is relatively poorly studied, only recently becoming possible
with the advent of widefield imaging. Quantitative FAF measurements
from the retina can vary dramatically, even within the same subject, due
to relatively subtle changes in the optical media and light sources (Delori
et al., 2011). Therefore, in the absence of carefully calibrated mea­
surements quantitative FAF measurements with current commercially
available devices may not be reliable for longitudinal measurements
even within the same subject, at least in the absence of any significant
calibration efforts.
Stimulation of the retina with short wavelength light (in the range of
400–590 nm) is often referred to as “blue light” FAF and elicits auto­
fluorescence between 520 and 800 nm (Fig. 1D). The source of this blue
light FAF originates from the bisretinoid family of compounds often
referred to as lipofuscin and including A2-
glycerophosphoethanolamine, A2E and A2-dihydropyridine-
phosphatidylethanolamine (A2-DHP-PE). These compounds represent
the product of irreversible chemical reactions of retinaldehyde and the
lipid phosphatidylethanolamine that form in the photoreceptors and
accumulate in the RPE with age. Normal FAF exhibits a characteristic
hypoautofluorescence in the central macula that results from the
attenuation of excitation light by macular pigments (xanthophylls).
Outside of the central macula, the pattern of blue-light FAF is homog­
enous except for blood vessels and the disc which lack short-wavelength
autofluorescence. In addition to these characteristic spatial variations,
short-wavelength autofluorescence shows characteristic age-related
changes in normal subjects (Delori et al., 2001). The relatively
featureless autofluorescence patterns of normal retina provides a useful
background for detecting pathological lesions with potential auto­
fluorescent properties such as Aβ (Koronyo et al., 2017).
Long-wavelength autofluorescence is commonly generated using
near-infrared light between 700 and 800 nm with excitation in the range
Fig. 1. Examples of retinal imaging modalities
from a 65 year old female illustrate commonly
used methods for evaluation of retinal disease and
retinal changes in neurodegenerative diseases. (A)
Color fundus photograph illustrating the macula,
optic disc and retinal arteries and veins. (B) Digital
collage of color fundus images of the same subject
demonstrating 60–90◦ field of view that includes
the peripheral retina outside the vascular arcades.
(C) Optical coherence tomography angiogram of
the parafoveal area illustrating the capillaries in
the area and the foveal avascular zone. Red and
green pseudocoloring represent the depth of retinal
capillaries in the superficial and deep retinal
layers, respectively. (D) Short wave fundus auto­
fluorescence image of the macula.
A.H. Kashani et al.
Fig. 2. Ultra-Widefield fundus photograph and optical coherence tomography angiogram from a human subject. (A) Optos™ pseudocolor ultra-widefield fundus
photograph illustrates the peripheral retina where traditional color fundus imaging does not typically reach. (B) Widefield optical coherence tomography angiogram
(Zeiss PlexElite™) demonstrates non-invasive imaging of retinal arteries, veins and capillaries beyond the arcades in the same subject.
>800 nm. This form of FAF is primarily from the melanin content of the
RPE cells and to a lesser degree from the underlying choroidal mela­
nocytes but it can also be generated by elevated lipofuscin levels in some
retinal diseases. In contrast to the short-wavelength autofluorescence,
long-wavelength autofluorescence has its peak signal intensity in the
central macula.
3.1.1.3. Hyperspectral fundus imaging. Hyperspectral retinal imaging
(HRI) is one of the most recently developed forms of fundus photog­
raphy. Hyperspectral imaging is based on the principal of spectroscopy
commonly used for geospatial applications and astronomy. HRI takes
advantage of the wide-range of spectral features in the eye as well as
advances in spectroscopic imaging over the last several decades (Reshef
et al., 2020). HRI requires specialized illumination and detection hard­
ware that allows the high-resolution collection of a broad range of
wavelength information across the visible and near-visible electromag­
netic spectrum for each pixel in the acquired image. This contrasts with
more conventional multispectral CFP (see section 5.1.1.1) which ac­
quires information with lower spectral resolution. The most common
application of HRI has been to quantify retinal vascular oxygen content
in the form of retinal oximetry (Kashani et al., 2011; Mordant et al.,
2011; Jaime et al., 2012). This particular method takes advantage of the
well-known spectra of oxy- and deoxyhemoglobin. Several research
groups and commercial entities have adopted similar methodology to
examine the spectral features of Aβ in eye tissue (More et al., 2019) as
well as the human eye in vivo (Hadoux et al., 2019; Sharafi et al., 2019).
At least one study has demonstrated a significant correlation between
brain PET amyloid burden in humans and retinal spectra associated with
Aβ (Hadoux et al., 2019). Further discussion of this imaging modality in
disease-specific contexts is provided below and in a recently published
review in the context of AD (Gupta et al., 2020; Santangelo et al., 2020).
3.1.2. Fluorescence lifetime imaging ophthalmoscopy
While hyperspectral imaging assesses the breadth of spectral infor­
mation available from retinal tissue, fluorescence lifetime imaging
(FLIO) aims to quantify one specific aspect of the fluorescence of
endogenous tissues, namely the duration of fluorescence (Dysli et al.,
2017a,b). Of note, FLIO imaging systems are strictly for research and are
not FDA approved for clinical use. Excitation of endogenous fluo­
rophores by monochromatic light will cause excitation of natural fluo­
rophores that decay with characteristic lifetimes. The average time
between the excitation of the tissue with monochromatic light and the
return to the ground state is measured using FLIO. The lifetime of flu­
orophores is both a characteristic of the fluorophore as well as the sur­
rounding molecular environment. Among the most common retinal
fluorophores are phenylalanine, tyrosine, tryptophan, nicotinamide
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Progress in Retinal and Eye Research 83 (2021) 100938
adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD),
retinal, hemoglobin, melanin, collagen, lutein, zeazanthin, and lip­
ofuscin. Due to the optical properties of the eye and safety consider­
ations, not all retinal fluorophores are detectable in vivo. FLIO
measurements of normal retina have demonstrated discrete patterns for
various retinal regions such as the fovea, optic disc, retinal vessels and
non-foveal retina (Dysli et al., 2017a,b). Of particular relevance to the
current review is the potential use of FLIO to detect molecules impli­
cated in neurodegenerative disease such as Aβ, tau, and huntingtin. We
will provide a disease-specific discussion of this methodology in the
relevant sections below.
3.1.3. Optical coherence tomography
OCT is a very well-established imaging modality that provides high-
resolution images of the retinal structure based on interferometric
methods. OCT was first described in 1991 (Huang et al., 1991) and was
adopted widely in ophthalmology in the subsequent decades because it
allowed quantitative measurements of retinal thickness, choroidal
thickness and even sub-layer thickness with micron level precision
(Asanad et al., 2019a,b) (Fig. 3). These kinds of measurements were
adopted to understand how retinal anatomy can vary in vivo with normal
aging, gender and ethnicity (Kashani et al., 2010). OCT measurements
also provide the diagnostic basis on which anti-vascular endothelial
growth factor agents became widely used in ophthalmology for treat­
ment of macular edema in a wide range of diseases including age-related
macular degeneration and diabetic retinopathy (Drexler and Fujimoto
2008). The high-resolution capability of OCT has progressively
improved but even the original time-domain system design was rapidly
adopted by neurologists to study changes in the RNFL in MS (Petzold
et al., 2010) and AD (den Haan et al., 2017). Subsequent studies using
more advanced spectral domain systems have replicated and expanded
upon the previous studies (den Haan et al., 2017).
While we will explore the disease specific findings of OCT in subse­
quent sections of this review, it is important to make a few generalizable
points about OCT studies of the retina in neurodegenerative disease.
First, most OCT systems image a relatively small portion of the retina
ranging from 3 × 3 to 6 × 6mm regions of the central macula or optic
disc region. Therefore, the majority of retinal tissue is not sampled with
standard OCT imaging protocols. More recently, widefield systems can
acquire up to 12 × 12mm FOV (or more) but are costly, not yet
commonly available and have lower resolution than smaller scan pat­
terns. Second, there are numerous manufacturers of OCT systems. It is
well known that scan patterns, segmentation algorithms and outcome
measures vary significantly among manufacturers (Garcia-Martin et al.,
2012a,b; Garcia-Martin et al., 2014a,b; Satue et al., 2014; Chan et al.,
2019). Therefore, when comparing across studies, it is critical to keep in
A.H. Kashani et al.
Fig. 3. Example of retinal layer and choroidal identification on enhanced depth imaging optical coherence tomography (EDI-OCT) compared to histology. (A) OCT
image depicts retinal layers relative to the corresponding retinal layers on (B) histology in a representative control micrograph stained with hematoxylin and eosin
within the macula. (Reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) 4.0 International License from Asanad S,
Ross-Cisneros FN, Nassisi M, Barron E, Karanjia R, Sadun AA. The retina in Alzheimer’s disease: histomorphometric analysis of an ophthalmologic biomarker. Invest
Ophthalmol Vis Sci. 2019; 60:1491–1500. https://doi.org/10.1167/iovs.18-25966).
mind the details of the OCT system and scan parameters used. Third,
even within the same commercial system, segmentation algorithms may
vary over time and therefore the consistency of measurements made
with different generations of the same device may vary in subtle but
significant ways (Chan et al., 2019). Fourth, almost all studies that are
published to date use two-dimensional representations of retinal fea­
tures such as thickness and vessel density. These two-dimensional rep­
resentations of three-dimensional biological structures have inherent
limitations which we discuss at the end of this article with respect to
future directions.
Lastly, it is important to emphasize that while the resolution of OCT
devices is on the micron scale, the reproducibility of measurements
depend on the experience and training of users. In experienced hands,
the reproducibility of OCT based measurements of retinal thickness can
be excellent (Intraclass correlation coefficient = 1.0 (Hu et al., 2015)
and the coefficient of variation very low (0.5% in (Hu et al., 2015) and
0.4% in (Obis et al., 2020)). To achieve this level of reproducibility and
precision, significant effort has to be expended for training of users and
quality control of data.
3.2. Functional imaging
There are several imaging modalities that measure functional aspects
of the neurosensory retina and supporting tissues including the RPE and
retinal vasculature. These methods are distinctly different from the
structural imaging modalities discussed above because they measure an
aspect of cellular or tissue function, such as blood flow or electrical
activity, rather than provide a static rendering of the retinal structure
such as retinal thickness. Below we will review the most relevant of
these methodologies so that they can be discussed in disease specific
contexts in later sections. The sections below are not meant to be
exhaustive reviews of the methodologies. Rather these sections are
meant to provide an overview of the method and relevance to neuro­
degenerative disease in particular.
3.2.1. Optical coherence tomography angiography
OCTA is a recent imaging modality based on OCT that was FDA
approved in 2015. OCTA provides information based on the movement
of red blood cells within retinal capillaries and OCTA output is often
displayed as a static map of retinal capillary density. It is important to
keep in mind that while maps of retinal capillary density are often
interpreted as anatomic representation of capillaries, they are actually
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Progress in Retinal and Eye Research 83 (2021) 100938
derived from the perfusion state of capillaries. In this sense, OCTA can be
considered an assessment of capillary structure and/or perfusion. This
technology has also been extensively reviewed elsewhere (Kashani et al.,
2017; Borrelli et al., 2018) but is worth discussing here because it is
uniquely suited to demonstrate microvascular changes in the retina that
may correlate with vascular changes in the CNS. OCTA allows
depth-resolved imaging of the retinal vasculature that is far superior to
invasive angiography using fluorescein and approaching histologic
resolution (Matsunaga et al., 2014; Spaide et al., 2015a,b,c). This allows
separation of the retinal capillaries into at least two (or more) capillary
plexi commonly referred to as the superficial and deep retinal layers
(Figs. 1C and 2B) (Matsunaga et al., 2014; Campbell et al., 2017). In the
peripapillary region, there is an additional plexus, the peripapillary
radial capillaries, that feeds the RNFL (Matsunaga et al., 2014). OCTA
analyses are frequently reported as a density metric such as “vessel
density,” “skeleton density” or “perfusion density.” In all cases these
values are reporting the detection of red blood cell flow in patent retinal
capillaries. By definition, any value reported using OCTA is a “perfusion
density” metric because capillaries without flow (or with very slow flow)
are not detected. A detailed discussion of OCTA methodology is avail­
able elsewhere (Kashani et al., 2017; Spaide et al., 2018). It is notable
that most studies performed with OCTA to date only include assessments
of the central macula or parafoveal capillaries (Fig. 1C). However,
commercially available wide-field OCTA devices that can image the
retinal periphery are rapidly becoming available and will likely play an
important role in the future (Fig. 2). Similar to OCT based measures of
retinal thickness the reproducibility of OCTA measures can be excellent
with experienced users, appropriate device settings and quality control
steps (Chen C et al., 2016, Conti et al., 2018).
Capillary level changes detected by OCTA correlate with clinical
disease severity in diabetic retinopathy (Kim et al., 2016a,b; Kashani
et al., 2017), retinal vein occlusion (Kashani et al., 2015; Koulisis et al.,
2017) and even inflammatory diseases of the eye (Kim et al., 2016a,b)
among many others (Kashani et al., 2017). Several recent studies have
demonstrated correlations between capillary features and neurodegen­
erative disease, most notably in AD (O’Bryhim et al., 2018; Querques
et al., 2019). Vascular contributions to cognitive impairment and de­
mentia are common and their diagnosis and monitoring represents a
significant unmet medical need. More than 50% of subjects with LOAD
pathology have significant comorbid vascular pathology (Schneider
et al., 2004; Schneider, Arvanitakis et al. 2007, 2009b; Schneider et al.,
2009a). Consensus statements from several leading groups have helped
A.H. Kashani et al.
outline the potential relevance of vascular contributions to cognitive
impairment and dementia (VCID) (Gorelick et al., 2011; Snyder et al.,
2015). These consensus statements called for the development of novel,
clinically feasible biomarkers of vascular cognitive impairment and
dementia for which OCTA is a promising modality. It is noteworthy that
the same limitations that apply to OCT imaging systems apply in large
part to OCTA imaging (Spaide et al., 2015a,b,c). Further discussion of
this imaging modality in disease-specific contexts is provided in the
following sections.
Given the novelty of OCTA it is appropriate to briefly discuss its
limitations and the importance of quality control processes in image
acquisition and analysis. OCTA images are particularly prone to arti­
facts, even more so than the underlying OCT images, because they are
derived from at least two high-quality and coregistered OCT scans. The
most common OCTA artifacts result from the motion of the eye relative
to the OCTA device during image acquisition (Spaide et al., 2015a,b,c).
Although efforts have been made to circumvent and correct eye motion
during image acquisition, this still remains one of the most common
artifacts of OCTA images, especially in diseased eyes. Motion correction
technologies attempt to correct these movements but also create unique
patterns such as stretch artifact, quilting artifact, or duplication arti­
facts. Another common type of artifact results from loss of signal
detection by the device. For example, shadow artifacts results from the
blockage of signal by media opacities like floaters. It has been shown
that media opacities affect OCTA quantitative measures (Spaide et al.,
2015a,b,c). Blink artifacts results from temporary blockage of signal by
the eyelid. Advances in eye tracking technology now detect most eye
blinks and enable rescanning of the appropriate area. Segmentation
errors are another common type of artifact. Although software errors in
detection of retinal layer boundaries are seen less frequently in normal
eyes, segmentation errors are common in diseased eyes where layer
boundaries are irregular or altogether absent (Spaide et al., 2015a,b,c).
Image decentration is another problem that appears especially in sub­
jects with difficulty with foveal fixation. Although not technically an
artifact, decentration can significantly impact reproducibility of quan­
titative measurements. Decentration refers to the misalignment between
the foveal avascular zone (FAZ) and the center of the OCTA en face
image. Decentration severity can be graded based on the distance be­
tween the center of FAZ and center of the en face image.
As mentioned before, some of the artifacts seen in OCTA images are
intrinsic to the underlying OCT technology, the most common of them
being the projection artifact. Projection artifacts occur when the light
passing through the superficial vessels is altered by reflection or ab­
sorption by the blood cells and surrounding tissue. This light that has
passed through the superficial vessels is reflected back by tissues un­
derlying the superficial blood vessels, such as the Retinal Pigment
Epithelium (RPE), and is detected by the device. The reflected light from
the RPE, creates the false impression of moving red blood cells in vessels
within the RPE and, thus, overestimates perfusion density. These pro­
jection artifacts are observed in almost all of OCTA images but there are
commercially available projection removal algorithms that minimize
the impact of these artifacts on images (Spaide et al., 2015a,b,c).
3.2.2. Electroretinography
Electroretinography (ERG) provides a measure of the electrical ac­
tivity in the neurosensory retina and RPE. ERGs provide information
about neuronal and non-neuronal electrical activity in response to a
light stimulus (Frishman 2013). The electrical activity of the retina, like
other neuronal tissue, is driven by ionic gradients, primarily sodium and
potassium, of the cellular components. ERGs provide very useful infor­
mation across a wide-range of retinal diseases and the pathophysiology
of ERG changes, at least for some disease processes, are well understood.
While this review will not attempt a comprehensive review of this topic,
it is worth noting the key features of ERGs here so that readers can have
context when reading disease specific findings in later sections.
ERGs are obtained by surface electrodes placed on the eye and
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eyelids while simultaneous light stimulation is provided to one or both
eyes. ERGs can be tuned to record light information preferentially from
rods or cones as well as the downstream retinal circuitry that processes
photoreceptor information. For example, the a-wave of the standard or
full-field ERG (ffERG) is primarily derived from rods and cones
depending on the dark adaptation status of the retina. The b-wave
represents responses primarily from Muller and bipolar cells. The c-
wave represents electrical activity of the RPE. Because of the summation
of electrical activity at the corneal surface, ERGs are not sensitive to
disease that affects a relatively small retinal area. There are very useful
variations on the ERG methods, such as multifocal ERG (mfERG), which
measures predominantly cone function in the central 30 degrees of the
macula and pattern reversal ERG (PERG), which measures predomi­
nantly ganglion cell activity (Baker et al., 1988; Frishman 2013;
Lachowicz and Lubiński 2018).
3.2.3. Visual evoked potentials
Visual evoked potentials (VEP) are not a form of direct retinal im­
aging but do reveal useful information about retinal function as well as
the afferent arm of the visual pathway. A VEP is a measure of the light-
induced electrical activity recorded from scalp electrodes placed over
the occipital cortex. It is a form of electroencephalography where the
signal-to-noise ratio can be significantly enhanced by averaging time-
dependent visual stimuli. The most widely used VEP data come from
measurements of the amplitude and latency of the initial negative peak
(N1), subsequent positive peak (P1 or P100), following negative peak
(N2) and ultimate positive peak (P2). Abnormal VEP responses can be
due to abnormalities along any portion of the afferent visual pathway
from the cornea and lens to the occipital cortex. VEPs are particularly
useful in persons in whom an assessment of the visual potential is needed
but the subject is unable to cooperate (e.g. children or developmentally
delayed adults). Just as with ERG testing, there are useful variations of
VEP testing, such a pattern-reversal VEP, which can provide more spe­
cific information about particular portions of the visual pathway. VEP
abnormalities have been noted in several neurodegenerative diseases
including MS and PD, suggesting they are not specific for a particular
disease process (Regan and Neima 1984). It is reasonable to assume that
any process which causes significant retinal dysfunction (e.g. glaucoma)
will also cause abnormalities in the downstream tissues impacting VEP.
Therefore, VEPs may have some useful role in assessing visual potential
and location of anatomic lesions in neurodegenerative diseases, espe­
cially when subjects are unable to cooperate with other forms of testing.
4. Disease specific applications of retinal imaging
4.1. Multiple Sclerosis
Multiple Sclerosis (MS) is an autoimmune disease classically char­
acterized by inflammation and demyelination of the CNS though
neuronal and axonal degeneration have more recently come to be
appreciated as critical processes in its pathogenesis (Campbell and
Mahad 2018). MS impacts about 300,000 people in the United States
and more than 2 million people around the world (Schiess and Calabresi
2016). The most characteristic lesions of MS are focal demyelinated
plaques in the CNS that are accompanied by inflammation and gliosis.
Unlike other neurodegenerative disorders, patients with MS often pre­
sents with visual symptoms at the early stages of the disease secondary
to retrobulbar optic neuritis. Vision loss is associated with dull retro­
bulbar pain and often aggravated by eye movement. Common visual
symptoms and signs include decreased visual acuity, loss of contrast
sensitivity, a worsening red-green color defect, and an enlarging central
scotoma, that usually peak at several days to a week (Group 2008). The
Optic Neuritis Treatment Trial evaluated 389 subjects with acute uni­
lateral optic neuritis without a diagnosis of MS (Evangelou et al., 2001)
and followed them for 15 years (Group 2008). This study showed that
the aggregate cumulative probability of developing MS at 15 years was
A.H. Kashani et al.
25% for subjects with ocular presentation without MRI lesions and 72%
for patients with one or more intracranial MRI lesions. Therefore, the
ocular findings in MS are of well-established clinical significance.
Although MS is the more common cause of optic neuritis (ON),
neuromyelitis optica (NMO) and anti-myelin oligodendrocyte glyco­
protein (MOG) antibody-positivity can also cause ON. It is clinically
important to differentiate MS from NMO because the prognosis and
treatment for NMO is different. OCT imaging has played a role in
differentiating these disease entities. Although up to 80% of NMO sub­
jects can be diagnosed by having a positive serum NMO antibody, NMO
ON typically has more severe peripapillary RNFL (pRNFL) and GCL
thinning than in MS (Filippatou et al., 2020a,b). Furthermore, micro­
cystic macular edema is also more common in the inner nuclear layer
