The Potential Role of Optical Coherence Tomography for Dementia Patients

Retinal imaging shows promise as a biomarker for dementia.


When making a diagnosis or determining retinal disease severity, ophthalmologists specializing in retinal diseases have the advantage of visualizing retinal tissue and utilizing imaging technologies with micron-level resolution. In contrast, the gold standard for the diagnosis of dementias such as Alzheimer disease (AD) remains neuropathology, which is only available if the patient expires and proceeds to brain autopsy. For neurologists, the diagnosis and management of patients with dementia is currently challenged by inadequate biomarkers for the underlying pathology.

This issue becomes especially complex because different dementias, each with its own specific neuropathology, can have overlapping clinical presentations. For example, AD can present with behavioral or speech abnormalities in the absence of the typical deficit in memory. Atypical presentations of AD are especially common among those with early-onset AD, when the diagnosis is made at the age of 65 years or less.1 Given that the retina is an easily imaged extension of the brain, retinal imaging has unique potential to improve the diagnosis of the underlying neuropathology in patients with dementias. In this article, we will discuss retinal imaging for neurodegenerative conditions, focusing on AD and frontotemporal degeneration (FTD).


In 1986, Hinton and colleagues demonstrated that AD patients have abnormal thinning of the retinal nerve fiber layer and a reduction in the number of retinal ganglion cells.2 This pathology was shown with histopathology of the optic nerves and retinas from AD patients. As OCT developed, several groups found that AD patients have inner retinal thinning (retinal nerve fiber layer and retinal ganglion cell layer thinning) using both retinal scans through the macula and peripapillary OCT.3-5 This finding was in line with the histopathologic data and demonstrated the potential for OCT to provide a biomarker for AD neuropathology.

Studies have also suggested that inner retina thinning correlates with disease severity.4,5 The exact mechanism causing inner retina thinning is not fully understood, although some have hypothesized that it is related to amyloid-beta.6 Alternative methods of retinal imaging have also been investigated, including studies of retinal vascular changes related to AD, choroidal thinning in AD, and fluorescence imaging of amyloid-beta.7-9 Reports by Koronyo-Hamaoui et al demonstrating the ability to use fluorescence imaging to visualize amyloid-beta within the retina after the oral administration of curcumin has been a subject of particular interest.8,10 According to these studies, curcumin binds to amyloid-beta and is a plaque-labeling fluorochrome, enabling noninvasive in vivo imaging of retinal amyloid-beta in humans. Additional studies to develop this technique are ongoing. There would be great value if the retina could be used to diagnose dementia in early stages when treatments would have the best chance of changing the course of the disease.


Interestingly, inner retina thinning has also been found in some other neurodegenerative diseases, including multiple sclerosis, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis (Lou Gehrig disease)5,11-13 Balcer et al demonstrated inner retina thinning in multiple sclerosis,11 which makes sense because multiple sclerosis can affect the optic nerves. Among these diseases, the use of OCT for multiple sclerosis is the most advanced, as OCT is used as an outcome measure in clinical trials for this disease and has utility during the clinical management of optic neuritis.14

Frontotemporal degeneration is an understudied dementia that is recognized to be of growing significance. It is as common as AD in people younger than 65 years old, and it is a leading cause of dementia among the middle-aged population, with an estimated prevalence of 15 to 22 in 100,000.15 FTD actually is an umbrella term for a group of diseases that can present with behavioral, speech, and/or motor abnormalities associated with forms of frontotemporal lobar degeneration (FTLD) neuropathology (FTD neuropathology is referred to as FTLD).16 Importantly, the clinical presentation of FTD can overlap with that of AD, as both dementias can have variable neurologic manifestations. In fact, up to 30% of patients clinically diagnosed with FTD are later found to have AD at the time of autopsy.17-19

Therapies for AD are limited, and there is no FDA-approved therapy for FTD, which means that patients with underlying AD neuropathologies misdiagnosed as FTD may be withheld from appropriate treatments, while those with underlying FTLD neuropathologies misdiagnosed as AD may be unnecessarily exposed to the side effects of AD drugs.20 Therefore, there is a tremendous need for biomarkers that can distinguish the neuropathological substrate for these dementias ante mortem. The neurology field has advanced to produce a validated cerebrospinal fluid (CSF) marker for AD (total tau:amyloid-beta),21 and positron emission tomography (PET) imaging with a radiotracer for amyloid-beta can also help to distinguish AD patients from controls without dementia.22 However, these biomarkers are both invasive, lumbar punctures have associated risks and contraindications (eg, anticoagulation), and PET imaging is costly. Further, secondary AD copathologies are common in other neurodegenerative disorders, such as Lewy body disease, and in older patients with FTD, causing altered levels of these AD-specific biomarkers.23,24 Thus, FTD-specific biomarkers are clearly needed.16


