Various mechanisms have supported several common conditions linking AMD to PD. First, both diseases are associated with inflammation. For example, a high concentration of complement factors was found in AMD in some studies . Others also supported the role of inflammation and neurodegeneration in AMD and PD [17,18,19]. Second, autophagy dysfunction results in the accumulation of misfolded proteins. This is reflected by the aggregation of lipofuscin in RPE cells of AMD patients  and alpha-synuclein in neurons of PD patients . Third, both the inflammatory process and autophagy dysfunction will induce oxidative stress, which is another common condition found in AMD and PD as both retina cells and brain cells consume a high proportion of oxygen [22, 23]. When the function of relieving oxidative stress declines due to aging and mitochondrial dysfunction in the RPE of AMD patients and the brain of PD patients, levels of reactive oxygen species and oxidative damage increase.
Structurally, both AMD and PD patients have been reported to undergo thinning of the RNFL [24,25,26]. Furthermore, this thinning process was related to the duration of PD. The phenomenon was reported to be due to the loss of retinal dopaminergic amacrine cells and impairment of ganglion cell axons. Based on this finding, the PD rating scale was made to predict the severity of PD based on the thickness of RNFL and other retinal layers by optical coherence tomography . Among these studies, one study reported a different result , where there was no difference in retinal thickness between the PD patients and the control group, even though visual acuity and contrast sensitivity were impaired. This could be attributed to the older age of this study group compared to other studies. The average age difference could lead to more difficulties in detecting the different thicknesses of RNFL and the other parts of the retina, since age itself is also a negative factor. Other related studies indicated the potential association between AMD and PD, such as the use of L-DOPA in treating PD that was reported as having a role in preventing AMD . In addition, a lower cognitive function was found among AMD patients [30, 31].
Several studies examined the association between AMD and PD, and all concluded that AMD patients have a higher risk of PD. In 2014, Chung et al. found that neovascular AMD is highly associated with PD during a 3-year follow-up period . They identified 877 cases of neovascular AMD and over 8770 controls between January 1, 2001 and December 31, 2008 in a 3-year follow-up period adjusted for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, and coronary heart disease. All subjects were older than 40 years. The diagnosis of neovascular AMD included ICD-9-CM code 362.42 (serous detachment of RPE), 362.43 (serous detachment of RPE), 362.52 (exudative AMD), and 362.53 (Cystoid macular degeneration). In 2018, Etminan et al. suggested that neovascular AMD may predict the onset of PD . They used the Canadian British Columbia Retinal Disease Database from 2009 to 2013. Neovascular AMD patients undergoing intravitreal injections (bevacizumab or ranibizumab) were included, but only adjusted for age in the cohort study. In 2019, the most updated publication by Choi et al. elucidated that AMD was associated with higher PD risk . They determined 2213 AMD and 306,127 non-AMD follow-up from 2006 to 2013, with adjustment for age, sex, household income, smoking, alcohol, physical activity, BMI, SBP, fasting glucose, total cholesterol, and Charlson comorbidity index. The study defined AMD by ICD-10 coded as H35.3 without specifying neovascular or non-neovascular AMD. Participants were all over 50 years. These three studies above adjusted their lifestyle, socioeconomic status, and clinical conditions.
Our result among non-neovascular and neovascular AMD was different from that of Chung and Etminan [8, 9], but consistent to Choi’s study . The reason might because that our study involved AMD with adjustment for different comorbidities and medications which is similar to Choi et al. . Since the detachment of RPE or cystoid macular edema could be two of clinical features of neovascular AMD but not exclusive ones. Thus, unlike Chung et al. , we defined AMD, including unspecific, non-neovascular and neovascular types, as ICD-9-CM codes 362.50, 362.51, and 362.52 rather than as the codes of AMD’s clinical features. In addition, participants younger than 50 years were excluded from our study. In addition, a relatively large number of AMD cases with long follow-up period also offered a more comprehensive result. These may make our result different from that of Chung and Etminan [8, 9], but consistent to Choi study .
During the analysis of AMD subtypes (Unspecified, non-neovascular, and neovascular AMD), there was no significant difference in risk of PD. The non-significant difference of PD risk between non-neovascular and neovascular may need further researches stratifying by the disease’s stage since it does not define the stage of AMD by the ICD-9-CM codes as non-neovascular or neovascular AMD. The follow up time in our study started from that AMD was diagnosed rather than the true duration of the disease which might be even longer than the time we recorded. Perhaps the duration or the stage of the AMD might be associated with different degree of the risk of PD.
One of the strengths of our study was the adjustment of sufficient clinical comorbidities and medications related to aging, with a large amount of data that could offer a statistically meaningful outcome. Although we did not adjust the lifestyle, which was proven to be a confounder in the model, comorbidities such as hypertension and hyperlipidemia might also reflect the lifestyle. In addition, the number of AMD patients in our study was relatively large, and the follow-up year was relatively long (5.66 ± 3.81 years in the AMD cohort and 5.48 ± 3.84 years in the non-AMD cohort, from 1998 to 2013). However, there were still limitations to this study. First, the inclusion of cases was based on the data from NHIRD. It was not as accurate as the diagnosis based on diagnostic criteria by researchers themselves. Second, the NHIRD contained mostly Taiwanese patients. Therefore, the result is difficult to generalize globally. Third, it was difficult to separate patients with neovascular and non-neovascular AMD since doctors might only classify them with the general term (ICD-9-CM code 362.50) without specifying the type. This made it impossible to determine the significant association between either type of AMD to the risk of PD due to limited specific data (Table 4). The results were consistent with those of Choi et al., who also compared AMD without specifying the subtype . Fourth, there are other degenerative ocular diseases, such as glaucoma, which are also worth surveying. Further studies are suggested to solve these problems.
In conclusion, we have a result that AMD is associated with a higher risk of PD with adjustment for sufficient clinical comorbidities and long follow-up time. However, further studies for comparing the association between PD and neovascular or non-neovascular AMD during long-term follow-up is needed with more information such as the stage of the disease.