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Patterns of Retinal Ganglion Cell Damage in Neurodegenerative Disorders: Parvocellular vs Magnocellular Degeneration in Optical Coherence Tomography Studies

OCT Findings in Neurodegenerative Diseases with Preferential Magnocellular Damage

Alzheimer’s Disease

Alzheimer’s disease is the most frequent cause of dementia and is hallmarked by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. AD is characterized by visual disturbances occurring early in the course of the disease and reflecting neuronal damage of the cerebral visual pathway. The symptoms affect various aspects of visual function such as visual field, color vision, contrast sensitivity, motion perception, visuospatial construction, visual attention, and fixation.

Several histological studies in AD demonstrated the impairment of the entire visual pathway, documented initially in the brain and subsequently in the retina and ON. In 1986, Hinton and colleagues provided the first evidences of optic neuropathy in AD, describing loss of RGCs and axons at postmortem histology of the ON. Subsequently, other histological studies showed degeneration of the inner retina, more pronounced in the superior and inferior quadrant of the ON. In 2011, Koronyo-Hamaoui and colleagues documented for the first time extracerebral Aβ deposits in postmortem human retinas of AD patients and ex vivo in APPSWE/PS1ΔE9 transgenic mice after curcumin administration. In recent years, other histological studies of human retina confirmed the occurrence of extracellular plaques and intracellular Aβ deposits in the inner retinal layers involving mainly the superior hemiretina. La Morgia and colleagues demonstrated that mRGCs, a subgroup of RGCs intrinsically photosensitive, are selectively affected by the amyloid pathology in AD. Remarkably, the loss of these cells occurred even with a normal RGC count, pointing to a specific AD pathology affecting mRGCs.

With the advent, in the last 15 years, of OCT, a non-invasive optical imaging technique of the retina and ONH, many studies investigated the occurrence of ON pathology in AD and five comprehensive meta-analyses summarized the results provided by these OCT studies.

In 2017, the most recent meta-analysis by den Haan and colleagues described the results on the average peripapillary RNFL in 24 studies including 887 AD patients and 864 controls, and the 4 peripapillary RNFL quadrants in 20 studies. The RNFL thickness was thinner in AD compared with controls [standardized mean difference (SMD) −0.98], corresponding to an absolute reduction of about 10 µm. RNFL thinning was more pronounced in the superior and inferior peripapillary quadrants and was age-related. The same meta-analysis reported also data about mild cognitive impairment (MCI) patients (322 AD patients, 216 MCI patients, and 367 healthy controls), and RNFL thickness of MCI patients resulted intermediate between AD patients and healthy controls with a SMD of −0.71 compared with controls.

Furthermore, seven studies reported that total macular thickness is significantly reduced in AD retinas compared with controls with the largest effect on the outer macular ring [according to standard macular measures from the Early Treatment Diabetic Retinopathy Study (ETDRS)]. Moreover, the meta-regression by den Haan showed that OCT type, mini-mental state examination score, glaucoma exclusion score, and age were not associated with the SMD in the AD group compared with controls.

Overall, it must be emphasized that the results of OCT studies in AD are quite heterogeneous, due to the relatively small sample sizes and the different methods used for the data analysis. Moreover, not all the studies examined reported a thinning of the RNFL in AD patients. Notwithstanding the technical limitations and some contrasting results, a specific pattern of axonal loss clearly emerged in the ON of AD patients, closely resembling the pattern of RGC loss described in glaucoma, i.e., the RNFL atrophy in the superior and inferior quadrants.