In contrast to the inner retina thinning associated with AD, we found outer retina thinning (photoreceptor layers) only in a group of deeply phenotyped FTD patients.25 We performed OCT on 27 consecutive FTD patients who were carefully phenotyped by neurologists at the Penn FTD Center by discussing diagnoses in a consensus conference, performing genetic analyses, and excluding AD with the CSF total tau:amyloid-beta biomarker. These patients were compared to 44 consecutively enrolled normal controls. All participants underwent a dilated eye exam to exclude confounding eye diseases. Statistically adjusting for age, sex, and race, FTD patients had a thinner outer retina than the controls (132 vs 142 μm, P=.004). FTD patients also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 μm, P=.003) and ellipsoid zone (EZ) (14.5 vs 15.1 μm, P=.009) than the controls but had similar thicknesses to the controls for the inner retinal layers.

FTD is primarily composed of 2 types of FTLD neuropathology. Approximately half are related to intracellular inclusions composed of the microtubule-binding protein tau (ie, FTLD-tau) or inclusions containing the DNA-binding protein TDP-43 (TAR DNA-binding protein-43, ie, FTLD-TDP).16 Except for only a few clinical syndromes that are predictive of the underlying pathology, it is not possible to differentiate these 2 distinct forms of underlying FTLD neuropathology based on the clinical presentation of an FTD patient. As pharmacologic therapies aimed at tau or TDP-43 develop and enter clinical trials, it is critical to develop biomarkers specific for these proteinopathies.

By examining our subset of patients with clinical syndromes specific for FTLD-tau or FTLD-TDP and using genetic data for patients with identifiable mutations, we categorized our FTD patients into subgroups of predicted molecular pathology (tauopathy, TDP-43, unknown). We found that the predicted tauopathy subgroup (N=19 patients, 31 eyes) also had a thinner ONL (88.7 vs 97.4 μm, P=.01) and EZ (14.4 vs.15.1 μm, P=.01) than controls. Other subgroups (FTLD-TDP, N=2; unknown pathology, N=6) were too small for meaningful analysis.25 An example of ONL thinning in an FTD patient with a MAPT (tau) mutation compared to a control is shown (Figure).

Figure. Frontotemporal degeneration with outer retina thinning. OCT images from a control and FTD patient showing outer nuclear layer thinning. The ETDRS grid is shown in A, D, and G with the green line indicating the location of the OCT scan and the red asterisk indicating the location of a point measurement. The control (B, E, H) is a 61-year-old white female. The patient (C, F, I) is a 60-year-old white female clinically diagnosed with the behavioral variant of FTD. This FTD patient has presumed tauopathy because she has a MAPT E10+16 C>T mutation. The Iowa Reference Algorithm segmentation lines for the ONL are shown in red and blue. Yellow lines indicate locations of hyper-reflectivity related to Henle’s fiber layer.26 Spectralis (Heidelberg Engineering) caliper point measurements (μm) of ONL thickness are labeled in white. Reprinted with permission from Wolters Kluwer.25

Finally, we investigated whether the outer retina thickness correlates with disease severity. We found that the outer retina thickness of patients was correlated with a measurement of global cognition (the Folstein Mini-Mental State Exam)27 (Spearman’s r=0.44, P=.03).25 Patients with a thinner outer retina had worse Mini-Mental State Exam results. This finding suggests that outer retina thickness may have prognostic utility for FTD.

With a group of FTD patients primarily composed of predicted tauopathy patients, we have shown that the outer retina thickness has potential as a diagnostic biomarker for FTD. While it is possible for AD patients to have ONL abnormalities along with inner retina abnormalities,10 we found outer retina thinning without inner retina abnormalities in our group of FTD patients. Microtubule function is known to be critical for photoreceptors,28,29 and data from the lab of Josh Dunaief, MD, at the University of Pennsylvania have shown that a microtubule-associated protein abnormality in mice can lead to outer retina abnormalities detectable by OCT.30

We hypothesize that our finding of photoreceptor layer (outer retina) thinning may be caused by abnormalities in the microtubule-associated protein tau. Further studies directly comparing large groups of FTD and AD patients are needed, as well as studies directly comparing tauopathy patients with TDP-43 proteinopathy patients. Additionally, we recommend OCT studies that carefully phenotype dementia patients and follow patients longitudinally, ultimately to autopsy, which is not an easy task. Such studies are needed to further develop the potential of OCT for these diseases.


While clinical presentations can overlap, AD and FTD have specific neuropathologies. Our recent findings add significantly to a growing body of evidence, suggesting that specific neurodegenerative diseases may have specific retinal pathologies. Together, these data indicate that OCT retinal imaging, and perhaps technologies beyond OCT, have strong potential as a biomarker for dementia. RP


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