(INL) of NMO subjects than in MS. Recent OCT based studies demon­
strate subclinical RNFL and GCL thinning in eyes of subjects with
AQP4-IgG seropositive NMO but without history of ON (Filippatou et al.,
2020a,b). Not only do these OCT findings help differentiate NMO from
MS, they serve as useful outcome measures in clinical trials (Bennett
et al., 2015). Furthermore, it is clinically important to distinguish MS
ON and NMO ON from anti-MOG-positive antibody ON by serum anti­
body testing and not by OCT findings. This antibody is present in
one-third of all recurrent ON subjects and its presence predicts a better
visual outcome than those with positive-NMO antibodies (Chen et al.,
2018).
4.1.1. Optic nerve and peripapillary retina in Multiple Sclerosis
Histopathology of the LGN in subjects with MS has demonstrated
significant axonal loss (32–45%) in the optic nerve and optic tract as
well as parvocellular neuronal loss (Evangelou et al., 2001). In fact, ON
is the initial clinical manifestation of MS in ~25% of patients and optic
neuropathy in the form of demyelinating plaques are found in a majority
of all postmortem samples, irrespective of any history of ON (Ikuta and
Zimmerman 1976; Toussaint et al., 1983; Kerrison et al., 1994; Group
2008). Although not consistently performed, T2 weighted MRI images of
the optic nerve can show hyperintense lesions with gadolinium
enhancement during acute attacks. In one study, MRI demonstrated
hyperintense lesions in 84% of symptomatic and 20% of asymptomatic
MS subjects (Miller et al., 1988). Interestingly, cross-sectional and pro­
spective MRI studies demonstrate that ON can be associated with
thickening of the optic nerve in the acute phase followed by atrophy
later (Hickman et al., 2004). This supports an initial inflammatory insult
associated with tissue edema followed by atrophy. This pattern is similar
to the pattern of ophthalmoscopic disc changes that are clinically
demonstrable if the disease presentation is captured during the acute
phase. In many cases ophthalmoscopic examination of the RNFL can
demonstrate visible attenuation of the RNFL when a history of ON is
present (Elbøl and Work 1990). One limitation of clinical examination is
that, in general, at least 50% of the RNFL must be lost for clinically
visible findings to be evident (Quigley et al., 1982). Therefore, there is
no doubt that involvement of the optic pathway is of major clinical
importance in MS but detection of the changes associated with demye­
linating lesions by clinical examination, MRI and histopathology each
have practical limitations.
The initial demonstration of peripapillary RNFL (pRNFL) attenuation
in MS using OCT was of major importance because it provided a much
easier, faster and less expensive method of detecting MS activity (Parisi
et al., 1999). Numerous studies have replicated and expanded upon the
finding using OCT as well as other non-invasive imaging methods (Steel
and Waldock 1998; Zaveri et al., 2008). Some degree of pRNFL atten­
uation occurs in MS subjects regardless of an ON history or changes in
visual acuity. The attenuation is greater in magnitude for subjects with
ON or measurable visual function deficits. Large meta-analyses of
Time-Domain OCT (Petzold et al., 2010) and Spectral Domain OCT
(Petzold et al., 2017) have been effectively used to demonstrate that MS
activity and duration correlate with thickness of the pRNFL. More
recently the availability of higher resolution Spectral Domain OCT
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Progress in Retinal and Eye Research 83 (2021) 100938
devices have allowed detailed analysis of individual retinal layers with
remarkable insights into the disease. A meta-analysis of 40 studies and
5776 eyes, revealed that eyes of subjects with MS but without ON have
~7 μm thinner pRNFL than controls and those with history of ON have
~20 μm thinner pRNFL than controls (Petzold et al., 2017). Further­
more, in subjects with clinically isolated syndromes, measurements of
GCIPL and RNFL can predict visual function and future disease activity
months to years after onset of acute ON (Lambe et al., 2020). Therefore
OCT can provide detailed quantitative measurements of the RNFL and
macular thickness changes associated with clinical features of MS at a
resolution that is not possible with clinical examination or neuroimaging
methods. Based on these results, it is very likely that OCT could serve in
several roles in the future diagnosis, prognostication and management of
MS (Saidha and Naismith 2019).
4.1.2. Degenerative neurosensory retinal changes in Multiple Sclerosis
The RNFL consists of the axonal projections of ganglion cells located
in the macula and throughout the retina. Therefore it is not surprising
that histopathological evidence of GCL attenuation is also present in MS.
A meta-analysis of 40 studies and 5776 eyes demonstrated that the
macular RNFL (mRNFL) was ~2 μm thinner in MS subjects without ON
and ~6 μm thinner in those with ON compared to controls (Petzold
et al., 2017). The GCL and inner plexiform layer (IPL) were ~6 μm
thinner in MS subjects without ON and ~16 μm thinner in those with
ON. Although these differences are small, they are highly significant and
some were even reproducible in a similar study performed much earlier
with Time Domain OCT (Petzold et al., 2010; Petzold et al., 2017).
Longitudinal data from several studies demonstrated that a 1 μm loss of
pRNFL per year may be detectable in large, longitudinal clinical trials of
2–3 years duration aimed at assessing the efficacy of neuroprotective
drugs in MS (Petzold et al., 2010; Petzold et al., 2017).
4.1.3. Inflammatory neurosensory retinal changes in Multiple Sclerosis
Retrospective studies demonstrate a correlation between increased
INL volume and MRI activity in MS (Gelfand et al., 2012; Saidha et al.,
2012). The same meta-analysis of 40 studies and 5776 eyes demon­
strated that the INL was about 1 μm thicker in subjects with MS but
without ON than control subjects (Knier et al., 2016). A similar small
difference in the combined outer nuclear layer (ONL) and outer plexi­
form layer (OPL) was found. Disease modifying therapy has also been
correlated with reduction in INL volume especially in cases where dis­
ease activity has essentially become undetectable (Knier et al., 2016). It
is notable that an overall decrease in total macular volume is associated
with increased disease activity. These apparently conflicting findings
highlight the difficulty of identifying consistent, reproducible and rele­
vant retinal changes for particular aspects of the disease process. The
opposite changes in RNFL and INL thickness suggest that it is important
to evaluate retinal sublayer thickness in addition to overall retinal
thickness. For example, it has been hypothesized that inflammation of
the INL is associated with increased INL volume while overall loss of
RNFL explains the decrease in total macular volume. This hypothesis is
supported by histopathology that confirms the presence of inflammatory
cells in the inner retina of MS patients (Green et al., 2010).
OCT-demonstrated edema in the INL has also been correlated with dis­
ease severity (Gelfand et al., 2012). These findings are reminiscent of
diffuse tissue infiltration with T-lymphocytes in normal appearing re­
gions of white and gray matter on histopathology (Kutzelnigg et al.,
2005). Automated segmentation of retinal layers using deep learning
methods have demonstrated impressive predictive ability in MS and may
become useful in the clinical setting with appropriate human guidance
(He et al., 2019). As we discuss later on (See section 7), novel methods of
image registration and analysis may help further refine layer specific
analyses that may have layer segmentation bias.
4.1.4. Retinal vascular changes in Multiple Sclerosis
Retinal vascular changes in the form of periphlebitis (inflammation
A.H. Kashani et al.
of the veins) are a well-known manifestation of MS (Kerrison et al.,
1994). This finding is consistent with subtle perivascular cuffing of
mononuclear cells in normal appearing regions of white and gray matter
on histopathology (Kutzelnigg et al., 2005). The relationship between
phlebitis and perfusion are unclear. MRI-based methods have been able
to demonstrate decreased cerebral blood flow within normal appearing
areas of white matter and gray matter in MS subjects as compared to
controls (Law et al., 2004; Steen, D’haeseleer et al., 2013), but it is
unclear if the periphlebitis and blood flow abnormalities are related.
Attenuated blood flow in MS also has been demonstrated in the retina
independently of obvious periphlebitis. In a study of 16 MS subjects and
17 controls, blood flow velocity and volume in retinal arterioles and
venules was significantly lower in MS subjects compared to controls
(Jiang et al., 2016). Interestingly, there was no correlation between
blood flow and RNFL thickness suggesting that these are independent
processes in MS. Similar significant reductions in blood flow have been
demonstrated in MS subjects compared to controls in at least one other
study (Liu et al., 2019a,b).
In two separate cross-sectional studies of relapsing remitting MS
patients compared to healthy controls the density of the retinal capil­
laries in the SRL of the macula and in the peripapillary region was
significantly reduced in those with a history of ON (Murphy et al., 2020;
Ulusoy et al., 2020). Capillary density in the DRL was also slightly
decreased in the MS group compared to controls. MS-associated ON was
also associated with atrophy of the inner retinal layers, mainly the RNFL
and ganglion cell-inner plexiform layer (GCIPL). In a study of 68 eyes of
45 MS subjects compared to 55 eyes of 32 healthy controls, optic nerve
head blood flow was lowest in MS-associated ON eyes. Although the
RNFL and retinal ganglion cell complex (GCC) thicknesses were reduced
in the eyes with ON, the OCTA measurements did not correlate with the
structural OCT (Spain et al., 2018). Therefore, it appears that optic nerve
head blood flow measures an MS effect independent of structural dam­
age. It is worth noting that OCTA based assessment of retinal capillary
changes are highly dependent on layer segmentation methods and al­
gorithms which may vary among devices. As we discuss in section 7,
novel methods of image analysis that are less dependent on layer seg­
mentation may help further address the relationship of retinal vascular
changes to neurosensory changes. In addition, more longitudinal studies
will be needed to explain the relationship between perfusion and atro­
phy over time. In the choriocapillaris layer, higher vessel densities were
associated with disease activity (Feucht et al., 2019), while choroidal
thinning was correlated with disease duration (Esen et al., 2016). These
findings could represent the vasodilatory effects during active inflam­
mation and the resultant atrophy, respectively.
4.1.5. Clinical correlation of retinal changes in Multiple Sclerosis
Retinal thickness changes have been correlated with clinical severity
of MS (Gordon-Lipkin et al., 2007; Sepulcre et al., 2007; Toledo et al.,
2008; Jiang et al., 2016). Thinning of the GCIPL seems to be the earliest
detectable OCT finding in MS and is a more sensitive biomarker for MS
than pRNFL (Garcia-Martin et al., 2012a,b; Walter et al., 2012;
González-López et al., 2014). GCIPL thinning occurs within weeks of
onset of acute ON and can precede the RNFL thinning. GCIPL thinning
within the first month of onset of ON is predictive of visual impairment
by 6 months (Gabilondo et al., 2015). An inter-eye difference of 4 μm in
GCL thickness is predictive of a previous attack of ON in patients with a
history of unilateral ON (Nolan-Kenney et al., 2019). The largest and
most robust differences between the eyes of MS and control eyes were
found in the pRNFL and GCIPL. While these changes are all relatively
small, it is very likely that in the correct clinical setting OCT can provide
confirmatory or additional evidence of underlying disease activity.
Physiological pRNFL thinning due to age occurs at 0.017% per year
starting at 18 years of age, with a 10–20 μm loss over 60 years (Kana­
mori et al., 2003). Above and beyond this, pRNFL thinning correlates
with impaired visual function and pRNFL thickness may predict visual
recovery after ON. pRNFL thinning at 75–80 μm has been found to be the
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Progress in Retinal and Eye Research 83 (2021) 100938
threshold level that predicts visual impairment in MS (Costello et al.,
2006). A decrease of one line in low-contrast letter acuity correlates with
pRNFL thinning of 4 μm. Maximal pRNFL thinning (~10–40 μm)
generally occurs after acute ON within 3–6 months and the first
detectable difference between the fellow eye occurs between 1 and 2
months, reflecting axonal degeneration immediately after the primary
demyelinating event. Stabilization of the pRNFL thickness occurs within
7–12 months from onset of disease (Henderson et al., 2010). Interest­
ingly, an inter-eye difference of 5 μm in pRNFL thickness is predictive of
a previous attack of ON in patients with a history of unilateral ON
(Nolan-Kenney et al., 2019). pRNFL measurements also correlate with
self-reported quality of life measures (Garcia-Martin et al., 2013) and
disease progression (Garcia-Martin et al., 2010; Garcia-Martin et al.,
2011; Saidha et al., 2013; Martinez-Lapiscina et al., 2016). These ste­
reotypical findings on OCT have led to the use of OCT based endpoints in
more than two dozen clinical trials in the past few decades, demon­
strating the value of OCT based biomarkers in assessing MS disease ac­
tivity (Lambe et al., 2020).
4.1.6. Retinal electrophysiology in Multiple Sclerosis
Subjects with MS frequently have delayed VEP even without a clear
history of ON. This presumably reflects demyelinating lesions in the
visual pathway but not necessarily in the optic nerve (Halliday, McDo­
nald et al. 1972, 1973; Matthews et al., 1977). One prospective study of
29 newly diagnosed MS subjects and 32 controls did not show any as­
sociation of VEP parameters to intraorbital optic nerve enhancement or
atrophy on MRI (Hickman et al., 2004). However, VEP amplitude and
latency have been shown to correlate with optic nerve volume in MS
patients (Hickman et al., 2002). A significant association exists between
PERG latency (and amplitude) and pRNFL thickness in MS subjects with
a history of ON (Parisi et al., 1999). Despite abnormal VEP amplitude
and latency in subjects with MS with ON compared to controls, the same
study demonstrated no association between VEP latency or amplitude
and pRNFL thickness (Parisi et al., 1999).
4.2. Late onset Alzheimer’s disease
Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder
and the most common form of dementia affecting over 26 million people
worldwide (2020). As advancing age is the single strongest risk factor for
AD, the term Late Onset AD (LOAD) is used to distinguish its most
common form from its more rare autosomal dominant genetic form of
younger onset, with a somewhat arbitrary age cut-off of symptom onset
of 65 years. LOAD is defined by neuropathologic changes including
neuronal loss, gliosis, extracellular accumulation of fibrillar
beta-amyloid (Aβ) and intraneuronal cytoskeletal abnormalities con­
sisting in part of hyper-phosphorylated tau (ptau) in the CNS (McKhann
et al., 1984; Jack et al., 2011). There are numerous animal models of AD
that mimic various aspects of the disease and of significant interest in
understanding the pathophysiology of the disease (Lim et al., 2020; Song
et al., 2020). Though deposition of diffuse and fibrillar Aβ in the CNS
occurs early during the presymptomatic stage of the disease (as early as
20 years prior to the development of overt dementia), ptau accumula­
tion in the form of neurofibrillary tangles is most strongly correlated
with neuronal death and clinical symptoms (Nelson et al., 2012). The
diagnosis of AD can be made based on clinical parameters alone
(“clinically probable AD”) for which specificity and sensitivity can vary
between 80 and 90%, or based on post-mortem diagnosis or on
AD-specific CSF and PET biomarkers for which the accuracy of detecting
AD pathology during life is generally higher (Jack et al., 2011). For in
vivo human studies, papers prior to 2000 tended to use clinical diagnoses
while AD-specific PET imaging and cerebrospinal fluid biomarkers
became available in the early 2000’s (Klunk et al., 2004; Jack et al.,
2018). It is important therefore to note what diagnostic criteria are used
when interpreting ophthalmologic studies in AD. A detailed review of
animal models as well as molecular and cellular findings associated with
A.H. Kashani et al.
retinal changes in AD has been published recently (Gupta et al., 2020;
Qin et al., 2020).
It is worth noting that ophthalmologic impairments in human
contrast sensitivity, color discrimination, motion perception, reading
speed and visual fields have been reported in LOAD (Sadun et al., 1987;
Katz and Rimmer 1989; Gilmore et al., 2006; Boucart et al., 2015). Some
visual dysfunction in LOAD has been associated with degeneration of
anterior visual pathways, namely the optic nerve and retina (Hinton
et al., 1986). However, it is unclear how early and specifically these
ophthalmologic manifestations can be reliably demonstrated in subjects
with LOAD (Uhlmann et al., 1991). It would not be surprising if there
was objective retinal pathology underlying these changes that was
detectable by retinal imaging methods. Below we summarize and syn­
thesize a large body of literature describing retinal imaging findings in
LOAD and implications of these findings in future studies. The numerous
references in this section are also summarized in Table 1.
4.2.1. Optic nerve changes in AD
In 1986, Hinton et al. provided the first histopathological evidence of
optic neuropathy in LOAD after observing diffuse RGC loss and axonal
atrophy in postmortem optic nerve tissues derived from severe LOAD
patients (Hinton et al., 1986). These findings were independently
corroborated on CFP (increased cup-to-disc ratios) and using red free
optic disc photographs that demonstrated RNFL defects in LOAD sub­
jects (Tsai et al., 1991). Subsequent histopathology studies further
demonstrated degeneration of the RNFL and the RGC, most severe su­
periorly and inferiorly with respect to the optic nerve (Blanks et al.,
1989; Bassi and Sadun 1990; Blanks, Torigoe et al. 1991, 1996a,b;
Curcio and Drucker 1993; Blanks et al., 1996a,b; La Morgia,
Ross-Cisneros et al., 2016).
OCT has been widely used to quantify retinal and retinal sublayer
thinning in living human subjects with LOAD. In a recent meta-analysis
comparing 1061 clinically-defined LOAD and 1130 control subjects,
there was significant pRNFL thinning in LOAD for all retinal quadrants,
most pronounced superiorly and inferiorly (Chan et al., 2019). These
OCT findings of superior and inferior retinal atrophy are consistent with
retinal histopathological findings in postmortem LOAD eyes described
above. The pattern of RNFL loss in LOAD seems to be specific in com­
parison to some other neurodegenerative diseases (Sadun et al., 1987; La
Morgia, Di Vito et al., 2017). Specifically, the superior and inferior RNFL
thinning in LOAD is consistent with loss of M-type RGCs that comprise
the magnocellular pathway (M-cells), are mainly located in the extra­
macular retina, and are more involved in low-resolution peripheral
vision (Sadun and Bassi 1990). This is in contrast to the P-type RGCs that
populate the papillomacular bundle in the temporal region of the optic
disc and mediate central vision. This difference may explain the pre­
served visual acuity that is observed in subjects with advanced LOAD
(Sadun et al., 1987) and may be associated with differences in vulner­
ability to LOAD pathology among RGC subtypes (La Morgia, Di Vito
et al., 2017).
4.2.2. Degenerative neurosensory retinal thickness changes in AD
Several lines of evidence demonstrate changes throughout the
neurosensory retina in subjects with LOAD. Postmortem histology from
subjects with neuropathologically confirmed severe LOAD (Braak Stages
V-VI) demonstrate a gradient of retinal thickness reduction whereby
thinning was greatest for the RNFL and RGC followed by the INL and
ONL in a superotemporal and superonasal pattern with respect to the
optic nerve (Asanad et al., 2019a,b) (Fig. 4). These changes have been
corroborated by in vivo OCT studies in LOAD. A meta-analysis of 380
clinically-defined LOAD patients and 293 controls from 11
cross-sectional studies showed a weighted mean difference of − 15.95
μm (p < 0.0001) in RNFL of LOAD subjects compared to controls
(Coppola et al., 2015). Another meta-analysis of 1257 LOAD subjects
and 1460 controls from 30 cross-sectional studies showing weighted
reductions in the thickness of macular GCIPL (− 3.66 μm, p = 0.01),
10
Progress in Retinal and Eye Research 83 (2021) 100938
macular volume (− 0.23 μm, p = 0.0003), total macular thickness (range
-9μm to − 14μm; p < 0.0001 for all retinal quadrants) and pRNFL
(− 5.99 μm, p < 0.0001) in clinically-defined LOAD subjects compared to
controls (Chan et al., 2019). Yet another meta-analysis of 887 LOAD
subjects and 864 controls showed standardized mean reductions in
pRNFL of LOAD subjects (0.98 μm, p < 0.0001) compared to controls.
This study also shows a standardized mean reduction in total macular
thickness of 0.88 μm (p = 0.0001) (den Haan et al., 2017).
The macula contains more than 50% of the RGCs in the entire retina
and RGC bodies are 10–20 times larger than the diameter of their axons.
Therefore, macular measurements of GCIPL may be more sensitive than
pRNFL measures (Cheung et al., 2015). Specifically, attenuation of the
mRNFL, GCL, and IPL collectively known as the retinal ganglion cell
complex (GCC) has been reported by several research groups (Kesler
et al., 2011; Marziani et al., 2013; Thomson et al., 2015; Cunha et al.,
2016; Garcia-Martin et al., 2016; Shao et al., 2018). A large metanalysis
comparing OCT measurements of macular thickness in 467
clinically-defined LOAD subjects and 518 controls has further confirmed
significant reductions in the GCIPL, GCC, macular full-thickness, and
macular volume (Chan et al., 2019).
The findings above, while very encouraging must be considered in
the context of at least a few well-conducted studies that have found no
significant thinning among subjects that meet clear and objective
criteria for probable LOAD (Haan et al., 2019a,b; Sánchez et al., 2020).
For example, in subjects with posterior cortical atrophy (PCA), a variant
of LOAD disproportionately affecting parietal and occipital cortex, there
was no reported association between any measure of retinal thickness
and LOAD status (Haan et al., 2019a,b). On the other hand, these in­
vestigators found a correlation between atrophy in parietal cortex and
RNFL thickness, regardless of the presence of fibrillar Aβ on PET scan
(tau-PET was not performed), supporting a transsynaptic mechanism for
RNFL thinning independent of amyloid pathology (den Haan et al.,
2018a,b). These findings most directly support the idea that trans­
synaptic retrograde degeneration of neurons is the cause of retinal
thinning although further research is needed. They also emphasize the
need for pathology or biomarker-based diagnoses to minimize con­
founding variables such as underlying vascular disease. As we discuss in
sections 6.6 and 7, assessment of cerebral vascular pathology in the
context of neurodegenerative disease is a major area of unmet medical
and research need. Advances in both understanding of the pathophysi­
ology of cerebrovascular disease as well as qualitative and quantitative
assessment of capillary level changes may add significant insight into
this confounding variable.
4.2.3. Degenerative neurosensory retinal changes in MCI and preclinical
AD
One particularly enticing application of retinal imaging in LOAD is to
detect incremental progression of disease or subclinical disease changes
that are otherwise undetectable with conventional neuroimaging. For
example, OCT measured changes in retinal structure and function in
subjects with cognitive impairment but without definitive dementia
could serve as a useful biomarker in disease prognosis and preventative
clinical trials. It is thought that the neurodegenerative process associ­
ated with LOAD precedes the onset of symptoms by 20 years or more
(Villemagne et al., 2013). In this context, the use of retinal imaging
markers may define early changes in neurodegenerative entities
including LOAD when interventions may be effective in preserving
neuronal tissue. In this section we will review the relevant literature that
suggests retinal based biomarkers may be useful in identifying early
changes associated with mild cognitive impairment (MCI) and/or pre­
clinical LOAD. Biomarker-based identification of AD pathology is
particularly important in this group in whom the diagnosis is not yet
clear.
A consistent and significant decrease in pRNFL and macular thick­
ness parameters has been demonstrated in subjects with MCI by several
cross-sectional studies and reviewed in at least two meta-analyses
 Table 1

