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Neurodegenerative Diseases

Albert J. Augustin, MD and Christian Dempe

Due to aging populations in many countries and the tendency of neurodegenerative diseases to appear with advanced age, their incidence is expected to further rise dramatically.¹ In addition to the development of new therapies, it is critically important to establish reliable methods that facilitate their early diagnosis and monitoring. As the eye develops as a protrusion of the brain, the retina shows many correlations with the brain in terms of anatomy and functionality. Changes in the brain caused by neurodegenerative diseases can also be observed in the retina.^2–5 In this sense, the eye provides a “window onto the brain,” making the noninvasive diagnosis of various neurodegenerative diseases possible.⁶ Optical coherence tomography (OCT) is a well-established method in ophthalmology that is quick, easy to perform, and makes it possible to noninvasively examine tissue with a nearly histopathological resolution. It provides very detailed images of ocular structures and enables the precise differentiation of various layers of the retina. Additionally, the newly developed OCT angiography (OCTA) allows us to distinguish flowing blood from static tissue and enables a quick and detailed visualization of the retinal and choroidal microvasculature in 3 dimensions. In contrast to other imaging techniques such as fluorescein angiography (FA) and indocyanine green angiography (ICGA) that do not provide objective quantitative measurement of perfusion, OCTA allows such a quantification of the circulation of the posterior part of the eye. OCTA already has shown significant potential for the routine diagnosis and monitoring of diseases with vascular pathologies of the eye today—especially in the area of the macula and the optic disc. It therefore might also be helpful in diagnosing and monitoring neurodegenerative diseases associated with vascular alterations.

OPTICAL COHERENCE TOMOGRAPHY PARAMETERS FOR EVALUATING NEURODEGENERATIVE DISEASES

In the eye, the following structural OCT parameters have been shown to be important for detecting neurodegenerative changes: the retinal nerve fiber layer (NFL), the ganglion cell layer and the inner plexiform layer (GCL-IPL), as well as macular thickness and volume. The NFL is the innermost layer of the retina and is formed by the axons of the ganglion cells, whose cell bodies are located in the GCL beneath the NFL. NFL reduction directly corresponds to optic nerve damage. The inner plexiform layer (IPL) and the outer plexiform layer (OPL) are located beneath the GCL (Figure 34-1). High-resolution spectral domain OCT (SD-OCT) allows segmenting of the individual layers of the retina precisely and quantifies them by specialized algorithms. As a whole, SD-OCT facilitates the objective and reliable diagnosis of changes in the NFL or the GCL-IPL complex. Additionally, the newly developed OCTA offers rapid visualization of vascular alterations of the eye in 3 dimensions. Using OCTA, a very detailed image of the retinal and choroidal microvasculature has been achieved in healthy eyes as well as in eyes with various diseases of the posterior segment associated with vascular abnormalities.7–12 OCT angiograms allow assessment of vessel pattern and density and have demonstrated differences in retinal capillary networks that have not been reported previously using FA. The foveal avascular zone (FAZ) is clearly demarcated in OCTA and alterations have been demonstrated in diabetic eyes (Figure 34-2).¹⁰ Moreover, OCTA visualizes the optic nerve head vasculature from the disc surface to the lamina cribrosa and can detect and quantify reduced disc perfusion and reduced peripapillary retinal perfusion (Figure 34-3).^13,14