The relative sparing of the RNFL in the temporal quadrant and the predominant involvement of the superior and inferior RNFL quadrants (e.g., SDM for AD vs controls in temporal sector was −0.42 vs −0.99 in superior sector) indicate a preferential contribution of parasol RGCs projecting to the magnocellular pathway (M-cells), which are mainly located in the extra-macular retina and are not specifically contributing to visual acuity. In this context, it should be mentioned that some authors suggested that RNFL thinning in the superior and inferior quadrants might be justified by the fact that more neurons physiologically are located in these quadrants where therefore neurodegeneration is more apparent (equal percentage corresponds to a greater absolute reduction in thickness). However, this pattern remains clearly distinguishable from that described in PD, where a predominant loss of the P-cells is reported. Furthermore, recent histological findings in postmortem AD retinal specimens reported that the axonal loss predominantly affected the larger fibers in the superior quadrants, and, to a lesser extent, the nasal and inferior quadrants, whereas the temporal quadrants, were largely spared. The reasons why the M-cells are more vulnerable to AD pathology is still unknown but might be related to the different vulnerability of RGCs to amyloid deposition, which has been already demonstrated in mRGCs, characterized by a big soma and branched dendrites, similarly to M-cells.

Multiple System Atrophy

Multiple system atrophy is a neurodegenerative disorder typically defined by parkinsonian and cerebellar features and autonomic failure. The occurrence of RGC loss has been recently reported by different OCT studies.

Mendoza-Santiesteban and colleagues compared 24 MSA patients to 20 PD and 35 controls demonstrating a significant RNFL and ganglion cell complex (GCL + IPL) thinning in the MSA patients compared with controls. Interestingly, in the MSA group the RNFL thinning was significant in the inferior quadrant relatively sparing the temporal region, thus clearly distinguishable from the PD cohort where a predominant temporal pattern was consistently found. The authors speculated that the different pattern of axonal loss could be due to different patterns of myelination by oligodendrocytes of M-cells axons, which might also explain the absence of visual complaints and normal visual acuity reported by MSA patients. Similar results in terms of pattern of RNFL loss have been reported also by other studies.

Glaucoma

Elevated intraocular pressure (IOP) is the main risk factor for glaucoma, but even glaucomatous patients with IOP within normal limit will progress in loosing RGCs. The hypothesis that larger RGCs are preferentially affected in human, and experimental glaucoma has received remarkable credit since Quigley and colleagues formulated it in 1987. This hypothesis was corroborated by postmortem examination of the human LGN of glaucoma patients where a selective neuronal loss in the layers receiving input from parasol cells was shown. Over the years, the selective damage of M-cells or S-cone pathway has been debated with contrasting opinions.

Nonetheless, recent studies in experimental glaucoma demonstrated that RGCs undergo morphologic changes before cell death, which are represented by reduction of soma volume, axon size, and dendritic tree area. These changes are consistent with cell shrinkage as an explanation for the apparent survival of midget cells reported in earlier studies. Weber and colleagues found a reduction in thickness and complexity of the dendritic tree in primate glaucomatous retinas, highlighting that M-cells and P-cells were involved to a similar extent. Moreover, psychophysical studies comparing responses of M and P pathways, found contrasting results, some supporting similar dysfunction for both pathways, whereas others suggested that visual functions such as contrast sensitivity and contrast gain signature, mediated by the M pathway, were reduced in glaucoma.

Even if the mechanisms underlying axonal damage in glaucoma are still not completely understood, the pattern of peripapillar and macular RNFL thinning is now well described by OCT studies.

Schuman and colleagues in 1995 showed for the first time a thinning of the RNFL in glaucomatous eyes as compared with normal eyes, more evident in the inferior quadrant. In 2005, using Stratus OCT (time-domain OCT) Leung and colleagues noticed the greatest reductions in peripapillary RNFL thickness in glaucoma at the superotemporal (11 o’clock) and inferotemporal (7 o’clock) sectors. These changes are congruent with the distribution of the most commonly reported visual field defect in glaucoma (125). Subsequently, numerous OCT studies have confirmed the typical pattern of relative sparing of peripapillary RNFL in the temporal quadrant and the resulting greater diagnostic performance to distinguish normal eyes from eyes with early glaucoma by looking at the inferior (inferotemporal) and superior (superotemporal) RNFL quadrants. In more recent years, with the advent of spectral-domain OCT and its greater spatial resolution, it has been possible to measure with higher reliability the thickness of the RNFL and the retinal ganglion cell plus inner plexiform (RGC+) just in the macula. Hood and coauthors demonstrated a greater thinning of the macular RGC+ thickness in the inferior macula (superior visual field) in glaucoma patients, corresponding to the typical arcuate RGC damage associated with local peripapillar RNFL thinning in a confined region of the disc, which the authors named “the macular vulnerability zone” (about 7:00 o’clock). Furthermore, the authors reported that the temporal region of the disc, where axons come from the upper and nasal macula, showed a milder damage until late stages of the disease.