A.H. Kashani et al.

Summary of retinal findings in human subjects with late onset Alzheimer’s disease.
Finding Preclinical No Difference MCI/Early AD vs HC No Difference Moderate-severe AD vs HC No Difference Biomarker confirmed (Aβ1; Complete eye exam* excluding
AD vs HC Tau2) confounding disease

OCT/Histology
pRNFL Asanad van de Kreeke Coppola et al., den Haan Tsai et al., (1991); Coppola et al., Haan et al., 2019a,b; van de Kreeke et al. (2019)1; Asanad et al., 2020; van de Kreeke
thinning et al., 2020 et al. (2019) (2015); Chan et al., et al., 2018a,b; (2015); La Morgia et al., (2016); Sadun Sánchez et al., Asanad et al., 20201,2; La et al., (2019); den Haan et al. (2018a,
(2019); den Haan Lad et al., et al., (1987), Chan et al., 2019; (2020); Lad et al., Morgia et al. (2016)1; b); Kesler et al., (2011); Ascaso et al.,
et al. (2018a,b); (2018) Asanad et al., 2019a,b; Cipollini et al., (2018); Ho et al., Koronyo et al. (2017)1; den (2014); den Haan et al., 2018a,b; Lad
Kesler et al., (2011); 2020; Koronyo et al., (2017); Asanad (2014), Blanks et al., Haan et al. (2018a,b)1,2; et al., (2018); Salobrar-García et al.,
Paquet et al., (2007); et al., 2019b (1989); Williams Asanad et al., 2019b1; Haan 2019; Sánchez et al., (2020)
Ascaso et al., (2014) et al., (2017) et al., 2019a,b1,2; Alves et al.,
20191,2
mRNFL Santos et al. van de Kreeke Coppola et al., Sánchez et al., Marziani et al., (2013); Cunha, lopes. Haan et al., 2019a,b; Santos et al. (2018)1; Sadda van de Kreeke et al., (2019); Sánchez
thinning/ (2018) et al. (2019) (2015); Chan et al., (2020); Alves 2016; Garcia-Martin et al., (2016); Sánchez et al., (2020) et al. (2019)1,2; Haan et al., et al., (2020); Marziani et al., (2013);
thickening (2019); den Haan et al., 2019 Kesler et al., (2011); Shao et al., 2019a,b1;van de Kreeke et al. Cunha, lopes. 2016; Haan et al., 2019a,
et al. (2018a,b); (2018); Thomson et al., (2015); (2019)1; den Haan et al. b; Sadda et al., (2019); den Haan et al.
Kesler et al., (2011); Salobrar-García et al., (2019) (2018a,b)1,2 2018a,b; Kesler et al., (2011); Ascaso
Paquet et al., (2007); et al., (2014); Garcia-Martin et al.,
Ascaso et al., (2014) (2016); Salobrar-García et al., (2019)
RGC-IPL Sadda et al. van de Kreeke Lad et al., Hinton et al., (1986); La Morgia et al., Haan et al., 2019a,b; van de Kreeke et al. (2019)1; Sadda et al., (2019); van de Kreeke
thinning (2019) et al., (2019); (2018); (2016); Blanks et al., (1989); Blanks Sánchez et al., Asanad et al., 20201,2; La et al., (2019); Asanad et al., 2020; Lad
Asanad et al., Sánchez et al., et al., 1996a,b; Bassi and Sadun (2020); Lad et al., Morgia et al. (2016)1; Haan, et al., (2018); Sánchez et al., (2020);
2020 (2020); Alves (1990); Blanks et al., (1991); Curcio (2018) et al. 2019a,b1; den Haan Marziani et al., (2013); Cunha, lopes
et al., 2019 and Drucker (1993); den Haan et al., et al. 2018a,b1,2; Asanad et al. et al., 2016; Garcia-Martin et al.,
(2018a,b); den Haan et al. 2018a,b; 20191; Curcio and Drucker (2016); Kesler et al., (2011);
Asanad et al., 2019a,b; Chan et al., (1993)1,2 Salobrar-García et al., (2019)
2019; Marziani et al., (2013); Cunha,
lopes et al., 2016; Garcia-Martin et al.,
(2016); Kesler et al., (2011); Shao
11

et al., (2018); Thomson et al., (2015);

Salobrar-García et al., (2019)
Total macular van de Kreeke Chan et al., (2019); den Haan et al. den Haan et al. 2018a,b/ Sánchez et al. (2020) den Haan et al. 2018a,b1,2; van de Kreeke et al., (2019); Asanad
thinning/ et al., (2019); Shao et al., (2018) 2018a,b; Salobrar-García et al., (2019) den Haan et al., (2018a,b)1,2; et al., 2020; den Haan et al., 2018a,b;
thickening Asanad et al., Sánchez et al., van de Kreeke et al. (2019)1; Sánchez et al., (2020); den Haan et al.,
2020 (2020) Asanad et al., 20201,2 (2018a,b); Salobrar-García et al.,
(2019)
Choroidal Bulut et al., (2018); Chan et al., 2019/ Haan et al., (2019a,b) Asanad et al. 20191; Haan Bulut et al., (2018); Asanad et al.,
thinning/ Asanad et al., 2019 et al., 2019a,b1,2 2019a,b; Haan et al., 2019a,b
thickening
Vascular
Capillary Sadda et al., Yoon et al., (2019); Bulut et al., (2018); Jiang et al., 2018a, Querques et al. Sadda et al. (2019)1,2; Haan Sadda et al., (2019); Haan et al., 2019a,
density (2019); Haan Jiang et al., 2018a,b b (2019) et al., 2019a,b1,2; Querques b; Querques et al., (2019); Jiang et al.,

Progress in Retinal and Eye Research 83 (2021) 100938

decrease et al., 2019a,b et al. (2019)1,2 2018a,b; Yoon et al., (2019)
Enlarged FAZ O’Bryhim Bulut et al. (2018) O’Bryhim et al. (2018)1,2 O’Bryhim et al., (2018); Bulut et al.,
et al. (2018) (2018)
Decreased Feke et al., (2015); Berisha et al., Feke et al., (2015); Berisha et al.,
blood flow (2007); Szegedi et al., (2020); Jiang (2007); Szegedi et al., (2020); Jiang
et al., 2018a,b et al., 2018a,b
Decreased Querques et al. (2019) Szegedi et al. (2020) Querques et al. (2019)1,2 Querques et al., (2019); Szegedi et al.,
vessel (2020)
reactivity
Decreased Berisha et al., (2007); Cheung et al., Berisha et al., (2007); Cheung et al.,
vessel (2014); Szegedi et al., (2020) (2014); Szegedi et al., (2020)
caliber
ERG
(continued on next page)
 A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

(Paquet et al., 2007; Kesler et al., 2011; Ascaso et al., 2014; Coppola

Abbreviations: OCT = Optical Coherence Tomography, ERG = Electroretinography, AD = Alzheimer’s Disease, HC = Healthy Controls, pRNFL = peripapillary retinal nerve fiber layer, mRNFL = macular retinal nerve fiber
layer, MCI = mild cognitive impairment, RGC = Retinal Ganglion Cells, IPL = Inner Plexiform Layer, FAZ = Foveal Avascular Zone, Blank cells indicate no data or study was available for that parameters. (*) Complete eye
et al., 2015; den Haan et al., 2017; Chan et al., 2019). A meta-analysis
Krasodomska et al., (2010); Sartucci
of 68 MCI patients and 293 controls from 11 cross-sectional studies
showed a weighted mean difference of − 13.39 μm (p = 0.013) in RNFL
Complete eye exam* excluding

Katz B, S Rimmer et al., 1989

of clinically-defined MCI subjects compared to controls(Coppola et al.,
2015). Another meta-analysis of 305 clinically-defined MCI subjects
confounding disease

and 1460 controls from 30 cross-sectional studies showed weighted

reductions in the thickness of macular GCIPL (− 10.19 μm, p = 0.05) in
et al., (2010)

MCI subjects compared to controls (Chan et al., 2019). Notably there

was no difference in macular volume or pRNFL except for a significant
weighted increase in nasal peripapillary thickness. A third
meta-analysis of 216 clinically-defined MCI subjects and 864 controls
showed standardized mean reductions in pRNFL of 0.71 μm in MCI
subjects (p = 0.008) compared to controls. This study also showed a
Biomarker confirmed (Aβ1;

standardized mean reduction in macular thickness of 0.88 μm (p =

0.0001) (den Haan et al., 2017).
These studies support the notion that subclinical retinal changes
accompany MCI and may be useful in detecting disease progression in
longitudinal studies. For example, a prospective study was reported in
27 cognitively healthy participants with pathologic cerebrospinal fluid
Tau2)

Aβ42/tau ratios consistent with the presence of AD pathology, and 16

cognitively healthy controls with normal Aβ42/tau ratios. Mean RNFL
was not only significantly thinner in asymptomatic LOAD participants
Katz B, S Rimmer

relative to controls, but also demonstrated high sensitivity (87%) but

No Difference

modest specificity (56%) in classifying cognitively healthy individuals

et al., 1989

with elevated CSF Aβ42/Tau ratios (Asanad et al., 2020) (Fig. 5). These
studies have set the stage for larger, multicenter, prospective studies
that could formalize these associations.

4.2.4. Inflammatory neurosensory retinal changes in MCI and preclinical

et al., (2010); Sartucci et al., (2010)
Parisi et al., (2001); Krasodomska

AD
In contrast to the above findings, a significant number of well-
Moderate-severe AD vs HC

performed studies report essentially no change or even an increase in

retinal thickness in association with early stages of dementia or MCI
(Lad et al., 2018; Shao et al., 2018; Alves et al., 2019; Hadoux et al.,
Parisi et al. (2001)

2019; Salobrar-García et al., 2019; van de Kreeke et al., 2019; Marquié

et al., 2020). For example, one study evaluated retinal thickness in
exam includes visual acuity, intraocular pressure measurement, and dilated fundus examination.

relation to amyloid accumulation in 165 cognitively healthy mono­

zygotic twins among which 18 were Aβ (+). OCT demonstrated no
thinning of the pRNFL, mRNFL, GCL, IPL, or total macula. In addition,
no significant associations were found between retinal thickness and
No Difference

PET Aβ levels following correction for multiple testing (van de Kreeke

et al., 2019). The reason for these negative findings is not clear but may
be related to the use of Aβ, which may represent earlier stages of
preclinical disease, rather than a neurodegenerative marker.
Shao et al. evaluated macular thickness in 25 clinically-defined
MCI/Early AD vs HC

LOAD, 24 MCI, and 21 control subjects. Relative to controls, the MCI

and LOAD cohort demonstrated macular thinning but also significant
ONL and photoreceptor thickening (Shao et al., 2018). Lad et al.
analyzed 15 clinically-defined mild-moderate LOAD, 15 MCI, and 18
control subjects. Average pRNFL and GCIPL thicknesses did not
significantly differ between groups but areas of thickening were found
adjacent to areas of thinning in the pRNFL and GCIPL (Lad et al., 2018).
No Difference

More recently, Marquie et al. conducted a 2-year longitudinal study to

investigate the relationships between retinal thickness and PET Aβ
levels. OCT showed nasal macular thickening which positively corre­
lated with amyloid uptake (Marquié et al., 2020). Alves et al. evaluated
morphological changes in retina and in brain white matter integrity
et al. (2012)
Preclinical
AD vs HC

using OCT and diffusion tensor imaging, respectively, among 17 early

Moschos

amyloid-PET defined LOAD and 23 control subjects and noted that INL
Table 1 (continued )

thickness was positively associated with fractional anisotropy in early

LOAD (Alves et al., 2019). Salobrar-Garcia et al. analyzed 39 mild and
Dysfunction
dysfunction
Outer retinal

21 moderate clinically-defined LOAD patients, and 40 control subjects.

Inner retinal

Relative to controls, mild LOAD patients showed thinning in the central

Finding

macula, whereas moderate LOAD patients showed thickening in this

region. Both mild and moderate LOAD cohorts showed pronounced

12
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

Fig. 4. Retinal histopathology of AD and control subjects. Light microscopy depicts (A) supero-temporal RNFL (black arrows) in control and (B) AD postmortem
tissue. Qualitative assessment of the supero-temporal RGCL, INL, and ONL (marked by red boxes) in (C) representative control and (D) subject with AD depicts
supero-temporal RGCL, INL, and ONL thinning most pronounced in the macular region of the subject with AD. All stains are hematoxylin and eosin. (Reproduced
under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) 4.0 International License from Asanad S, Ross-Cisneros FN, Nassisi M,
Barron E, Karanjia R, Sadun AA. The retina in Alzheimer’s disease: histomorphometric analysis of an ophthalmologic biomarker. Invest Ophthalmol Vis Sci. 2019;
60:1491–1500. https://doi.org/10.1167/iovs.18-25966).

thinning of the mRNFL, GCL, and OPL. However, the ONL was signifi­
cantly thicker in mild and moderate LOAD relative to controls (Salo­
brar-García et al., 2019). A common interpretation of these results is that
there is inflammation early in the neurodegenerative process that could
manifest as thickening of specific retinal sublayers. A similar observa­
tion has been proposed and demonstrated in MS (Green et al., 2010;
Gelfand et al., 2012).
One particularly confounding possibility is that degenerative
changes in one retinal layer are offset by thickening from inflammatory
changes in other layers. This would result in no detectable change in
overall retinal thickness until the degenerative process overtakes the
inflammatory stage of the disease. This possibility would explain the
absence of any significant change in retinal thickness in a number of
studies discussed above. Careful retinal sublayer analysis in larger,
prospective studies should help answer this question. In addition, more
sophisticated methods of OCT analysis will enable further exploration of
layer specific changes and volume changes independently of layer seg­
mentation (see section 7).

Fig. 5. Peripapillary retinal nerve fiber

layer thickness is reduced in subjects with
preclinical AD. (A) The thicknesses of the
retinal nerve fiber layer (temporal, superior,
nasal, inferior) was measured using OCT in
the regions outlined in black. (B) Depicts
least-squares mean (95% CI) total retinal
nerve fiber layer thickness adjusted for side
and region between cognitively healthy
controls (blue) and cognitively healthy par­
ticipants with pathologic CSF Aβ42/Tau
levels (red). (Adapted from Asanad S, Fan­
tini M, Sultan W, Nassisi M, Felix CM, Wu J
et al. (2020) Retinal nerve fiber layer
thickness predicts CSF amyloid/tau before
cognitive decline. PLoS ONE 15(5):
e0232785. https://doi.org/10.1371/journal.
pone.0232785 under the terms of the
Creative Commons Attribution License).