Approximately 46.8 million people worldwide suffer from dementia, of which Alzheimer’s disease (AD) is the most common form. Its clinical characteristics include difficulties with memory, orientation, and language, as well as decreased intellectual capacity, impaired judgment, and personality changes that increase with disease progression.1 Numerous studies have been investigating the use of OCT in detecting neurodegenerative changes in the eyes of AD patients.^15–31 Despite small sample sizes, these studies consistently show a reduction in the thickness of the NFL in AD patients as compared to healthy individuals. Two meta-analyses and a recent review confirm these findings.^32–34 Figure 34-4 shows SD-OCT results in an eye with reduced NFL as compared to a healthy eye. NFL thinning can already be observed in patients with mild cognitive impairment (MCI), which can progress to AD.^18–21,30 This alteration can thus be used to document the progression of the disease and to make a prognosis.³⁵ Although still discussed controversially, most studies document a significant correlation between NFL thinning and cognitive dysfunction in the patient.^{24,27,31,36–39} As a whole, current data strongly suggest that NFL thinning is a promising structural parameter for differentiating between AD patients and healthy individuals as well as for monitoring disease progression. Of course, large-scale studies as well as longitudinal studies are needed to verify these findings. Additionally, vascular alterations also associated with AD may also serve as a biomarker.^40–42 Recent epidemiological studies have provided direct evidence linking AD and vascular risk factors.^43–46 Moreover, it has been shown that AD patients exhibit significantly reduced venous blood flow, as compared to healthy individuals correlated by age, and there is evidence of microvascular abnormalities in AD and multi-infarct dementia.18,47,48 Recent studies have shown structural alterations such as a marked tortuosity and a lengthening of the brain capillaries in early cases of AD.⁴⁹ In this regard, OCTA may be a promising method to detect perfusional and structural abnormalities in AD.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system and is accompanied by inflammation and the demyelination of neurons, which ultimately leads to axonal and neuronal degeneration. Approximately 20% to 50% of MS patients seek medical attention for the deterioration in vision that accompanies optic neuritis (ON).^50,51 NFL thinning is a well-documented structural marker for axonal degeneration in MS patients both with and without ON, and correlates with changes in vision and cognitive capacity in MS patients (with and without ON).^52–56 A greater reduction in the NFL is associated with a worse visual prognosis.^52,56–66 In MS patients without ON NFL thinning is significantly less than in patients with ON (7.08 μm vs 20.38 μm; P < 0.0001).⁶¹ Moreover, macular thickness and volume as well as GCL-IPL thickness are also reduced in MS patients (Figure 34-5).^{51,58,67–72} These parameters appear to correlate with many visual dysfunctions even better than NFL thickness and can potentially better predict axonal damage.^61,67,73 Reduction in GCL-IPL thickness correlates with atrophy of the gray matter in the brain, and has been established as an important structural marker for MS.^62,74 Additionally, there is some evidence that vascular abnormalities may be a poor prognostic sign in MS.^75–78 Ocular circulation abnormalities were observed in MS patients, and it has been suggested that a more rigid retinal vasculature may lead to a quicker circulation of blood from choroidal to retinal vasculature.^79–82 A first study using OCTA in MS patients shows that perfusion of the optical nerve head was significantly lower in MS patients with ON than in healthy controls or MS patients without ON.⁸³ Even if the study sample size was relatively small, these promising results indicate that OCTA could be a useful technology to detect perfusion disturbances in MS patients. Additional studies are required to investigate if perfusion alterations may provide early insights into MS pathology.

PARKINSON’S DISEASE AND OTHER NEUROLOGICAL DISEASES

Studies also exist for other neurodegenerative diseases such as dementia with Lewy bodies or Parkinson’s disease (PD), in which NFL thinning or a reduction of the GCL was described in the affected patients.^84–90 Along with AD, PD is one of the most common progressive diseases of the central nervous system in advanced age, and is accompanied by slowness of movement (bradykinesia), muscle stiffness (rigidity), shaking (tremor), and postural instability. These symptoms are caused by a lack of dopamine due to the death of dopaminergic (DA) neurons in the substantia nigra. A precise clinical diagnosis of PD is difficult, especially in early stages of the disease. OCT examinations could prove to be another helpful diagnostic tool in this context: A meta-analysis revealed that in patients with PD, the NFL exhibited thinning in all 4 quadrants as compared to healthy controls.⁹¹ A correlation between the extent of NFL loss and the severity and duration of PD was described.⁹² A recent study has shown retinal thinning in association with a remodeling of the capillary bed in PD patients. Using OCT and FA, a foveal thinning and a significantly smaller FAZ were detected in PD patients as compared to healthy controls.⁹³ These results are in good agreement with vascular alterations discovered in the substantia nigra of PD patients.⁹⁴ Interestingly, the altered FAZ seems to be caused by a lengthening of the foveal capillaries. This might be promoted by damaged foveal DA neurons located in the FAZ in the human retina.^95,96 Thus, measuring retinal NFL thickness in PD may be a significant detector of visual hallucination and is correlated with PD duration and severity. Additionally, OCTA scans allow investigating the vascular changes in the different layers of the retina in PD patients, and provide structural evidence for retinal dopamine loss and foveal dysfunction in PD.

SUMMARY

The eye facilitates noninvasive access for the investigation and evaluation of specific diseases of the central nervous system. Numerous studies show that OCT measurements of NFL thickness as well as GCL-IPL thickness can serve as adjunctive biomarkers for neurodegenerative processes in the brain. Within the next few years OCT will be entrenched as a relevant parameter not only for clinical research but also for neurological routine diagnostics, and may help to observe both the progression of a disease and the success of a therapy. Of course, further longitudinal studies are needed to judge sensitivity and specificity of OCT measurements to disease progression. Moreover, various neurodegenerative diseases are associated with vasculature and perfusion abnormalities. Since measuring cerebral blood flow can be challenging, in this regard OCTA is a promising new method. It noninvasively provides a very precise three dimensional image of the entire microvascular system of the retina and choroid in just a few seconds and allows quantifying its perfusion. Thus, OCTA allows for a common assessment of both the morphology and the perfusion status and therefore will surely contribute to a better understanding of the pathology and the progression of various neurodegenerative diseases. There is a possibility and growing evidence of the role of OCTA measurements as an adjunctive biomarker for neurodegenerative disease progression such as MS, PD, and Alzheimer disorders. In order to validate the role and functionality of OCTA in diagnosing and monitoring these neurodegenerative diseases, more data has to be collected.

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