Overall, the pattern described by OCT studies in glaucoma clearly points to a predominant damage of the inferior and superior ON quadrants where M-cells are preferentially located, with a relative sparing of the temporal sector (P-cells), similar to what has been described in AD and MSA.

Conclusions

Optical coherence tomography is an extraordinary tool to assess anatomy in vivo, to describe subtle differences in the patterns of neurodegeneration and to provide possible mechanistic insights for ON damage in different human diseases.

Mechanisms of neurodegeneration may act at different levels of the RGC/ON system, which is composed by RGC dendritic tree, the soma, the axon in its unmyelinated intraretinal component and the transition through the lamina cribrosa at the ONH, and the post-laminar myelinated component. Moreover, large and small RGCs and thicker and thinner axons display different conduction velocities, thus metabolic requirements and myelin sheath turnover. All these elements, and others that we know less, such as vascularization, support from glial cells and anatomical microenvironment come into play, possibly differentiating mechanistically the neurodegenerative pattern.

It must be also considered that a trans-synaptic degeneration may occur in some circumstances, such as in the specific case documented in AD where both the SCN and the mRGCs are affected by amyloid deposition supporting the hypothesis of a global involvement of the retinohypothalamic tract. Despite evidences are not conclusive it cannot be excluded that retinal degeneration in these disorders can be also contributed by trans-synaptic neurodegeneration.

Current evidence for PD suggest a number of possible co-occurring pathological events. Dopaminergic depletion may affect the connecting circuitry such as the amacrine cells, possibly leading to RGC de-afferentation and dendritic remodeling. However, mounting evidence highlight α-synuclein deposition in PD retinas, and mitochondrial dysfunction, not surprisingly, may ultimately lead to prevalent damage of the P-cells. This is consistent with current OCT results pointing to a predominant “mitochondrial-like” pattern of ON degeneration. The α-synuclein deposition in the retina, which might support a primary neurodegenerative process, parallels the recent findings of α-synuclein deposition demonstrated in the skin nerves of PD patients.

In AD, similar to PD, there is deposition of an abnormally folded protein, i.e., β-amyloid, which, however, presents with a peculiar retinal topography involving preferentially the peripheral retina in the superior quadrant, as recently shown. At this regard, Koronyo and coauthors have recently demonstrated that amyloid plaques can be visualized in vivo in AD human eyes using oral curcumin, opening the possibility to use the eye as a reliable and easily accessible biomarker for this disease.

Overall, in AD the OCT results, as well as the histological studies, point to a predominant affection of the M-cells, which somehow links AD to what is observed in glaucoma. This parallel may suggest that a relevant role is played by the ONH anatomy, where fibers turn 90° to engage into the transition through the lamina cribrosa, where a still poorly understood mechanism hits the larger axons driving M-RGC loss. The dichotomy between the two opposite patterns of prevalent P-cells vs M-cells vulnerability is further reflected in other two neurodegenerative disorders, HD as opposed to MSA. Remarkably, MSA that is a synucleinopathy with parkinsonism displays an OCT pattern more similar to AD, whereas HD is closer to PD. This latter link may be again supported by the common intrinsic mitochondrial dysfunction, whereas the link between MSA and AD in terms of retinal pathology remains puzzling and deserves further investigations.

Overall, OCT proves to be a powerful tool to assess anatomically neurodegeneration in vivo providing, once solidly validated by complementary postmortem histological studies, a great potential in all neurodegenerative disorders for monitoring natural history and ultimately possibly validate neuroprotective therapeutic strategies by proving their efficacy.