13
A.H. Kashani et al.
4.2.5. Neurosensory retinal amyloid beta deposition in LOAD
A pathologic hallmark of LOAD is deposition of Aβ and ptau in the
CNS (McKhann et al., 1984; Montine et al., 2016). Therefore, identifi­
cation of these proteins in the retina has been an area of intense interest.
Retinal Aβ protein deposition in postmortem LOAD retinal tissue and
transgenic mice (APPSWE/PS1E9) has been demonstrated following cur­
cumin staining (Koronyo-Hamaoui et al., 2011; Chibhabha et al., 2020;
Sidiqi et al., 2020). These findings have been corroborated by recent
human studies, which have similarly demonstrated Aβ plaque accumu­
lation highest in the mid-to far-peripheral regions of superior and infe­
rior hemiretinas (Alexandrov et al., 2011; La Morgia, Ross-Cisneros
et al., 2016; Koronyo et al., 2017). Immunohistochemistry studies
illustrated Aβ distribution localized to the RGC in postmortem LOAD
eyes with selective loss of intrinsically photosensitive subtypes of RGCs
known as melanopsin-containing RGCs (mRGCs) (La Morgia,
Ross-Cisneros et al., 2016). Since mRGCs drive circadian photoentrain­
ment, the authors hypothesized that mRGC loss may also contribute to
circadian dysfunction characteristically seen in LOAD (La Morgia,
Ross-Cisneros et al., 2016). Koronyo et al. analyzed Aβ plaque deposition
in whole mount retinas from 8 LOAD and 7 control postmortem eyes.
LOAD retinas showed a 4.7-fold increase in plaque aggregation which
correlated with Aβ burden in both the primary visual cortex and ento­
rhinal cortex (Koronyo et al., 2017).
Despite these findings, there is some controversy regarding the
detection of these proteinopathies in human retina in LOAD (Blanks
et al., 1989; Ho et al., 2014; Williams et al., 2017; den Haan et al.,
2018a,b). Ho et al. and Williams et al. were unable to identify Aβ and
ptau deposits in retinal cross-sections of autopsy-confirmed LOAD cases
relative to age-matched controls (Ho et al., 2014; Williams et al., 2017).
Haan et al. reported ptau accumulation in the IPL and OPL in 6 post­
mortem LOAD eyes as well as diffuse Aβ deposition throughout the inner
retina in both LOAD cases and controls (den Haan et al., 2018a,b). While
it is not exactly clear why these studies did not detect pathologic retinal
14
Progress in Retinal and Eye Research 83 (2021) 100938
Aβ accumulation, one plausible reason is the relatively limited
cross-sectional sampling of the retina in comparison to the retinal whole
mounts used in studies with positive Aβ findings in the retina (Alber
et al., 2020).
One potentially exciting avenue for detection of retinal Aβ is the use
of autofluorescence, hyperspectral imaging and fluorescence lifetime
imaging ophthalmoscopy (FLIO). Pilot studies demonstrate significant
differences in the fluorescence lifetimes of retinal fluorophores between
7 CSF-defined preclinical LOAD participants and 8 controls using FLIO.
Fluorescence lifetimes were not only significantly prolonged in pre­
clinical LOAD retinas, but also correlated with CSF Aβ and tau levels and
GCIPL thickness measured by OCT (Sadda et al., 2019). Hadoux and
colleagues demonstrated remarkable differences in retinal reflectance
patterns using hyperspectral imaging. In addition, retinal hyperspectral
scores were notably associated with brain Aβ burden as measured by
PET (Hadoux et al., 2019). The pathogenesis of these spectral differences
are not clear and much further investigation is needed. However, the
general concept of leveraging the spectral properties of Aβ for detection
in the retina is promising. A clever variation on this theme is the use of
exogenous agents to label amyloid in vivo. For example, Koronyo et al.
demonstrate putative amyloid containing lesions in the retina of 10
human subjects with AD compared to 6 healthy controls using a cur­
cumin labelling scheme and fundus autofluorescence imaging (Koronyo
et al., 2017). It is not yet clear how quantitative this method can be but
prospective clinical studies are in progress.
4.2.6. Subretinal amyloid beta deposition in age-related macular
degeneration and LOAD
Aβ is also known to be present in pathologic and non-pathologic age-
related changes called drusen (Anderson et al., 2004; Isas et al., 2010).
Drusen typically occur in the subretinal space with the greatest preva­
lence in the posterior pole and show some physiologic age-related
accumulation (Hoh Kam et al. 2010). The most common pathologic
Fig. 6. Color fundus photographs and positron
emission computed tomograms (PET) demon­
strating clinical correlation of retinal and brain
imaging findings in (A,B) 74 year old subject
without dementia and (C,D) 69 year old subject
without dementia. (A) Color fundus photograph of
the macula demonstrates numerous drusen (area
7.35 mm2) and (B) F-AV45 (florbetapir) PET yields
positive standard uptake values (SUVR) of 1.15
(values greater than or equal to 1.10 are consid­
ered positive). (C,D) Similar images for a 69 year
old female subject without dementia. (C) This
subject had minimal drusen on fundus images and
(D) similarly negative SUVR ratio of 1.04. SUVR
values indicate the ratio of cortical to cerebellar A-
beta accumulation. (Adapted with permission from
Shoda C et al., Journal of Alzheimer’s Disease 62
(2018) 239–245 (doi 10.3233/JAD-170956).
A.H. Kashani et al.
association of drusen is age-related macular degeneration but numerous
studies have examined the potential role of Aβ accumulation in drusen
and LOAD (Ohno-Matsui 2011). Unlike intraretinal Aβ deposits, drusen
are easily detectable on clinical examination and with a variety of
ancillary diagnostic imaging methods. Interestingly, macular drusen
area on CFP independently correlates with cerebral Aβ accumulation as
measured by florbetapir PET in elderly people without dementia (Fig. 6)
(Shoda et al., 2018). Histopathology of specimens from subjects with
neuropathologically diagnosed LOAD demonstrates increased numbers
of drusen compared with age-matched controls (Ukalovic et al., 2018).
These findings are supported by epidemiological findings correlating
decreased MMSE and late stages of age-related macular degeneration in
the Blue Mountain Eye Study (Pham et al., 2006). However, histopath­
ological assessment of 157 autopsy eyes from subjects greater than 75
years of age did not support an increase in prevalence of age-related
macular degeneration among subjects with LOAD (Schwaber et al.,
2020). This suggests that the pathophysiology of Aβ accumulation in
drusen is likely independent of the severity of age-related macular
degeneration.
4.2.7. Retinal vascular changes in MCI and AD
Several lines of evidence in human LOAD have also provided evi­
dence of retinal vascular pathology. The retina is supplied by two
separate vascular structures. The central retinal artery branches from
the ophthalmic artery and feeds the retina through additional branches
from the optic nerve head directly into the neurosensory retina. This
“retinal” blood supply is further subdivided into capillary layers or plexi
depending on the depth of the capillary bed within the neurosensory
retina and the topographic location within the retina. The retinal cir­
culation is responsible for supplying the inner two-thirds of the neuro­
sensory retina. In contrast, the posterior ciliary arteries also branch from
the ophthalmic artery but supply the choroidal circulation which is
anatomically distinct from the retina and immediately posterior to it.
The choroidal circulation provides the nutrient supply to the outer one-
third of the retina. Here we will review relevant findings in both vascular
systems in subjects with AD.
Numerous studies have demonstrated changes in LOAD in the large
caliber retinal vessels (100–200 μm) emanating from the optic disc
including: narrowed vessel caliber (Berisha et al., 2007; Frost et al.,
2013; Cheung et al., 2014; Szegedi et al., 2020), increased tortuosity
(Frost et al., 2013; Cheung et al., 2014; Williams et al., 2015), reduced
blood flow (Berisha et al., 2007; Feke et al., 2015; Szegedi et al., 2020),
and altered blood oxygen saturation (Einarsdottir et al., 2016; Stefáns­
son et al., 2017; Szegedi et al., 2020). Notably increase in arteriolar
tortuosity and decrease in caliber have been demonstrated in the cortical
microvasculature of transgenic mouse model of AD (Dorr et al., 2012).
In addition to the large caliber vessel changes there are a number of
studies demonstrating capillary level changes in the retina of LOAD
subjects. Decreased blood flow rates in the precapillary arterioles and
post-capillary venules in the macula have been demonstrated (Jiang
et al., 2018a,b) corresponding to the decreased flow rates observed in
the larger retinal vessels at the disc (Berisha et al., 2007; Feke et al.,
2015). Aβ accumulation and subsequent plaque formation in vessel
walls may occlude and thus impair blood flow (Berisha et al., 2007; Dorr
et al., 2012). Schultz et al. reported significant reduction in capillary
pericyte number between retinal sections derived from LOAD and
non-demented patient cases (Schultz et al., 2018) reminiscent of the loss
of brain pericytes reported in the AD cortex and hippocampus (Sengillo
et al., 2013).
Several studies have demonstrated significant attenuation of capil­
lary density or perfusion in the retina of subjects with dementia (Bulut
et al., 2018; Jiang et al., 2018a,b) or MCI (Jiang et al., 2018a,b; Yoon
et al., 2019). Due to the high cost and limited availability of PET and CSF
studies, most of these correlations are often made with only MMSE as
measure of disease status and little information is available about co­
morbid vascular disease. Since the prevalence of comorbid vascular
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Progress in Retinal and Eye Research 83 (2021) 100938
contributions to cognitive impairment and dementia is significant, many
of these studies cannot rule-out the confounding role of cardiovascular
risk factors versus amyloid angiopathy in the correlation with OCTA
based metrics. Notably in a study where MRI and CSF amyloid levels are
used to characterize LOAD patients, the correlation between retinal
capillary density metrics and LOAD status is less clear (Querques et al.,
2019). In this study, a significant impairment of arteriolar reactivity, but
not capillary density, was noted in response to flicker stimulation of the
retina in subjects with MCI and LOAD compared to normal. This study
also accounted for vascular comorbidity. In addition, vascular reactivity
impairment was inversely correlated with CSF Aβ levels and directly
correlated with GCL thickness (Querques et al., 2019). A reduction in
RNFL thickness, retinal arteriolar diameter and blood flow was also
recently reported in subjects with clinically-defined LOAD or MCI using
a different imaging methodology but flicker induced reactivity was not
observed (Doppler OCT and Retinal Vessel Analyzer) (Szegedi et al.,
2020).
There is controversy regarding retinal capillary changes in preclini­
cal LOAD. One study of 32 subjects with biomarker positive LOAD
(positive CSF Aβ42 or Florbetapir or Pittsburgh compound B PET li­
gands) but CDR score of 0 showed increasing foveal avascular zone and
decreased retinal thickness in biomarker positive subjects compared to
biomarker negative controls (O’Bryhim et al., 2018). Notably this study
did not report a change in capillary density. In contrast, Haan et al.
showed no significant decrease in capillary density or increase in foveal
avascular zone in LOAD participants with Aβ PET and CSF positivity,
after adjusting for age and sex. There were no associations between any
retinal vascular parameters and CSF biomarkers or MMSE scores (Haan
et al., 2019a,b). However, there was a positive and significant associa­
tion between retinal vessel density in the macula and Fazekas score
suggesting some form of underlying vascular association (Haan et al.,
2019a,b). One limitation of these studies is that assessment of retinal
capillary density is limited by layer segmentation methods that vary
across commercial devices and analysis methods. As we discuss in Sec­
tion 7, volume based image analysis methods may help overcome this
difficulty.
4.2.8. Choroidal vascular changes in AD
In contrast to the retinal circulation, there are fewer studies exam­
ining the choroidal circulation. This may be partly because the choroidal
circulation is anatomically separate from the retina, does not share the
common embryological origins of the CNS vasculature, and does not
have a BRB. Therefore, there is less reason to suspect a direct correlation
between changes in the choroidal circulation and CNS pathology.
Nevertheless, the choroidal blood supply is an extremely important
source of nutrition for the outer retina and may, at least, reflect changes
in the metabolic activity of the retina. In the population based Beijing
Eye Study on 3009 subjects, there was a significant positive association
between OCT measured choroidal thickness and MMSE score even after
adjusting for age, axial length, gender, anterior chamber depth, lens
thickness, visual acuity and depression score (Jonas et al., 2016).
In a meta-analysis of 203 clinically-defined AD subjects and 307
controls from 5 cross-sectional studies using OCT, subfoveal choroidal
thickness was significantly thinner in LOAD subjects than controls
(standard mean reduction − 1.03 μm, p < 0.001) (Chan et al., 2019). It
should be noted that some studies have reported conflicting results for
choroidal thickness measurements as well (Gharbiya et al., 2014,
Bayhanet al., 2015; Bulut et al., 2016; Trebbastoni et al., 2017; Bulut
et al., 2018; Haan et al., 2019a,b; López-de-Eguileta et al., 2020).
A recent histopathological study of choroidal thickness and vascu­
larity in 8 severe LOAD (Braak V-VI) and 11 control postmortem eyes
demonstrated global choroidal thinning in the superior hemi-retinas.
Intriguingly, regional analysis of the central macular choroid demon­
strated significant thickening in CSF-biomarker defined LOAD, which
strongly correlated with stromal vessel number (Asanad et al., 2019a,b)
(Fig. 7). Quantification of choroidal vasculature using OCT and OCTA is
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

Fig. 7. Qualitative assessment of the choroid in controls and subjects with Alzheimer’s Disease. Representative light microscopy revealed qualitative (A) superonasal
choroidal thinning in patients with AD relative to (B) controls. Representative light microscopy revealed qualitative (C) superotemporal macular choroidal thickening
with increased vascularity in patients with AD relative to (D) controls. All stains are hematoxylin and eosin. Abbreviation: AD, Alzheimer’s disease. (Reproduced
under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) 4.0 International License from Asanad et al., Alzheimer’s and Dementia:
Diagnosis, Assessment and Disease Monitoring 11 (2019a) 775–783; doi.org/10.1016/j.dadm.2019.09.005).

much less developed and more subjective than quantification of retinal
circulation (Ferrara et al., 2016) and there is a significant amount of
work to be done in assessing choroidal changes in LOAD. Specifically,
analysis of choroidal changes on OCT is confounded by the even more
obscure borders and anatomy of the choroid and choriocapillaris (in
comparison to the less obscure retinal boundaries). As we discuss in
Section 7 below, volume based assessments of the choroid and chorio­
capillaris may help address this technical challenge.
4.2.9. Visual pathway electrophysiology of Alzheimer’s disease
Several studies have provided evidence of retinal electrophysiologic
dysfunction in LOAD that is complementary to the histopathologic
findings of GCL, RNFL and optic nerve atrophy described above. For
example, in the retina, multifocal ERG amplitudes were significantly
reduced and implicit times were delayed in subjects with AD (Sen et al.,
2020a,b). In addition, decreased N95 amplitude and increased implicit
time by PERG examination significantly correlated with pRNFL thick­
ness reduction in clinically-defined LOAD (Parisi et al., 2001; Kraso­
domska et al., 2010; Moschos et al., 2012). PERG measured ganglion cell
activity demonstrates significant amplitude reduction while PVEP
assessment of retinocortical conduction time and ffERG are normal in
LOAD subjects compared to controls. This suggests that signal conduc­
tion velocity in the primary visual pathways may be spared from LOAD
pathology at least in some stages of the disease (Rimmer et al., 1989).
Variations on PERG and VEP stimulation paradigms to further isolate the
magnocellular visual pathways in LOAD subjects seem to suggest that
they are more affected (Sartucci et al., 2010) in support of histopatho­
logic findings discussed above demonstrating preferential atrophy of
larger ganglion cell axonal profiles also indicative of magnocellular
neurons (Sadun and Bassi 1990).
4.2.10. Cognitive impairment in AD and retinal thickness
As cognitive decline is the most relevant and salient concomitant of
the severity of brain pathology in AD, its correlation with retinal
pathology is of interest. Though impairment in episodic memory is the
most prominent symptom in early AD, executive function is also
affected. Far less commonly, language and visuospatial deficits may be
the presenting symptom. Considering this clinical heterogeneity, the
large variety of assessment instruments used and the absence of
appropriate norms across diverse populations, the use of cognitive
impairment and decline as outcome measures in retinal studies poses
significant challenges.
One notable trend in the literature assessing retinal findings in sub­
jects with dementia is the widespread use of the MMSE as an outcome
measure. The MMSE is a screening instrument. It is easy to administer
and is reported in the majority of studies as an assessment of the severity
of cognitive impairment in subjects with probable or possible LOAD. In
many cases the complete characterization of the AD status of subjects is
not presented. The MMSE is a relatively easy screening test (low ceiling)
which does not assess all cognitive domains (e.g. does not assess exec­
utive function). It exhibits poor sensitivity in relatively healthy partic­
ipants (Spencer et al., 2013) and in MCI (Arevalo-Rodriguez et al., 2015;
Tsoi et al., 2015).
It is therefore not surprising that there are mixed reports on the as­
sociation of MMSE and retinal thickness parameters. For example,
Cipollini et al. illustrated significant thinning in global pRNFL, GCC and
total macular volume in 25 clinically-defined LOAD patients in com­
parison with 17 controls. However, OCT-derived measurements did not
correlate with MMSE scores but did correlate with measures of
constructional praxis and processing speed (Cipollini et al., 2020).
Similarly, in a study of 57 CSF amyloid positive and PET amyloid pos­
itive LOAD subjects, MMSE did not correlate with any retinal thickness
parameter (Haan et al., 2019a,b). In subjects with PCA, a variant of AD
largely affecting the visual cortex, there is no reported association be­
tween any measure of retinal thickness and LOAD status including
MMSE score (Haan et al., 2019a,b). In contrast, other studies show some
association between retinal thickness parameters and MMSE in subjects
with LOAD. For example, Cunha et al. show a correlation of 0.33 and

16
A.H. Kashani et al.
0.43 for average macular thickness and foveal thickness, respectively,
with MMSE in a univariate analysis of 24 clinically-defined LOAD pa­
tients (mean MMSE = 17) and 24 controls (Cunha et al., 2016). It is
likely that more sensitive and comprehensive measures of cognition,
perhaps composite measures emphasizing episodic memory and execu­
tive function, might be better suited for correlation with retinal changes
in AD (Guzmán-Vélez et al., 2018).
4.2.11. Longitudinal studies of retinal imaging in AD and dementia
Longitudinal data seem to provide complementary evidence to sup­
port a potential causal association between neurodegenerative changes
and retinal atrophy. One longitudinal study of 3289 Dutch adults reports
the association of retinal thickness with both incident and prevalent
dementia, including LOAD specifically (Mutlu et al., 2018). As expected
this study reports that thinner RNFL is associated with an increased risk
of dementia overall and more specifically with incident dementia
(Hazard Ratio per standard deviation increase in RNFL 1.44 CI
1.19–1.75 for dementia and 1.43 CI 1.15–1.78 for LOAD) but not
prevalent dementia. Thinner GCIPL was associated with prevalent de­
mentia (odds ratio per standard deviation decrease in GCIPL 1.37 CI
0.99–1.9) (Mutlu et al., 2018). A second study of 32,038 subjects in the
United Kingdom without clinically diagnosed neurodegenerative dis­
ease demonstrated that thinner RNFL was associated with worse
cognitive performance at baseline and progressively worse cognitive
testing 3 years later (Odds Ratio 1.92 CI 1.29–2.85, p < 0.001) (Ko et al.,
2018). A 27-month longitudinal study conducted by Santos et al. re­
ported significant mRNFL thinning in preclinical LOAD. Although IPL
and ONL thinning were also observed, these thickness changes were
reportedly attributed to age-related decline, as expected over the time­
span of the study. Notably, only the mRNFL significantly correlated with
PET Aβ levels (Santos et al., 2018). One challenge with longitudinal
studies is coregistration of images across subjects and across time so that
subtle subclinical changes can be detected. As we discuss later on (See
section 7.2), novel methods of image registration and analysis may help
address this challenge.
4.3. Autosomal Dominant Alzheimer’s disease
As discussed in the previous section, the vast majority of AD cases
present late in life with some heritable component (estimated at
58–79%) due to common genetic variants with small effects, and are
termed “sporadic” late onset AD (LOAD) (Ringman et al., 2014). How­
ever, around 1% of cases are inherited as Autosomal Dominant AD or
ADAD (Moulder et al., 2013). Mutations in three genes cause ADAD:
presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor
protein (APP). All pathogenic mutations increase the relative production
of longer-length Aβ species,a finding not consistently observed in LOAD
(Szaruga et al., 2015). Mutations in PSEN1 are the most common, ac­
counting for about two-thirds of ADAD cases, APP the second most
common, and PSEN2 the least common. For persons carrying pathogenic
mutations, the future development of AD can be reliably predicted.
Furthermore, the age of disease onset can be estimated as this age tends
to be consistent among persons with the same mutation (Ryman et al.,
2014). PSEN1 has the youngest age of onset (as early as the 20’s but
more commonly in the 40’s or 50’s). Overall, the average age of onset is
45.7 ± 6.8 years, so there is a lower incidence of the comorbidities of
aging such as cardiovascular disease and diabetes that frequently
confound the diagnosis of LOAD and its underlying pathophysiology.
Clinical and pathological phenotypes of ADAD share numerous simi­
larities with LOAD (namely progressive dementia associated with
accumulation of β-amyloid plaques and ptau neurofibrillary tangles),
but may differ in the mechanisms leading to pathologic accumulation of
Aβ (Ringman et al., 2014). Nevertheless, ADAD can serve as a model to
study AD pathophysiology, biomarkers, and potential disease modifying
therapies in the absence of confounding age-related disease.
Early studies in subjects with ADAD identified elevated plasma Aβ
17
Progress in Retinal and Eye Research 83 (2021) 100938
and CSF tau in pre-symptomatic mutation carriers (Ringman et al.,
2008). Clinical, biochemical, and radiologic changes in ADAD have
well-established temporal associations demonstrating that the disease
process is active decades before clinical symptoms present (Bateman
et al., 2012) and have been shown to parallel those seen in LOAD
(Dubois et al., 2016). For example, while clinical disease activity in
ADAD is detectable using the Clinical Dementia Rating sum of boxes
testing within 1 year of overt dementia, the earliest change seen is a
decrease in Aβ in the CSF ~25 years before presentation. The precuneus
shows elevated levels of amyloid deposition on PET using Pittsburgh
compound B approximately 25 years before disease onset as well a
decline in glucose metabolism as measured by [F18] fluorodeoxyglucose
(FDG) PET 17 years before disease onset. Performance on a composite of
neuropsychological assessments, including episodic memory, complex
attention, processing speed, and a general cognitive screen, are
abnormal several years before clinically manifest disease. Hippocampal
volume attenuation is detectable a few years before disease onset. This
ordering of biomarkers and clinical tests strengthens the hypothesis that
clinical diagnosis of AD is made late in the biological cascade and tar­
geting both diagnosis and pharmacologic manipulation of Aβ earlier in
the course of the disease may lead to better clinical outcomes. In this
context, retinal studies in asymptomatic carriers of ADAD mutations are
underway and are of significant potential interest. A recent study
showed decreased retinal thickness in 10 presymptomatic carriers of a
common PSEN1 mutation relative to 10 matched non-carriers. Differ­
ences were most evident in the outer nuclear layer. Interestingly, there
was no effect of age on retinal thickness nor were there any differences
in retinal vascular parameters assessed on fundus photography (number
of branch points, tortuosity, or fractal dimension) (Armstrong et al.,
2020). In another recent study, early stage (asymptomatic) carriers of
ADAD causing mutations demonstrated increased capillary blood flow
and blood flow heterogeneity compared to controls or late stage
(symptomatic) carriers of the same mutations (Singer M, Ringman J
et al. in press).
4.4. Parkinson’s disease
Parkinson’s Disease (PD) affects more than 10 million people
worldwide and is the second most common neurodegenerative disease
in the developed world (Archibald et al., 2009; Veys et al., 2019) and
numerous animal models have informed out understanding of the dis­
ease pathophysiology (Pingale and Gupta 2020). The pathologic hall­
mark of PD is the abnormal deposition of cytoplasmic inclusions
comprising the α-synuclein (αsyn) protein leading to the progressive loss
of dopaminergic neurons. In particular, dopamine depletion following
neuronal loss in the nigrostriatal pathway leads to characteristic motor
symptoms in PD including bradykinesia, resting tremor, rigidity, and
postural instability. However, there are numerous non-motor manifes­
tation of PD including alterations in mood and sleep, autonomic nervous
system disturbances, visual hallucinations, and dementia
(Ortuño-Lizarán et al., 2018). Consistent with this clinical spectrum of
extra-motor symptoms in PD, studies have demonstrated αsyn neuro­
pathology in the CNS, peripheral nervous system and various end-organs
(Beach et al., 2010). Dopamine and dopaminergic receptors have been
demonstrated in the retina via radioligand binding analyses (Borbe
et al., 1982) and histopathology (Archibald et al., 2009). Evidence of
dopaminergic loss in retina of subjects with PD confirms the presence of
neurodegenerative changes in the retina (Archibald et al., 2009). Clin­
ical impairments reported in subjects with PD include reading difficulty,
impaired visual acuity, color discrimination, motion perception, and
contrast (Archibald et al., 2009; Weil et al., 2016). Notably, the
impairment in at least some of these clinical measures, such as contrast
sensitivity, is reversible with administration of levodopa (Bulens et al.,
1987; Hutton et al., 1993; Giaschi et al., 1997). Though symptoms and
signs of extrapyramidal dysfunction and responsiveness to L-dopa make
the clinical diagnosis of PD more reliable and not as
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

Table 2
Summary of retinal imaging studies characterizing human subjects with Parkinson’s disease.
Finding PD vs Controls No Difference Biomarker Complete eye exam* excluding confounding
confirmed (αsyn) disease

OCT/Histology
pRNFL Inzelberg et al., 2004; Altintaş et al., 2008;
thinning Moschos et al., 2011; Garcia-Martin et al.,
2012a,b; La Morgia et al., 2013; Kirbas
et al., 2013; Garcia-Martin et al. (2012a,b);
Rohani et al., 2013; Jiménez et al., 2014;
Satue et al., 2014; Garcia-Martin et al.
(2014a,b); Bodis-Wollner et al., (2014);
Beach et al., (2014); Garcia-Martin et al.
(2014a,b); Bayhan et al., 2014; Yu et al.,
2014; Kaur et al., 2015; Sari et al., 2015;
Pilat et al., 2016; Ucak et al., 2016; Satue
et al., 2017; Moschos and Chatziralli, 2018;
Visser et al., 2018; Chrysou et al., 2019;
Sung et al., 2019
mRNFL Pilat et al., 2016; Garcia-Martin et al.
thinning (2014a,b) Ahn et al., 2018
RGC-IPL Hajee et al., 2009; Shrier et al., 2012 Adam
thinning et al., 2013; Garcia-Martin et al. (2014a,b)
Bayhan et al., 2014; Bodis-Wollner et al.,
(2014) Kaur et al., 2015; Ucak et al., 2016;
Moschos and Chatziralli, 2018; Ahn et al.,
2018; Chrysou et al., 2019; Sung et al.,
2019
Total macular Altintaş et al., 2008; Aaker et al., 2010;
thinning Cubo et al., 2010; Satue et al., 2014;
Garcia-Martin et al. (2014a,b);
Garcia-Martin et al. (2014a,b); Mailankody
et al., 2015; Stemplewitz et al., 2015; Pilat
et al., 2016; Satue et al., 2017; Ahn et al.,
2018; Huang et al., 2018; Chrysou et al.,
2019
Choroidal Miri et al., 2015; Moschos and Chatziralli,
thinning 2018
Vascular
Capillary Kwapong et al., 2018
density
decrease
FAZ decrease Miri et al., 2015
ERG
Inner retinal Ikeda et al., 1994; Peppe et al., 1995;
dysfunction Tagliati et al., 1996; Garcia-Martin et al.,
2014a,b; Huang et al., 2018
Outer retinal
Dysfunction
Aaker et al., 2010; Archibald et al., 2011;
Tsironi et al., 2012; Albrecht et al., 2012;
Roth et al., 2014; Mailankody et al., 2015;
Bittersohl et al., 2015; Nowacka et al.,
2015; Stemplewitz et al., 2015; Pillai
et al., 2016; Polo et al., 2016; Gulmez
Sevim et al., 2019
Lee et al. 2014; Schneider et al., 2014;
Müller et al., 2014
Albrecht et al., 2012; Lee et al. 2014; Roth
et al., 2014; Schneider et al., 2014; Müller
et al., 2014; Mailankody et al., 2015; Pilat
et al., 2016; Polo et al., 2016; Gulmez
Sevim et al., 2019
Archibald et al., 2011; Shrier et al., 2012
Albrecht et al., 2012; Lee et al. 2014; Roth
et al., 2014; Schneider et al., 2014; Kaur
et al., 2015; Bittersohl et al., 2015;
Nowacka et al., 2015; Ucak et al., 2016;
Pillai et al., 2016; Polo et al., 2016;
Gulmez Sevim et al., 2019; Uchida et al.,
2018
Bodis-Wollner et al., Inzelberg et al., 2004; Altintaş et al., 2008;
(2014); Beach et al., Moschos et al., 2011; Garcia-Martin et al.,
(2014) 2012a,b; La Morgia et al., 2013; Kirbas
et al., 2013; Garcia-Martin et al. (2012a,b);
Rohani et al., 2013; Jiménez et al., 2014;
Satue et al., 2014; Garcia-Martin et al.
(2014a,b); Kaur et al., 2015; Sari et al.,
2015; Pilat et al., 2016; Ucak et al., 2016;
Satue et al., 2017; Moschos and Chatziralli,
2018; Visser et al., 2018; Sung et al., 2019
Aaker et al., 2010; Archibald et al., 2011;
Albrecht et al., 2012; Mailankody et al.,
2015; Bittersohl et al., 2015; Nowacka
et al., 2015; Stemplewitz et al., 2015; Polo
et al., 2016; Gulmez Sevim et al., 2019
Garcia-Martin et al. (2014a,b); Pilat et al.,
2016; Ahn et al., 2018; Lee et al. 2014
Bodis-Wollner et al., Hajee et al., 2009; Shrier et al., 2012;
(2014); Beach et al., Garcia-Martin et al. (2014a,b); Moschos
(2014) and Chatziralli, 2018; Ahn et al., 2018;
Adam et al., 2013; Gulmez Sevim et al.,
2019; Mailankody et al., 2015; Kaur et al.,
2015; Pilat et al., 2016; Ucak et al., 2016;
Sung et al., 2019
Albrecht et al., 2012; Lee et al. 2014;
Mailankody et al., 2015; Pilat et al., 2016;
Polo et al., 2016; Gulmez Sevim et al., 2019
Altintaş et al., 2008; Aaker et al., 2010;
Shrier et al., 2012; Satue et al., 2014;
Garcia-Martin et al. (2014a,b);
Garcia-Martin et al. (2014a,b); Mailankody
et al., 2015; Stemplewitz et al., 2015; Pilat
et al., 2016; Satue et al., 2017; Ahn et al.,
2018; Huang et al., 2018
Archibald et al., 2011; Shrier et al., 2012;
Albrecht et al., 2012; Lee et al. 2014; Kaur
et al., 2015; Bittersohl et al., 2015;
Nowacka et al., 2015; Ucak et al., 2016;
Pillai et al., 2016; Polo et al., 2016; Gulmez
Sevim et al., 2019
Miri et al., 2015; Moschos and Chatziralli,
2018
Kwapong et al., 2018
Miri et al., 2015
Ikeda et al., 1994; Peppe et al., 1995;
Garcia-Martin et al., 2014a,b; Huang et al.,
2018

Abbreviations: = Optical Coherence Tomography, ERG = Electroretinography, PD = Parkinson’s Disease, pRNFL = peripapillary retinal nerve fiber layer, mRNFL =
macular retinal nerve fiber layer, RGC = Retinal Ganglion Cells, IPL = Inner Plexiform Layer, FAZ = Foveal Avascular Zone, Blank cells indicate no data or study was
available for that parameters. (*) Complete eye exam includes visual acuity, intraocular pressure measurement, and dilated fundus examination.

biomarker-dependent as that of AD, it is more difficult to differentiate
dementia with Lewy bodies from AD. In elderly persons with PD or
dementia with Lewy bodies, concomitant diseases of aging should be
considered as confounders when assessing retinal changes. Below we
summarize and synthesize a large body of literature describing retinal
imaging findings in PD and implications of these findings in future
studies. The numerous references in this section are also summarized in
Table 2.
4.4.1. Parkinson’s disease retinal histopathology
The initial evidence for retinal involvement in PD came from histo­
pathologic evidence demonstrating reduced tyrosine hydroxylase
immunoreactivity in the retina of 5 subjects with PD (Nguyen-Legros
1988; Witkovsky 2004). This finding has been corroborated and
expanded on by several subsequent studies. Histopathology of 4 PD eyes
and 12 control eyes demonstrated αsyn immunoreactivity localized
within the GCL, IPL and INL corresponding with the anatomic distri­
bution of dopaminergic amacrine cells (Beach et al., 2014; Bod­
is-Wollner et al., 2014). Prominent accumulation of phosphorylated
αsyn deposition has been demonstrated in the RGC of subjects with PD
compared to controls and significantly correlates with cortical p-synu­
cleinopathy, disease severity, and functional motor scores
(Ortuño-Lizarán et al., 2018). It is notable that at least one study has
demonstrated more diffuse αsyn deposition throughout the retina of PD

18
A.H. Kashani et al.
(Ho et al., 2014).
These findings are complemented by high performance liquid chro­
matography demonstrating modulation of retinal dopamine levels in
subjects receiving recent L-DOPA therapy compared to those who did
not receive similar therapy (Harnois and Di Paolo 1990). Similar data
from rodent and primate models of PD using a neurotoxin for dopami­
nergic cells, 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP),
demonstrates a dose-dependent reduction in tyrosine hydroxylase ac­
tivity in retinal amacrine cells (Ghilardi et al., 1988a,b; Tatton et al.,
1990).
4.4.2. Peripapillary RNFL changes in Parkinson’s disease
In a meta-analysis of 1916 subjects with PD and 2006 controls there
was a significant association between diagnosis of PD and thinning of
the pRNFL (Cohen’s d = − 0.42, CI -0.54 to − 0.29) and the GCIPL (d =
− 0.40, CI -0.72 to − 0.07) (Chrysou et al., 2019). There was no detect­
able association with sectoral thinning, duration of disease or severity of
symptoms in this study. A number of studies have revealed preferential
thinning of the inferior and temporal pRNFL quadrants (Inzelberg et al.,
2004; Moschos et al., 2011; Garcia-Martin et al., 2012a,b; Kirbas et al.,
2013; La Morgia, Barboni et al., 2013; Sari et al., 2015; Satue et al.,
2017; Visser et al., 2018; Sung et al., 2019). However, results have been
mixed among other studies (Rohani et al., 2013, Bayhanet al., 2014;
Garcia-Martin et al., 2014a,b; Jiménez et al., 2014; Yu et al., 2014; Kaur
et al., 2015; Pilat et al., 2016; Pillai et al., 2016; Ucak et al., 2016;
Hasanov et al., 2019). Despite the differences in sectoral location, it is
clear that retinal thinning, predominantly in the inner retina, is present
in subjects with PD. Careful evaluation of device parameters, segmen­
tation algorithms and reliability as well as disease stage may explain
why some studies do not report significant retinal thickness changes in
the pRNFL (Archibald et al., 2009; Albrecht et al., 2012; Tsironi et al.,
2012; Roth et al., 2014; Mailankody et al., 2015). For example, it is
possible that changes in macular thickness precede detectable RNFL
changes of the ganglion cell body, dendritic field and synaptic connec­
tions are the primary site of cell damage. Interestingly, some studies
report changes in functional parameters in the absence of structural
thinning suggesting that functional changes may precede detectable
attenuation in pRNFL thickness (Tsironi et al., 2012).
4.4.3. Macular OCT changes in Parkinson’s disease
In a meta-analysis of 1916 subjects with PD and 2006 controls there
was a significant association between diagnosis of PD and thinning of
most sectors of the macula (Cohen’s d range − 0.37 to − 0.57) (Chrysou
et al., 2019). The majority of studies investigating the macula in PD have
reported significant reduction in one or more layers, especially the
mRNFL, GCL, and IPL (Hajee et al., 2009, Cubo et al., 2010; Kaur et al.,
2015; Sari et al., 2015; Ucak et al., 2016; Satue et al., 2017; Ahn et al.,
2018; Moschos and Chatziralli 2018; Sung et al., 2019). These OCT
findings are complementary to the histopathologic findings described in
the inner retinal layers (Bodis-Wollner et al., 2014). It has also been
proposed that the slope or shape of the foveal pit may have some utility
as a marker of PD-specific changes (Shrier et al., 2012; Pilat et al., 2016)
although there is significant normal variation in foveal morphology that
needs be taken into account when considering such an association.
There is significant disagreement in the literature regarding retinal
thickness changes in the outer retina in subjects with PD. Significant
thickness changes of the outer retina including the OPL, photoreceptor
layer, and RPE layer have been reported in some studies (Müller et al.,
2014; Roth et al., 2014; Pilat et al., 2016) and refuted in others (Uchida
et al., 2018; Chrysou et al., 2019). Very similar to the layer specific
changes reported in subjects with AD, there appear to be layer specific
changes in PD which may offset each other (Garcia-Martin et al., 2014a,
b). This requires further investigation and may explain the findings from
a large number of studies that fail to detect changes in overall retinal
thickness (Aaker et al., 2010; Archibald et al., 2011; Tsironi et al., 2012;
Schneider et al., 2014; Nowacka et al., 2015; Pillai et al., 2016; Polo
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Progress in Retinal and Eye Research 83 (2021) 100938
et al., 2016). As we discuss later on (See section 7.2), novel methods of
image registration and analysis may help circumvent these limitations.
4.4.4. Retinal vascular changes in Parkinson’s disease
Few studies have evaluated the retinal microvasculature in PD. Miri
et al. assessed the perifoveal capillary network in 23 PD patients and 13
healthy controls using invasive injection of contrast dye (fluorescein
angiography). PD patients exhibited significant reduction in FAZ area
and foveal thickness. In addition, foveal thinning was highly associated
with disease duration and motor impairment in PD patients (Miri et al.,
2015). Choroidal thickness reduction in the subfoveal area as well as in
the inner and outer quadrants in PD retina has also been demonstrated
(Moschos and Chatziralli 2018). More recently, Kwapong et al. analyzed
the SRL and DRL capillary densities in 38 early PD and 28 control sub­
jects using OCTA. SRL density was markedly reduced relative to healthy
controls and correlated with GCIPL thickness, suggesting a vascular
contribution or consequence of retinal degeneration in PD (Kwapong
et al., 2018).
4.4.5. Clinical correlation of retinal changes in PD
Researchers have hypothesized that retinal thinning in PD reflects a
primary loss of dopaminergic amacrine cells and a decrease in dopamine
neurotransmitter levels in the retina that is presumably reflective of
similar changes in the CNS. There are functional implications of this
hypothesis including correlation of retinal changes with abnormalities
in visual function, motor function and cognitive function. A large meta-
analysis of 36 studies (n = 1916 subjects with PD and 2006 controls)
found significant thinning of the inner retinal layers in PD but only a few
significant correlations were found between retinal thickness and clin­
ical severity, perhaps due to the heterogeneity in the underlying data
and methodology among the studies (Chrysou et al., 2019). Nevertheless
there are some interesting studies that are worth mentioning. For
example, in one study of 14 PD subjects and 14 controls there was a
significant association between impaired contrast sensitivity and inner
retinal thickness among normal subjects that was absent in subjects with
PD (Adam et al., 2013). Direct evidence for a common pathophysio­
logical mechanism in the retina and CNS of PD subjects also exists.
Namely, a significant association has been shown between the thickness
of the inner retina and dopamine aminotransferase activity in the sub­
stantia nigra via PET imaging (Ahn et al., 2018).
Although in most studies the heterogeneity of PD duration, severity
and clinical stage precludes rigorous analysis of clinical PD staging and
retinal thickness measures (Chrysou et al., 2019) cross-sectional asso­
ciations between the severity of PD and retinal thinning in the macula
(Bayhanet al., 2014; Sari et al., 2015; Pilat et al., 2016; Ahn et al., 2018;
Sung et al., 2019) and pRNFL (Jiménez et al., 2014; Mailankody et al.,
2015; Pilat et al., 2016) have been reported. In a few studies, the severity
and duration of PD has been shown to correlate with the GCIPL layer
thickness (Sari et al., 2015). There are very few longitudinal studies to
support these cross-sectional associations. At least in one study that
evaluated the same 30 PD subjects and 30 controls over a 5 year period,
the attenuation in the temporal and supratemporal pRNFL was signifi­
cantly greater in subjects with PD than controls (Satue et al., 2017). In
this same study, PD progression using the Hoehn and Yahr scale also
correlated significantly with thinning in the supratemporal pRNFL
(Satue et al., 2017). Nevertheless, in some well-performed studies there
were no reliable correlations between retinal thickness measures of any
kind and severity or duration of motor symptoms using consensus PD
assessment tools such as the Unified Parkinson’s Disease Rating Scale
(Albrecht et al., 2012).
Cognitive impairment is one of several clinical features of PD that
significantly impacts the quality of life of PD subjects. Most PD patients
develop dementia and as many as 26% of non-demented subjects have
MCI (Litvan et al., 2011). There are generally very few studies that show
associations between cognitive impairment in PD and retinal thickness
parameters. However, cognitive assessment in PD is subject to the same
A.H. Kashani et al.
challenges as those in AD described above. In many of these studies the
mean MMSE is above 27 suggesting that a representative spectrum of
subjects with cognitive impairment was not available for analysis
(Mailankody et al., 2015; Visser et al., 2018). Even in one study of 61 PD
subjects and 30 controls with mean MMSE of 24, there was no correla­
tion between cognitive impairment and retinal thickness parameters
(Lee et al., 2014). Notably, a significant correlation between MoCA score
(which includes measures of executive function and is more sensitive for
detecting MCI) and thickness of the macular GCIPL has been demon­
strated (Sung et al., 2019). As mentioned earlier, since the GCIPL is the
location of the dopaminergic amacrine cells in the retina as well as
ganglion cell bodies, this may suggest that detection of early changes in
retinal structure require targeted sublayer analyses with careful atten­
tion to segmentation methods. As we discuss later on (See section 7.2),
novel methods of image registration and analysis may help circumvent
these limitations.
4.4.6. Visual pathway electrophysiology in Parkinson’s disease
Some of the earliest work implicating electrophysiological abnor­
malities in the visual pathway in PD comes from studies using VEP in PD
subjects. Specifically, increased VEP latency in response to mid-spatial
frequency stimuli have been demonstrated in PD subjects by several
studies (Bodis-Wollner and Yahr 1978; Onofrj et al., 1986; Ikeda et al.,
1994). These abnormalities are at least partially reversible during
L-dopa therapy (Bodis-Wollner and Yahr 1978; Peppe et al., 1995) and
are inducible with dopamine antagonists (Onofrj et al., 1986). In at least
one study, progression of ERG and PERG changes has been correlated
with clinical disease progression (Ikeda et al., 1994). Studies comparing
VEP latency and measures of retinal function such as PERG (Nightingale
et al., 1986) suggest that at least part of the VEP abnormality is sec­
ondary to retinal dysfunction. PERG abnormalities in the retina of sub­
jects with PD are also responsive to administration of L-dopa (Peppe
et al., 1995; Tagliati et al., 1996) and can be induced in non-PD subjects
and monkey models with selective D2-receptor antagonists I-sulpiride
(Tagliati et al., 1994). Primates treated with the MPTP demonstrate
decreased retinal dopamine levels, abnormal PVEP latencies and PERG
amplitudes as well as systemic signs of PD (Ghilardi et al., 1988a,b).
Notably the changes in PVEP and PERG were transiently reversible with
administration of levodopa-carbidopa in the primate model (Ghilardi
et al., 1988a,b).
Structure-function correlation of the retina support the notion that
the electrophysiologic changes described above are part of a common
degenerative process of PD. For example, in a group of 46 PD subjects
and 33 controls, foveal thickness measurements and PERG N95 ampli­
tude each were remarkably predictive of disease severity and quality of
life scores in PD patients (Garcia-Martin et al., 2014a,b). Similarly a
combined mfERG and OCT study comprising 53 PD and 41 control
subjects found diminished amplitude and prolonged implicit time of the
P1 mfERG wave component in addition to macular thinning in PD pa­
tients relative to controls. The diagnostic efficacy of ERG and structural
parameters when combined greatly outweighed the performances of
these biomarkers individually (Huang et al., 2018). However, the as­
sociation between macular volume, foveal thickness, RNFL thickness
and VEP latency appears poor (Altintaş et al., 2008). As we discuss
previously, this may be because measurement of specific retinal layers is
necessary to detect the relevant pathological process and segmentation
errors or variances can easily obscure such subtle changes. As we discuss
later on (See section 7.2), novel methods of image registration and
analysis may help circumvent these limitations.
4.5. Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant neurodegen­
erative disorder caused by expansion of the cytosine-adenine-guanine
(CAG) polyglutamine triplet repeat in the HTT gene on chromosome
4p16.3.(1993) HD has a prevalence and annual incidence of 2.71 and
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Progress in Retinal and Eye Research 83 (2021) 100938
0.38 in 100,000, respectively (Pringsheim et al., 2012). Numerous ani­
mal models have informed our understanding of this disease in humans
(Howland et al., 2020). Though somewhat variable, the age of symptom
onset among carriers of pathogenic CAG repeat expansions is earlier
with longer expansions (Andrew et al., 1993). The histopathological
hallmarks of HD include abnormal aggregations of intranuclear and
cytoplasmic inclusions of the huntingtin (htt) protein, which lead to
progressive cortical and striatal atrophy. Patients classically present
with a clinical triad of motor, cognitive, and behavioral abnormalities
(Ross et al., 2014). Motor symptoms characteristically include invol­
untary, jerky, or slow writhing movements (chorea), most obviously
involving the upper extremities. Ocular motility deficits such as saccade
apraxia, saccade hypometria, and smooth pursuit impairment have also
been described in various stages of HD and are reviewed extensively
elsewhere (Anderson and MacAskill 2013). Below we summarize and
synthesize the available body of literature describing retinal imaging
findings in HD and implications of these findings in future studies. The
numerous references in this section are also summarized in Table 3.
4.5.1. Huntington’s Disease retinal histopathology
Autopsy-derived brain and retinal tissue samples from 1 HD and 2
control subjects showed the expected findings of significant cortical
atrophy associated with htt and ubiquitin deposits in the caudate nu­
cleus and putamen but the retina was devoid of protein aggregations or
degenerative changes both macroscopically and histologically (Pet­
rasch-Parwez et al., 2005). This is in contrast to reports in animal
models, which have demonstrated progressive retinal degeneration in
R6/2 HD mice (Helmlinger et al., 2002). Due to the paucity of human
histopathology in HD and the discrepancy between human and animal
studies, it is possible that under-sampling in human tissue resulted in
false negative finding. It is also possible that retinal manifestations of HD
pathology are different than other CNS manifestations.
4.5.2. Huntington’s Disease peripapillary RNFL
Several researchers have shown clinical evidence of pRNFL thinning
in HD preferentially of the temporal quadrant (Kersten et al., 2015;
Gatto et al., 2018, Gulmez Sevim et al. 2019). Temporal thinning in the
pRNFL corresponds with the small axonal fibers comprising the papil­
lomacular bundle which is a pattern of retinal atrophy classically seen in
mitochondrial disorders (Carelli et al., 2009). Therefore, despite the
absence of histopathologic evidence of retinal involvement there is
significant in vivo evidence suggesting pRNFL thinning in HD.
4.5.3. Huntington’s Disease macular RNFL
Although several studies failed to demonstrate any changes or cor­
relations between total macular thickness and HD status (Kersten et al.,
2015; Gatto et al., 2018) retinal sublayer analysis has revealed signifi­
cant thinning for all of the inner retinal layers including the mRNFL,
GCL, IPL, and INL. These atrophic changes in the inner retina are
coincident with thickening in the outer retinal layers that may explain
the absence of significant changes in total retinal thickness measures
(Andrade et al., 2016, Gulmez Sevim et al. 2019). Among retinal layers,
however, thinning of the GCL correlated the strongest with HD and
measures of disease progression which suggest earlier involvement of
the ganglion cell bodies in HD as compared to the axonal fibers (Satue
et al., 2016, Gulmez Sevim et al. 2019).
4.5.4. Functional impairment and Huntington’s Disease retinal findings
Several studies have reported significant correlations between
retinal thickness measures and clinical assessments of HD severity. For
example total mean RNFL thickness significantly correlated with total
functional capacity scores among 14 genetically confirmed HD subjects
and 13 matched controls (Gatto et al., 2018). Both duration of disease
(R2 = − 0.57, p = 0.006) and Unified Huntington’s Disease Rating Scale
(R2 = − 0.56, p = 0.01) were significantly and inversely correlated with
macular volume in 26 HD patients and 29 controls (Kersten et al., 2015).
A.H. Kashani et al.
Table 3
Summary of retinal imaging studies characterizing human subjects with Huntington’s disease.
Finding HD vs Controls No Difference
OCT
pRNFL thinning Kersten et al., (2015), Gatto et al.,
(2018), Gulmez Sevim et al., 2019
mRNFL thinning Gulmez Sevim et al., 2019, Andrade
et al., (2016)
RGC-IPL thinning Gulmez Sevim et al., 2019, Andrade
et al., (2016)
Total macular Kersten et al., (2015),
thinning Gatto et al., (2018)
Choroidal Andrade et al. (2016)
thinning
ERG
Inner retinal dysfunction
Outer retinal Pearl et al., (2017); Knapp et al.,
Dysfunction (2018)
Abbreviations: = Optical Coherence Tomography, ERG = Electroretinography, HD = Huntington’s Disease, pRNFL = peripapillary retinal nerve fiber layer, mRNFL =
macular retinal nerve fiber layer, RGC = Retinal Ganglion Cells, IPL = Inner Plexiform Layer, Blank cells indicate no data or study was available for that parameters. (*)
Complete eye exam includes visual acuity, intraocular pressure measurement, and dilated fundus examination.
Notably, these correlations increased in strength following exclusion of
presymptomatic patients from the analysis. Other sublayers including
the GCL, IPL and mRNFL thicknesses significantly correlate with HD
duration, CAG repeat number, and Unified Huntington’s Disease Rating
Scale scores (Gulmez Sevim et al. 2019). Similar associations have been
reported between clinical measures of HD severity and one or more
macular thickness measures in other studies (Andrade et al., 2016).
4.5.5. Visual pathway electrophysiology in Huntington’s Disease
In a recent study comprising 18 HD and 10 control subjects, signif­
icantly increased b-wave amplitudes in HD at light- and dark-adapted
red flash intensities were reported (Pearl et al., 2017). In addition,
greater numbers of CAG triplet repeats correlated with higher b-wave
amplitudes. These results expand upon the initial foveal blue light
studies by Paulus et al. demonstrating increased photoreceptor thresh­
olds in HD (Paulus et al., 1993), and suggest electrophysiologic
dysfunction in retinal cone photoreceptor pathways in HD. More
recently, Knapp et al. evaluated retinal structure and function in a
25-year-old man with presymptomatic HD (Knapp et al., 2018).
Although retinal structure appeared normal on OCT, ERG amplitudes
were decreased in dark- and light-adapted a- and b-waves as well as in
light-adapted 30 Hz flicker testing (Knapp et al., 2018). In addition,
mfERG showed a decrease in response amplitude suggesting predomi­
nant involvement of cone photoreceptors and downstream pathways.
These findings in presymptomatic disease may also suggest early
involvement of the photoreceptor pathway in HD that precedes retinal
morphologic changes measured by OCT. This is also consistent with the
retinotopic pattern of degeneration involving the parvocellular neurons
of the papillomacular bundle described above (La Morgia, Di Vito et al.,
2017). This is at least consistent with the R6/2 mouse model of HD that
develops cone-rod degeneration measurable by ERG (Ragauskas et al.,
2014). Nevertheless, these results should be interpreted with caution
given the small numbers of subjects involved.
4.5.6. Huntington’s Disease visual evoked potentials
The majority of reports have illustrated decreased amplitude with
normal peak latency in the VEP responses of HD patients (Ellenberger
et al., 1978; Rizzo et al., 1980; Oepen et al., 1981; Josiassen et al., 1984).
The magnitude of the amplitude decrease seems to correlate with the
severity or duration of the disease (Ellenberger et al., 1978). One
potentially confounding variable in these assessments is the effect of
medication on observed waveform abnormalities. In particular, VEP
amplitudes were lower in HD patients receiving antipsychotic treatment
as compared to patients who were not receiving treatment in at least one
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Progress in Retinal and Eye Research 83 (2021) 100938
Genetically confirmed (CAG) Complete eye exam* excluding
confounding disease
Kersten et al., (2015), Gatto et al., Kersten et al., (2015), Gatto et al.,
(2018), Gulmez Sevim et al., 2019 (2018), Gulmez Sevim et al., 2019
Gulmez Sevim et al., 2019 Gulmez Sevim et al. 2019, Andrade et al.,
(2016)
Kersten et al., (2015), Gatto et al., Kersten et al., (2015), Gatto et al., (2018)
(2018)
Andrade et al. (2016)
Pearl et al., (2017); Knapp et al., (2018) Pearl et al., (2017); Knapp et al., (2018)
study (Josiassen et al., 1984). Nevertheless, VEP amplitudes were still
significantly lower for both medicated and unmedicated HD patients
relative to controls. Importantly, similar VEP irregularities are also seen
in psychiatric diseases and are not specific for HD (Josiassen et al.,
1984). Notably, at least one study has not been able to demonstrate
similar findings using PVEP over a two year period (Ehle et al., 1984).
4.6. Cerebral small vessel disease
Cerebral small vessel disease (CSVD) refers to a group of human
cerebrovascular diseases that affect small intraparenchymal arterioles in
the CNS (Pantoni 2010; Iadecola 2013; Cannistraro et al., 2019) and
many aspects of these diseases have been replicated in animal models
(Tuo et al., 2020). Common causes of human CSVD include hypertensive
arteriolosclerosis, cerebral amyloidosis, lupus vasculitis, and cerebral
autosomal dominant arteriopathy with subcortical infarcts and leu­
koencephalopathy (CADASIL). CSVD is responsible for approximately
25% of strokes worldwide (both ischemic and hemorrhagic), and is
associated with increased risk of recurrent stroke (Rensma et al., 2018).
It is also a primary contributor to cognitive decline, with up to 45% of
dementia cases in the general population being associated with CSVD
(Gorelick et al., 2011; Gorelick and Pantoni 2013; Sachdev et al., 2014).
Current clinical and research practices for identification of CSVD rely on
neuroimaging (usually MRI) evidence of parenchymal brain injury
caused by CSVD (Wardlaw et al., 2013; Cannistraro et al., 2019; Das
et al., 2019). These biomarker findings include, white matter hyper­
intensity (WMH), lacunar infarcts, cerebral microbleeds (CMB), con­
vexal subarachnoid hemorrhage (cSAH), cortical superficial siderosis
(cSS), large hemorrhagic stroke lesions, and enlarged perivascular space
(PVS) (Fig. 8) (Wardlaw et al., 2013).
Population-based series including imaging and autopsy data identi­
fied two primary CVSD subtypes that account for the vast majority of
cases (Cannistraro et al., 2019). Hypertension-related Angiopathy
(HTNA) is a form of acquired CVSD and represents a small vessel dis­
order caused by prolonged uncontrolled hypertension. Rather than a
single pathological entity, HTNA represents a group of hypertensive
cerebral angiopathies that frequently overlap and include hyaline arte­
riolosclerosis, hyperplastic arteriolosclerosis, segmental arterial disor­
ganization, and microaneurysms (Pantoni 2010). The changes in lumen
morphology and biological properties associated with these conditions
are thought to lead to a cascade of secondary injury processes including
decreased cerebral blood flow (up to and including vascular occlusion
and acute ischemic infarction), leakage of blood products from micro­
aneurysm (results in hemorrhagic lesions ranging in severity from CMBs
A.H. Kashani et al.
to large hypertensive hemorrhages), and chronic ischemia of oligoden­
drocytes dysfunction leading to loss of myelin integrity (manifesting as
white matter disease) (Wardlaw et al., 2013; Promjunyakul et al., 2018).
Cerebral amyloid angiopathy (CAA) is another form of CVSD that is
acquired and caused by deposition of Aβ in the walls of small-to-medium
cortical and leptomeningeal arterioles and arteries (Biffi and Greenberg
2011). In turn, the development of amyloid-related angiopathy results in
loss of vessel compliance and decreased cerebral vascular reactivity.
Ultimately these changes in vessel physiology lead to accumulation of
ischemic (WMH) and hemorrhagic (cSAH, CSS, large cortical hemor­
rhages) lesions, leading to acute stroke and progressive diffuse cortical
atrophy (Pantoni 2010). Because of shared links to Aβ deposition CAA is
usually associated with AD, with the two conditions representing spe­
cific manifestations (vascular vs. parenchymal) of an overarching dis­
order of amyloid cerebral production, processing and clearance
(Greenberg et al., 2020).
4.6.1. Retinal histopathology in cerebral small vessel disease
There have been to date no dedicated studies of retinal histopa­
thology in CVSD, either in the CAA or HTNA form. This in part relates to
the ease of acquiring detailed information on vascular structures of in­
terest in vivo by a variety of techniques (fundus photography and OCTA
being the most commonly implemented, see below). It is worth
mentioning that retinal vascular changes identified in amnestic MCI and
AD patients may partially reflect separate contributions from CSVD
(either CAA or HTNA), which is comorbid in a large proportion of cases
(Matej et al., 2019). Histopathological studies of AD retinas showed
pathogenetic Aβ deposits accumulating within and along retinal vascu­
lature in a manner highly reminiscent of CAA (La Morgia, Ross-Cisneros
et al., 2016; Koronyo et al., 2017). As for HTNA, histopathological
Fig. 8. Representative MRI findings in cerebral small vessel disease.
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Progress in Retinal and Eye Research 83 (2021) 100938
retinal changes associated with hypertension have been consistently
associated with risk for cerebrovascular disease (Henderson et al.,
2011). Additional studies of retinal histopathology and CSVD are
required to identify tissue changes specific to CSVD, and correlate them
with characteristics neuroimaging findings and disease progression.
4.6.2. Neurosensory and peripapillary retinal changes in cerebral small
vessel disease
Retinal structural changes have so far received limited attention in
CSVD investigative efforts. RNFL defects on fundus photography were
shown to be associated with WMH in a large study including Korean
community-dwelling individuals who participated in health checkups
(Kim et al., 2011). RNFL and GCL were shown to be associated with
CSVD, primarily in terms of WMH prevalence and severity (Qu et al.,
2020). Additional studies, ideally including longitudinal evaluation of
both retinal neurosensory changes in relation to the progression of
capillary and arteriolar pathology, are warranted at this time. As we
discuss in sections 5 and 7, high-resolution capillary imaging of the
retina and novel image analysis and registration methods will provide
excellent tools for assessing longitudinal and subclinical changes.
4.6.3. Retinal vascular changes in cerebral small vessel disease
For the purposes of our discussion, the retinal vasculature can be
divided into macrovascular components that are generally greater than
100 μm in diameter (retinal arteries and venules) and microvascular
components (arterioles, venules and capillaries) that are less than 100
μm in diameter. Many studies classify retinal vascular changes as
“retinopathy” which is a generic term that applies to almost any vascular
changes in the retina. In the context of this manuscript, we will use
“retinopathy” to refer specifically to end-stage capillary changes
A.H. Kashani et al.
(microaneurysms, cotton wool spots, retinal hemorrhages, hard exu­
dates) that are secondary changes resulting from obliteration or signif­
icant structural abnormality of the retinal capillaries. These distinctions
are important because color fundus photography is not able to resolve
end-arteriolar and capillary changes in the retina but can clearly show
the secondary results of chronic capillary pathology such as micro­
aneurysms, cotton wool spots, hemorrhages and hard exudates. In
contrast, studies using OCTA are specifically designed to look directly at
capillary changes and not secondary effects of capillary damage.
Multiple studies have investigated the association between mea­
surements of neuronal and retinal macrovascular integrity on fundus
photography and CSVD (Wu et al., 2017). In addition, retinopathy on
fundus imaging is associated with prevalence and progression of cere­
bral infarcts and WMH in population-based studies (Cooper et al., 2006;
Longstreth et al., 2007; Cheung et al., 2010; Hanff et al., 2014). These
retinal photography findings were also associated with CSVD neuro­
imaging markers among patients presenting with acute stroke, and
preferentially identified patients presenting with CSVD-related stroke
subtypes (primary intracerebral hemorrhage and lacunar infarcts)
(Lindley et al., 2009; Ong et al., 2013; Liew et al., 2014; Wei et al.,
2016). Among quantitative retinal vasculature metrics arteriolar mean
diameters and fractal dimensions (as derived from high-resolution
fundus images) were repeatedly found to associate with CSVD MRI
markers, especially WMH and lacunar infarcts (Kwa, van der Sande
et al., 2002; Doubal et al., 2010; McGrory et al., 2019). In the Rotterdam
Study retinal venular diameter did not associate with baseline CSVD
severity, but did correlate with progression on follow-up MRI scans
(progression of WMH and new lacunar infarcts) (Ikram et al., 2006). A
recent study using OCTA has further demonstrated associations between
markers of retinal capillary health and function with intracranial
vascular health and function (Ashimatey, D’Orazio et al., 2020). In this
study, lower retinal capillary perfusion density was significantly asso­
ciated with worse MRI measures of cerebrovascular reactivity, lower
perfusion in the middle cerebral artery perfusion territory as well as
impaired cognition (Ashimatey, D’Orazio et al., 2020) (Fig. 9). Collec­
tively these data strongly suggest that retinal capillary changes mirror
vascular pathology in the brain at all levels of the vascular tree.
One of the advantages of MRI for CSVD is the ability to distinguish
between subtypes, which in turn has direct implications for associated
clinical manifestations and prognosis (Cannistraro et al., 2019). To date,
few studies distinguished between different forms of CSVD when
exploring associations with retinal imaging. Retinopathy lesions on
fundus imaging were found to be more common among survivors of
CSVD-related stroke compared to other stroke subtypes (Baker et al.,
2010a,b; Gobron et al., 2014). Among subtypes of CSVD-related stroke,
cases of amyloid-related lobar intracerebral hemorrhage demonstrated
the highest prevalence of microvascular wall signs and retinopathy
findings on fundus imaging (Baker et al., 2010a,b). A study in rural
Ecuador found associations between hypertensive retinopathy and
CSVD findings on MRI, but did not distinguish between hypertensive
and amyloid subtypes (Del Brutto, Mera et al., 2016). Another study
found reduction in arteriolar fractal dimensions to be more common in
CSVD-related vascular impairment compared to AD, but did not further
distinguish between different small vessel disease etiologies (Jung et al.,
2019). While more evidence is needed to definitively assess whether
retinal imaging modalities can accurately subtype CSVD, this potential
application would directly impact research and clinical care practices.
In addition to OCT/OCTA, other retinal vascular imaging modalities
were investigated for association with CSVD. In one study, the diagnosis
of Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) was
associated with an almost five-fold increase in the prevalence of CSVD
(as defined by MRI evaluation) compared to NAION-free controls (Kim
et al., 2019a,b). Decreased retinal vasoreactivity determined via Dy­
namic Vessel Analyzer was associated with impaired cerebral vaso­
reactivity (assessed via transcranial Doppler), a key marker of CSVD
(Bettermann et al., 2017). Central retinal artery blood flow (as
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Progress in Retinal and Eye Research 83 (2021) 100938
determined via Doppler) was notable for lower end-diastolic and mean
velocities, and higher pulsatility and resistive indexes among CSVD
patients compared to controls. Doppler flow velocities were also asso­
ciated with WMH severity on MRI (Hiroki et al., 2003). While limited,
evidence from these studies suggest that a multimodal approach to
retinal imaging may increase the yield of current CSVD research ap­
proaches, focused primarily on retinal imaging.
4.6.4. Visual pathway electrophysiology in cerebral small vessel disease
There have been to date no studies leveraging visual pathway elec­
trophysiology to study CSVD. However, multiple studies investigated
response in cerebral blood flow to visual pathway stimulation, via either
Transcranial Doppler ultrasound or functional MRI. Patients with CAA
demonstrate reduced cerebral vascular reactivity to visual pathway
stimulation, consistent with imaging and histopathology studies indi­
cating greater disease severity in the occipital lobe (Smith et al., 2008;
Peca et al., 2013).
4.6.5. Autosomal dominant cerebral small vessel disease
Thus far there are few studies of retinal changes in genetically-
determined CSVD but this is a rapidly growing area of investigation
with exciting initial findings. Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL) is the
most common genetic form of CSVD (Federico et al., 2012). CADASIL is
an autosomal dominant genetic disorder caused by mutations in the
NOTCH3 gene, encoding a transmembrane receptor expressed almost
exclusively in vascular smooth cells and pericytes (Monet-Leprêtre et al.,
2009). Accumulation of the mutated protein product leads to formation
of toxic extracellular deposits, leading to alterations in small vessel
physiology similar to those observed in CAA. Among
genetically-determined forms of CSVD, CADASIL has been the topic of
most studies looking into potential application of retinal imaging tech­
niques. In an early study of 10 consecutive subjects with skin biopsy or
genetically confirmed CADASIL, color fundus photographs and
dye-based retinal angiography demonstrated bilateral arteriolar
sheathing in 30% of subjects, arteriolar narrowing in 80% of subjects
and arteriovenous nicking in 90% of subjects (Haritoglou et al., 2004).
Notably, the prevalence of focal arteriolar narrowing and arteriovenous
nicking in population-based studies is much lower that reported in this
small cohort (~14%) (Wong et al., 2007). Subsequent studies focused
primarily on OCT and OCTA. Genetically confirmed CADASIL cases
were shown to have significantly increased OCT-based mean arterial and
venous diameters compared to controls (Alten et al., 2014). OCT mea­
surements of arterial and venous mean diameters were also found to
correlate with lacunar infarcts and cerebral microbleeds on MRI (Fang
et al., 2017). In one study of OCTA in CADASIL, vessel density of the DRL
was found to be significantly decreased in affected patients compared to
healthy controls (Nelis et al., 2018). Larger and longitudinal studies will
be ultimately needed to validated and expand upon these findings.
Additional evidence on the use of retinal imaging has also recently
emerged for disorders with mixed small and large vessel CNS manifes­
tations. In Fabry disease, retinal and conjunctival vessel tortuosity rep­
resents an important diagnostic finding. Analysis of retinal and
conjunctival vasculature demonstrated increased vessels tortuosity in
Fabry disease patients (Sodi et al., 2019a,b). Evidence of abnormal RNFL
and vessel appearance on OCT have also been reported in smaller studies
of Mitochondrial Encephalopathy, Lactic acidosis, and Stroke-like epi­
sodes (MELAS) syndrome (Cho and Yu 2015; Sultan et al., 2017) Taken
together, these findings suggest that retinal imaging of neuronal and
vascular structures may aid in early diagnosis and longitudinal moni­
toring of rarer genetic forms of CSVD.
4.7. Frontotemporal Dementia
Frontotemporal Dementia (FTD) is a heterogeneous group of
neurodegenerative diseases characterized by neuronal and glial
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

Fig. 9. Optical coherence tomography angiography (OCTA) images and quantification of retinal capillary changes in a subject with cognitive impairment and
control. The figure shows 3 × 3mm2 parafoveal OCTA images of two subjects with CDR-SOB scores = 0 and CDR-SOB = 1, and ages 76 and 73 years, respectively.
Neither subject has diabetes but both have hypertension. Images on the second and third columns show the corresponding skeletonized images and pseudo-colored
maps of the capillary density. The subject with CDR-SOB = 0 has more localized areas of higher capillary density than the age and medical condition similar subject
with CDR-SOB >0. (Reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) 4.0 International License from Ashimatey
et al., Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring in press 2020).

proteinaceous inclusions preferentially involving the prefrontal and
anterior temporal lobes of the brain. The age of FTD onset is typically
younger than in LOAD (peaking in the 60’s) with an incidence ranging
from 5 to 22/100,000 person-years with a rough estimate of
20,000–30,000 prevalent cases in the United States (Neary et al., 2005;
Knopman and Roberts 2011). FTD is associated with two principal
proteinopathies including microtubule-associated protein tau and
transactive response DNA-binding protein 43 (TDP-43) and this het­
erogeneity is captured with the neuropathological term “frontotemporal
degenerations” (Irwin et al., 2015). FTD and ALS occur on a spectrum in
some families, most commonly in association with C9orf72 expansions.
FTD is predominantly a behavioral disorder featuring significant
changes in personality and social conduct. Notably, however, patients
may also present with language impairment, cognitive deficits in exec­
utive function, and motor symptoms (Neary et al., 2005). Therefore,
FTD is more commonly referred to as a group of 3 clinical syndromes:
behavioral variant, progressive non-fluent aphasia, and semantic de­
mentia(Neary et al., 2005; Ferrari et al., 2017). These syndromes relate
more to the areas of the brain involved rather than the subtype of protein
accumulation. The clinical presentation correlates poorly with the un­
derlying proteinopathy and clinical diagnosis remains especially chal­
lenging given the phenotypic variability of this disease (Neary et al.,
2005). Interestingly, a significant fraction of subjects with presumed
FTD are later diagnosed with AD by neuropathology (Kertesz et al.,
2005; Knopman et al., 2005; Forman et al., 2006). While the specific
pathology of the frontotemporal degenerations has not been histopath­
ologically demonstrated in the human retina, abnormal accumulation of
tau has been demonstrated in the aging retina (Leger et al., 2011).
Therefore, non-invasive retinal imaging may provide a potentially useful
biomarker for this disease though studies of retinal changes in FTD must
take into account the considerable genetic and pathological heteroge­
neity in this group of disorders. Below we summarize and synthesize a
large body of literature describing retinal imaging findings in FTD and
implications of these findings in future studies. The numerous references
in this section are also summarized in Table 4.
4.7.1. Neurosensory retinal thickness in Frontotemporal Dementia
Studies of the retina in FTD are very few. Ferrari et al. compared
retinal thickness between 17 FTD patients and 49 healthy controls using
OCT (Ferrari et al., 2017). This cross-sectional study showed significant
pRNFL and GCIPL thinning in FTD relative to controls (Ferrari et al.,
2017). However, retinal thickness did not correlate with MMSE scores
(Ferrari et al., 2017). Kim et al. measured macular thickness in 38 FTD
patients with probable tau proteinopathy and 44 healthy controls using
OCT (Kim et al., 2017). After adjusting for age, race and sex, significant
thinning of the outer retinal photoreceptor complex, most pronounced
in the ONL and in the IS/OS junction (Ellipsoid Zone), was observed in
subjects with probable tauopathy but not in those with other subtypes of
disease. Specifically, the ONL was about 10% thinner in FTD associated
with tauopathy than in controls. In contrast, the inner retinal layers
comprising the GCC were relatively unaffected. Outer retinal thickness
also correlated significantly with MMSE scores in the whole cohort of
FTD subjects (Kim et al., 2017).
A 16-month longitudinal study to further investigate disease pro­
gression in the retina showed persistent outer retinal thinning in FTD
without significant involvement of the inner retinal layers (Kim et al.,
2019a,b). Outer retinal thickness similarly correlated with MMSE scores
prospectively, suggesting a possible relationship between the retina and
the severity of disease. The investigators hypothesize that since
microtubule-associated tau is found in the retina as a photoreceptor
ciliary protein, a tau-based mechanism for outer retinal atrophy may be
responsible for the observations (Kim et al., 2019a,b). Importantly, Kim
et al. also performed objective CSF testing to exclude participants with
confounding AD (Kim et al., 2017). Additional morphologic analyses of
postmortem eyes correlated with retinal changes in well-characterized,
homogeneous FTD cohorts are necessary to improve our understanding

24
A.H. Kashani et al.
of retinal markers for this spectrum of disease.
5. Future directions and conclusions
We have mentioned at several points throughout this article that
there is a significant need for longitudinal studies to address the cau­
sality and temporal relationship of retinal imaging findings in the dis­
eases we have reviewed. Beyond this there are a number of limitations
that are associated with retinal imaging methodologies and studies that
are worth further addressing because they significantly impact the
conclusions that may be derived from the retina and retinal imaging
about neurological processes. In addition, these limitations provide
significant opportunity for methodological development in future
studies that we will discuss in the next section. For the purposes of this
article and discussion we categorize these limitations and future di­
rections in the following groups: field-of-view size, image registration, 2-
dimensional versus 3-dimensional analyses, imaging artifacts, and study
design. We believe that one or more of these categories underly the often
contradictory or inconsistent findings in the literature.
5.1. Wide-field retinal imaging
In general, most studies of retinal findings in neurodegenerative
disease are limited by the field-of-view of the imaging modality whether
that is fundus photography or OCT based imaging. In the vast majority of
cases the field-of-view is limited to the macula or optic disc. Specifically,
for OCT imaging the central 6 × 6mm or even 3 × 3mm parafoveal
region of the macula is the most commonly imaged region of the retina
and for fundus photographs the 30–50◦ (approximately 10–15 mm;
Fig. 1A) immediately adjacent to and temporal to the optic nerve head is
the most commonly imaged. It is important to note that by virtue of the
study design and imaging device, large areas of the peripheral retina are
excluded from analysis in these studies (compare Figs. 1A and 2A).
While it is not clear exactly how important the peripheral retina is
compared to the central retina, it is worth keeping in mind the sampling
bias introduced by this limitation. For example, some histopathological
studies suggest that retinal amyloid deposition occurs primarily in the
peripheral (extramacular) retina (Koronyo-Hamaoui et al., 2011; Kor­
onyo et al., 2017) and would not be detected by studies that are only
assessing central macular images.
The adoption of wide-field imaging methods that we discuss in sec­
tion 5.1.1 will change this bias in the future and is particularly relevant
to studies of neurodegenerative disease. Wide-field color fundus imag­
ing is rapidly becoming the standard-of-care throughout ophthalmology
practices and will grow in popularity in research settings as well (Pan­
war et al., 2016). Wide-field OCT and OCTA are also a subject of intense
investigation and technological development (Eastline et al., 2019)
(Fig. 2). One important point to keep in mind in evaluating data from
different field-of-view OCT and OCTA images is that the image
Table 4
Summary of retinal imaging studies characterizing human subjects with frontotemporal dementia.
Finding FTD vs Controls No Difference
OCT
pRNFL thinning Ferrari et al.
(2017)
mRNFL thinning Kim et al., (2017); Kim et al.,
2019a,b
RGC-IPL thinning Kim et al., (2017); Kim et al.,
2019a,b
Total macular Kim et al., (2017); Kim et al.,
thinning 2019a,b
Abbreviations: = Optical Coherence Tomography, FTD = Frontotemporal Dementia, pRNFL = peripapillary retinal nerve fiber layer, mRNFL = macular retinal nerve
fiber layer, RGC = Retinal Ganglion Cells, IPL = Inner Plexiform Layer, Blank cells indicate no data or study was available for that parameters. (*) Complete eye exam
includes visual acuity, intraocular pressure measurement, and dilated fundus examination.
Progress in Retinal and Eye Research 83 (2021) 100938
resolution often varies inversely with field-of-view and therefore subtle
findings (e.g. capillary level findings) may be difficulty to resolve in
larger images. While the wide-field capabilities of these devices are just
beginning to be explored it is very likely that technological development
and clinical demand will push the development of wide-field OCT and
OCTA in the next several years. Implementation of these technologies in
studies of retinal changes and neurodegenerative disease will provide
data on aspects of retinal anatomy that were not previously available. By
imaging more of the peripheral retina, future studies may better explain
the differences between histopathologic studies and in vivo imaging
studies.
5.2. Image registration
The detection of subtle, subclinical changes in retinal thickness,
capillary density and especially sublayer thickness requires precise
measurements that are reliable between and among subjects. For
example, at least one cross-sectional study that did not find significant
differences in average RNFL or GCIPL of subjects with LOAD (or MCI)
compared to controls, did report focal regions of RNFL thickening
immediately adjacent to areas of thinning (Lad et al., 2018). This sug­
gests that quantifying retinal thickness or sublayer thickness across
relatively large regions of retina may obscure subtle changes that cancel
each other out. This problem is also encountered in the analysis of
retinal images from subjects with retinal disease (e.g. macular edema or
retinal atrophy). Therefore, one important consideration in the analysis
of retinal imaging data is image registration. Image registration is crit­
ical to ensure comparison of analogous retinal regions of the same
subject from different time points in longitudinal studies or analogous
retinal regions from different subjects in cross-sectional studies. This is
particularly relevant in OCT studies of retinal thickness but also appli­
cable to other imaging modalities. Because accurate image registration
is difficult, almost all the studies we describe in this review report
average retinal thickness values across large regions (often pre­
determined by commercially available software) of the OCT scan. Image
registration between or among subjects is generally not considered at
all. This is a significant area of improvement which is particularly
applicable to longitudinal studies of the retina in subjects with neuro­
degenerative disease especially since effect sizes are usually small and
may be masked by slight changes in image sampling area.
Image registration is a computational technique for finding one-to-
one correspondence between pairs of images and useful for image
analysis techniques including quantitative measures of retinal changes
(thickness, capillary density), image fusion or stitching. Multiple image
registration techniques have been described in the field of medical
image processing (Toga and Thompson 2001; Murphy et al., 2008; Teng
et al., 2010; Gavaghan et al., 2011; Oliveira and Tavares 2014). These
techniques have been used for registration of OCT and OCTA images to
evaluate treatment efficiency (Lee et al., 2015) understand retinal
Biomarker confirmed (tauopathy, TAR DNA–binding Complete eye exam* excluding
protein 43) confounding disease
Kim et al., (2017); Kim et al., 2019a,b
Kim et al., (2017); Kim et al., 2019a,b
Kim et al., (2017); Kim et al., 2019a,b
25
A.H. Kashani et al.
diseases (Chen et al., 2014; Lee et al., 2015; Antony et al., 2016), correct
motion artifacts (Kraus et al., 2012) and assist with layer segmentation
(Duan et al., 2018). The majority of these methods have been performed
on 2D images because of the technical challenges and computation cost
of 3D image registration. However, the latter is more likely to provide
anatomically accurate information for both qualitative and quantitative
analyses. More importantly, it is possible and likely that 3D based
measurements would capture more subtle retinal changes that are so
prevalently (but inconsistently) reported in the neurodegeneration
literature. Furthermore, many of the layer specific findings (or lack
thereof) among current studies would benefit from a method that
allowed qualitative and quantitative evaluation of retinal sections
independently of layer segmentation.
Techniques for within and between subject image registration have
been proposed previously. Within subject registration of OCTA image
volumes has been reported to align vascular pattern of repeated scans
(Zhang et al., 2019). However, between-subject OCTA registration is not
feasible due to lack of features that can be reliably used for registration.
In fact, vascular patterns in OCTA are the dominant features and are not
expected to match across subjects. However, since OCTA is generated
from more than one OCT image, the same registration for OCT volumes
is applicable to OCTA images. In OCT, retinal layer boundaries and
foveal pit are considered as distinctive features across subjects (Khansari
et al., 2020). These features can be used for reliable registration of be­
tween and within subjects OCT image volume. Several methods have
been developed for cross-subject OCT registration in 2D (Gibson et al.,
2010; Chen et al., 2014; Lee et al., 2015).
Khansari et al. developed an automated 3D registration technique for
cross-subject registration of OCT image volumes in subjects with retinal
vascular disease (Khansari et al., 2020). This technique consisted of an
initial restricted affine transformation to define anatomically consistent
volumes of interest. Affine transformation is similar to rigid trans­
formation which also corrects shear and scale between pairs of images.
Afterwards, an efficient B-spline transformation using stochastic
gradient descent is performed to align layers boundaries and foveal pit
within the VOI. B-spline finds local deformation between pair of images
and is particularly powerful for 3D registration. The authors showed
high accuracy of the registration in terms of aligning eight different
retinal layer boundaries in healthy and subjects with diabetic retinop­
athy complications. This method is particularly unique because the
determinant of Jacobian matrix which is partial derivative of the
vector-field at each voxel for the non-linear deformation was used to
visualize tissue expansion and contraction independently of layer seg­
mentation (Fig. 10). Additionally, tensor-based morphometry was per­
formed for detection of group-wised localized structural changes in
different stages of DR. Tensor based morphometry measures significance
of local structural differences between groups of images based on voxel
level statistics. In Khansari et al., 2020, for each voxel, t-test was per­
formed on Jacobian values between healthy and diabetic subjects to
generate a p-value map. Voxels in the p-value map with values less than
a threshold (i.e. p < 0.05) were considered to be significantly deformed.
Fig. 10 shows example non-linear registration of OCT of subjects with
diabetic retinopathy to a normative image which is generated by
registering and averaging multiple healthy OCTs. Color-coded Jacobian
maps show the magnitude of local retinal expansion and constriction
independently of retinal layer segmentation. Once OCT of different
subjects are registered, the transformation can be applied to the corre­
sponding OCTA image volume of each subjects. This brings OCTA im­
ages into a common space allowing meaningful layer-based analysis of
vascular morphology between and among subjects (Sarabi et al., 2019).
Future applications of this method can be performed in a layer seg­
mentation independent manner and will likely be more sensitive for
detecting the subclinical retinal changes described in various neurode­
generative diseases.
26
Progress in Retinal and Eye Research 83 (2021) 100938
5.3. 2D vs 3D OCTA analysis
Another major limitation of retinal imaging that is particularly
relevant in studying neurodegenerative disease is that most data (fundus
photographs) are available and analyzed only in 2-dimensional (2D)
format. However, OCT and OCTA data that are available in 3D volumes
are still also largely analyzed in 2D formats. This is partly because of the
ease with which 2D analyses can be performed. However, 2D repre­
sentations (e.g. en face images) of 3D retinal structures are inherently
limited because they confound vascular and tissue relationships that are
likely to be important in detecting pathological changes, especially
subtle ones that are characteristic of neurodegenerative diseases. Un­
fortunately, there are significant technical challenges associated with
rendering and analyzing 3D data. For example, OCTA data are often
compromised by high noise levels, vessel discontinuity and low vessel
visibility that mainly affects the appearance of small capillaries. Addi­
tionally, OCTA imaging artifacts such as motion and projection of large
vessels and challenges in image registration negatively impact the true
visualization and geometry of the retinal vessel network (Spaide et al.,
2015a,b,c; Holmen et al., 2020). To enable true 3D OCTA analyses,
multi-scale and multi-orientation curvilinear enhancement techniques
need to be developed to separate blood flow from static tissues and
obtain a high-quality vessel and tissue maps. Recent studies have
demonstrated the potential advantages of 3D OCTA analysis in retinal
images. For example, several studies have (Chen et al., 2016; Spaide
2016; Spaide et al., 2017) shown that the correlation of intraretinal fluid
and retinal capillaries can be represented effectively by volume
rendering analysis of 3D-OCTA data. OCTA 3D vessel density can better
quantify foveal ischemia in diabetic retinopathy compared to the 2D
vessel density (Wang et al., 2019).
To reduce speckle noise in 2D-OCT images, numerous algorithmic
approaches (Adler et al., 2004; Jian et al., 2009; Wong et al., 2010; Fang
et al., 2012; Mayer et al., 2012; Xu et al., 2012; Boroomand et al., 2013;
Cameron et al., 2013; Luan and Wu 2013) have been developed. Since
OCTA is constructed by subtracting several OCT images, some of the
proposed techniques for OCT speckle noise reduction that can incorpo­
rate the retinal microvascular structures of various size and orientation
into the denoising framework are also applicable to OCTA. Among the
exiting techniques, the 3D curvelet transform has been applied suc­
cessfully to both structural OCT (Jian et al., 2010) and OCTA (Shi et al.,
2017), but it may be more appropriate for OCTA vessel enhancement.
Curvelet is a model-based filtering approach with high directional
sensitivity and anisotropy characteristics and it can provide an efficient
representation of edges and other singularities along curves. Compared
to conventional filtering methods, curvelet can avoid excessive denois­
ing and preserve capillary details in OCTA (Fig. 11). A novel 3D shape
modeling framework was recently developed based on curvelet
modeling to produce a novel and high-quality 3D OCTA microvascular
visualization which had not been previously demonstrated and might
provide a unique tool for clinical and scientific analysis (Zhang et al.,
2019). This framework includes a surface reconstruction process that is
applied to transform 3D discrete OCTA volume representations to 3D
continuous triangular surface representations (Fig. 12). The algorithmic
advances would make 3D tissue analyses much more feasible and
potentially enable more accurate OCT and OCTA based metrics.
Hessian-based methods (Frangi et al., 1998; Sato et al., 1998) have
been also widely used to identify and enhance tubular structures in both
2D and 3D medical images. The Frangi filter (Frangi et al., 1998) is one
of the most common multiscale hessian-based methods that has been
applied to OCTA enface images (Yousefi et al., 2015). To construct the
vesselness measure, Frangi uses the eigenvalues ratio of the Hessian
matrix (second gradient). The tubular vessel shape is usually repre­
sented by the two large eigen values and one small eigen value. How­
ever, due to the OCTA projection artifact, the 3D deformed geometry of
the large vessels won’t be properly detected by the default Frangi ves­
selness measure. Recently, researchers proposed a projection resolved
A.H. Kashani et al. Progress in Retinal and Eye Research 83 (2021) 100938

Fig. 10. Representative 3D registration and

Jacobian maps of OCT image volumes in two
subjects with diabetic retinopathy using
non-linear registration. Images are a cut
through the volume. (A) OCT volume of the
one subject with visible diabetic macular
edema and alterations in the shape of the
foveal pit. (B) Cut through the normative
atlas image demonstrating retinal structure
of a healthy subject. (C) Color-coded Jaco­
bian map demonstrating magnitude of
localized contraction and expansion in
diseased subject versus healthy subject in­
dependent of layer segmentation. (D) OCT
volume of another subject with visible tissue
loss. (E) Cut through the atlas image which
represents the retinal structure of a healthy
subject. (F) Color-coded Jacobian map
demonstrating magnitude of localized
contraction and expansion in diseased sub­
ject versus healthy subject independent of
layer segmentation. Red indicates areas of
expansion (edema). Blue indicates areas of
contraction (tissue loss).

technique based on the 3D Frangi vesselness measure for suppressing the the OCTA binary vessel segmentation that is obtained by automatic
tail artifact of large vessels in OCTA (Liu et al., 2019a,b). As part of their thresholding on OOF vesselness map using Otsu’s global thresholding
method, the authors suggested the plateness measure by modifying the (Otsu 1979). The above 3D-OCTA preprocessing framework has been
3D Frangi vesselness to measure the probability that a structure belongs employed to develop 3D-OCTA microvascular shape analysis (Zhang
to elongated vessels. In addition to the previously mentioned tech­ et al., 2019) and study the morphological and topological vessel changes
niques, other filter-based and hybrid methods have been also developed in subjects with diabetic retinopathy (Fig. 12). Future applications of
for enhancement of the OCTA vessels. Several groups presented an these methods to other data sets from subjects with neurodegeneration
automatic algorithm by combining a joint Markov-Gibbs model, a Naïve may yield novel insights into neurosensory and retinal vascular changes
Bayes (NB) classifier, and a 2D connectivity filter for segmentation of 2D in those diseases without the confounding effects of layer segmentation
superficial and deep retinal maps of normal and diabetic eyes (Chu et al., and 2D analyses (Fig. 11).
2016; Eladawi et al., 2017; Chlebiej et al., 2019). Others have developed
an OCT amplitude-decorrelation algorithm to enhance the SNR of flow
5.4. Study design
detection and microvascular network connectivity in cross-sectional
images (Jia et al., 2012).
One of the most significant limitations of studies that attempt to
Recently, an effective OCTA 3D vessel enhancement module has also
assess any retinal feature in neurodegenerative disease is the study
been demonstrated by combining curvelet denoising (Shi et al., 2017)
design. It is critical to state clearly from the outset of any study what the
and optimally orientated flux (OOF) (Law and Chung 2008; Sarabi et al.,
purpose of the proposed retinal findings are intended to be as this will
2019). OOF is a localized multi-scale curvilinear structure detector that
guide the essential details of the study design. For example, retinal
computes the vesselness measure based on the projected image gradient
findings may serve in early detection of subclinical disease, as bio­
at the boundary of a spherical region centered at every image voxel. The
markers of disease progression/regression, to characterize in vivo disease
main advantage of OOF is providing robust vessel detection response in
pathophysiology, or may be only associated clinical findings. Some
presence of closely located structures which makes it an ideal tool for
studies may aim to impact clinical care or enable drug development
vessel enhancement in OCTA dense microvascular networks. Fig. 11
while other studies may aim to make contributions to our understanding
demonstrates pre-processing results of a normal subject using the com­
of disease pathophysiology. In any case, given the small effect sizes that
bined curvelet and OOF approach. The results show that the combina­
are anticipated in most retinal imaging studies it is critical to power
tion of curvelet and OOF techniques resolved both the vessel
studies appropriately from the outset.
discontinuity and noise adjacent to tiny vessels while preserving the
Because of the optical accessibility of the retinal tissue and the high
microvasculature geometry in 3D-OCTA. In addition, Fig. 11 illustrates
resolution imaging methods that are available, it would seem logical to

Fig. 11. New Fig 12 Demonstration of the 3D OCTA surface reconstruction and the subsequent shape and Reeb analysis that may be used for future quantitative
analyses of retinal vessels. (A) The original 3D OCTA volume is processed to reconstruct (B) the 3D vessels surface representation. Using (B), we can perform intrinsic
shape analysis for (C) large and small vessels classification, and (D) Reeb graph analysis to quantify valuable 3D vessel geometry and topology.

27
A.H. Kashani et al.
Fig. 12. New Fig 11 Example of OCTA images from a normal subject before and after preprocessing algorithm for image registration and optimization for further
analysis. (A) Original 3D-OCTA image volume. (B) Enhanced OCTA volume obtained by applying 3D curvelet denoising on previous panel. (C) OCTA vesselness map
generated by computing the optimally oriented flux response of previous panel. (D) OCTA binary vessel mask obtained by applying Otsu’s global thresholding on
previous panel. (E–H) Selected enface views of images in above panels.
target the use of retinal findings as risk factors for future development of
disease. In this context, relatively low cost and rapid retinal screening
tests can be used to guide more resource intensive and likely specific
screening efforts (such as PET or CSF studies). The relatively high spatial
resolution of retinal imaging modalities may also be useful to assess for
subclinical disease onset and subclinical disease progression. In this
context, a retinal biomarker of early disease or risk must be validated
using objective measures of the underlying neurodegenerative disease
status (e.g. PET, CSF and blood) because clinical findings can be sub­
jective, subtle or altogether absent. In many cases, these objective
measures are not used because of ethical, financial or logistical reasons.
For example the availability of PET scanners is relatively limited and
lumbar puncture may seem like a relatively risky proposition for
otherwise asymptomatic subjects. Nevertheless, studies should strive to
use objective diagnostic criteria from blood, brain imaging, CSF, or ge­
netic testing to ensure the most accurate associations with retinal find­
ings. In addition, there are few or no studies that assess retinal findings
across a sufficiently large sample and sufficiently broad spectrum of
disease severity to rigorously validate the association of the retinal
findings with the underlying neurodegenerative disease.
Another major methodological limitation of many studies is the
challenge of performing comprehensive ophthalmologic evaluations to
establish clear inclusion/exclusion criteria. There are confounding and
highly prevalent ophthalmic disorders that can significantly impact
retinal measures of thickness, perfusion and neurosensory function.
Appropriately anticipating, quantifying and controlling for these con­
founding variables is possible and requires close collaboration between
ophthalmologists and neurologists. While an extensive discussion of
each of these diseases is out of the scope of this review article we review
the pertinent findings and rationale for carefully considering some of the
most prevalent comorbid ocular disease (diabetic retinopathy, glaucoma
and myopia) in the exclusion and inclusion criteria of future studies
below. There is also the possibility that these disease processes are not
confounding. It has been suggested that there are common underlying
pathophysiological mechanisms between what are considered primarily
retinal diseases and neurodegenerative diseases (Lynch and Abràmoff
2017; Sen et al., 2020a,b).
Myopia was estimated to impact 23% (1.4 billion people) of the
world population in 2000 and is expected to increase in prevalence to
50% (4.7 billion people) by 2050 (Holden et al., 2016). Myopia can be
progressive in nature with age or relatively stationary. The increased
28
Progress in Retinal and Eye Research 83 (2021) 100938
axial length of the eye that occurs in myopia induces magnification error
in many types of retinal images that require careful quantification and
correction (Bennett et al., 1994; Lee et al., 2018; Llanas et al., 2019). In
addition, myopia is associated with pathologic thinning of the choroid
which may impact studies assessing choroidal thickness changes in
neurodegenerative disease (Ang et al., 2019).
Glaucoma is another ocular disease characterized by subtle, but
significant, thinning of the RNFL (Weinreb et al., 2014) and attenuation
of the retinal peripapillary capillaries (Zabel et al., 2019). Glaucoma is
highly prevalent especially in older demographics and among Asian and
African American races (Tham et al., 2014). Glaucoma is also highly
underdiagnosed (Quigley 2011; Tham et al., 2014) because it is largely
an asymptomatic disease until the disease is very advanced. By some
estimates, more than 110 million people worldwide will have some form
of glaucoma by 2040. Most importantly, many of these people may not
be diagnosed with or know they have the disease for many years.
Therefore, some form of glaucoma screening is essential in studies un­
dertaking any evaluation of retinal thickness in subjects with possible or
actual neurodegenerative disease.
In 2014 an estimated 422 million people worldwide had diabetes
mellitus (WHO Fact Sheet; https://www.who.int/news-room/fact-shee
ts/detail/diabetes). Diabetic retinopathy is estimated to effect 29% of
adults in the United States with diabetes (Zhang et al., 2010). Diabetic
retinopathy can cause many retinal manifestations including retinal
thickening, retinal thinning and attenuation of retinal capillary density.
As with glaucoma, diabetic retinopathy can be essentially asymptomatic
for many years or even decades. Therefore, it is critical to assess for the
presence of diabetes mellitus in study subjects as well as some assess­
ment of diabetic retinopathy severity. It is equally as important to assess
the duration and control of diabetes mellitus.
5.5. Retinal vascular reactivity
Many of the studies of retinal vascular changes in neurodegenerative
disease focus on the static aspects of the retinal vasculature (e.g. capil­
lary density, vessel tortuosity, retinal hemorrhages etc). While these are
interesting metrics of vascular structure, they are only indirect measures
of vascular function, if any measure of function at all. Improvements and
advances in retinal imaging now allow measurement of capillary level
changes associated with physiologic stimuli For example, OCTA based
measurements of retinal capillary blood flow and/or caliber can be
A.H. Kashani et al.
reliably made during physiologic fluctuations in inhaled oxygen and
carbon dioxide (Ashimatey et al., 2019; Kushner-Lenhoff et al., 2020).
This method has been employed to demonstrate preclinical changes in
retinal vascular reactivity in subjects with diabetes even before the onset
of clinically evidence retinopathy (Ashimatey et al., 2019; Singer et al.,
2020). Similar physiologic changes have been measured using non-FDA
approved methods such as AO-SLO (Duan, Bedggood et al. 2016, 2017).
These methods will allow quantification of retinal vascular function
which has not been possible in the past. This may be advantageous for
several reasons including having larger and reversible effect sizes that
can be more reliably measured. In addition, changes in retinal vascular
function likely precede changes in retinal vascular structure. Future
application of these methods in cross-sectional and longitudinal studies
will provide novel and potentially interesting insights into the patho­
physiology of neurodegenerative diseases, especially cerebrovascular
disease and Alzheimer’s Disease. When coupled with measures of retinal
function, these studies also have the potential to provide new insight
into neurovascular coupling.
6. Conclusions
The notion that neurodegenerative changes in the brain are present
in the retina is supported by extensive evidence from in vivo retinal
imaging studies as well as evidence from histopathology specimens. This
evidence is particularly strong and well-established from histopatho­
logic and cross-sectional studies of subjects with Multiple Sclerosis and
Alzheimer’s Disease. These studies show significant changes in inner
retinal layers and most profoundly in the retinal nerve fiber layer.
Interestingly, layer specific findings involving the ganglion cell layer,
inner nuclear layer and photoreceptor layers have been demonstrated in
different neurodegenerative diseases. This suggests that clinical stages of
these chronic diseases may manifest in the retina in differing, and often
very subtle ways. For example, the findings that a subtle increase in
inner nuclear layer thickness correlates with MRI activity in Multiple
Sclerosis suggests that inflammation attributable to the underlying dis­
ease process is present in the retina. This hypothesis seems to be sup­
ported by histopathologic evidence of inflammatory cells in the inner
retina of subjects with Multiple Sclerosis. Advances in OCT analysis al­
gorithms using 3D metrics may provide additional insight into these
subtle layer specific changes. More recent findings of amyloid deposition
in the neurosensory retina and retinal vasculature suggest that the am­
yloid pathology that correlates with Alzheimer’s Disease status is also
present in the retina. Use of wide-field and hyperspectral imaging
methods presents a novel and exciting opportunity in detecting retinal
amyloid lesions in vivo. Advances in OCT metrics and hyperspectral
imaging are also potentially applicable to Parkinson’s Disease and
Huntington’s Disease where cross-sectional and histopathological evi­
dence for retinal involvement also exists.
Unfortunately, the clinical utility of retinal findings in neurodegen­
erative disease has been limited because, in most cases, the cross-
sectional data and associations are from subjects with relatively
advanced disease. Multiple Sclerosis is one exception where optic nerve
findings and OCT retinal thickness measures have demonstrated clinical
utility because the initial manifestations of the disease can be primarily
ocular. With the growing evidence that subtle retinal findings are
detectable during the presymptomatic stages of Alzheimer’s Disease (as
well as other neurodegenerative diseases), reliable and more sensitive
retinal imaging methods would present a significant clinical benefit in
detection, monitoring and possibly even therapeutic development. At
the least, there should be awareness among ophthalmologists, neurol­
ogists and clinician-scientists about the growing number of clinical trials
that are recruiting subjects at risk for neurodegenerative disease as well
as the potential for ocular manifestations of these diseases.
In addition, large scale and prospective studies are also needed to
assess the temporal relationship between retinal imaging findings and
known biomarkers associated with preclinical neurodegenerative
29
Progress in Retinal and Eye Research 83 (2021) 100938
disease (i.e. CSF and PET amyloid etc).
Retinal imaging presents a particularly unique opportunity in at least
two largely unexplored fronts, Autosomal Dominant Alzheimer’s Dis­
ease and Cerebral Small Vessel Disease. The confounding role of
Vascular Cognitive Impairment and Dementia in assessing neurode­
generative changes in the aged population is particularly challenging to
address. Ongoing prospective studies (e.g. MarkVCID) using optical
coherence tomography angiography have particular promise in detect­
ing and quantifying retinal vascular changes at the capillary level that
may be indicative of similar changes in the brain vasculature. Overall,
the potential of retinal imaging in understanding of neurodegenerative
disease and in its clinical management is very promising but remains to
be fully realized. Novel imaging methods (wide-field imaging, optical
coherence tomography angiography and hyperspectral imaging) and
analysis algorithms (3D versus 2D) will provide more opportunities to
apply retinal findings to neurodegenerative disease with very exciting
implications scientifically and clinically.
Author contributions
Amir H Kashani 35% (conceptualization, methodology, data cura­
tion, project administration, resources, supervision, original draft
writing, review and editing).
Samuel Asanad 15% (data curation, original draft writing, review
and editing).
John Ringman 5% (original draft writing, review and editing).
Alessandro Biffi, 5% (original draft writing, review and editing).
Yonggang Shi, 5% (review, supervision and editing).
Helena Chui, 5% (review, supervision and editing).
Jane W. Chan 5% (original draft writing, review and editing).
Jiong Zhang 5% (original draft writing, review and editing).
Mona Sharifi 5% (original draft writing, review and editing).
Maziar Khansari 5% (original draft writing, review and editing).
Maxwell Singer 5% (original draft writing, review and editing).
Farzan Abolahi 5% (original draft writing, review and editing).
Funding sources
This work was supported by the National Eye Institute (USA,
K08EY027006 to AHK) and National Institute for Neurological Diseases
(USA, UH3NS100614 to AHK), an unrestricted grant from Research to
Prevent Blindness (USA) to the USC Department of Ophthalmology,
Brightfocus Foundation (USA, CA2020004 to AHK)), National Institutes
of Health (USA, R01AG062007 and P30AG066530 to JMR).
Declaration of competing interest
The authors have no competing interests to declare. AHK received
research funding and honoraria from Carl Zeiss Meditec (Dublin, CA,
USA). Funding sources did not have any role in the conception, writing
or editing of this manuscript.
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