Increased Risk of Parkinson Disease Following a Diagnosis of Neovascular Age-Related Macular Degeneration: A Retrospective Cohort Study SHIU-DONG CHUNG, JAU-DER HO, CHAO-CHIEN HU, HERNG-CHING LIN, AND JAU-JIUAN SHEU PURPOSE:
To investigate the risk for Parkinson disease during a 3-year follow-up period after a diagnosis of neovascular age-related macular degeneration (AMD) using a nationwide population-based dataset in Taiwan. DESIGN: A retrospective matched-cohort study. METHODS: We identified 877subjects with neovascular AMD as the study cohort and randomly selected 8770 subjects for a comparison cohort. Each subject was individually followed for a 3-year period to identify those who subsequently developed Parkinson disease. Stratified Cox proportional hazard regressions were performed as a means of comparing the 3-year risk of subsequent Parkinson disease between the study and comparison cohorts. RESULTS: The incidence rate of Parkinson disease was 5.32 (95% confidence interval [CI]: 3.03-8.72) per 1000 person-years in patients with neovascular AMD and 2.09 (95% CI: 1.59-2.70) per 1000 person-years in comparison patients. The log-rank test indicated that subjects with neovascular AMD had a significantly lower 3-year Parkinson disease–free survival rate than comparison subjects (P < .001). After censoring cases in which patients died during the follow-up period and adjusting for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, and coronary heart disease, the hazard ratio of Parkinson disease during the 3-year follow-up period for subjects with neovascular AMD was 2.57 (95% CI: 1.42-4.64) that of comparison subjects. CONCLUSION: In this study, subjects with neovascular AMD were found to be at a significant risk of Parkinson disease during a 3-year follow-up period after their diagnosis among Taiwanese Chinese. Further study is needed to confirm our findings and explore the underlying
Accepted for publication Sep 25, 2013. From the Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei, Taiwan (S.D.C.); Sleep Research Center (S.D.C., H.C.L.) and Departments of Ophthalmology (J.D.H.) and Neurology (J.J.S.), Taipei Medical University Hospital, Taipei, Taiwan; Department of Ophthalmology, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan (C.C.H.); School of Medicine, Fu-Jen Catholic University, Hsingchuang, Taiwan (C.C.H.); and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (J.J.S.). Inquiries to Dr Jau-Jiuan Sheu, Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan, 252 Wu-Hsing St, Taipei 110, Taiwan; e-mail: [email protected]
464
Ó
2014 BY
pathomechanism. (Am J Ophthalmol 2014;157: 464–469. Ó 2014 by Elsevier Inc. All rights reserved.)
P
ARKINSON DISEASE IS A NEUROLOGIC SYNDROME
characterized by movement difficulties including a slowing of movements, rigidity, tremors, and postural instability. Risk factors include drug, substance, or toxin exposure;1–3 infections;4 and vascular insults.5 Vascular Parkinson disease, an important cause of Parkinson disease, commonly occurs in older people with vascular risk factors such as hypertension, diabetes, and hyperlipidemia.5,6 Idiopathic Parkinson disease, the second most common neurodegenerative disorder, is a parkinsonian syndrome without an obvious known cause. As no specific underlying cause has been identified, Parkinson disease is regarded as an age-related neurodegenerative disorder that develops from interactions among aging, a genetic predisposition, and environmental exposure, which trigger neurodegeneration.7 Age-related macular degeneration (AMD) is a leading cause of visual loss in aged people in the Western world and also a common eye disorder in elderly ethnic Chinese people in Taiwan.8,9 Although Chinese people were reported to have lower prevalence rates for early and late AMD compared to Western populations,10,11 Chinese individuals in Taiwan were found to have a similar prevalence of AMD compared to other ethnic groups.9,12 Epidemiologic studies have reported the modifiable risk factors of late AMD, including cardiovascular disease and cardiovascular risk factors.13–15 AMD is characterized by the presence of drusen and retinal pigmentary abnormalities in the macula in the early stage and geographic atrophy or choroidal neovascularization in the late stage.16 Like Parkinson disease, the pathogenesis of AMD is still not fully understood and is attributed to a complicated interplay of aging, genetic, and environmental factors.16 The core element of the pathophysiology of AMD is senescence of retinal pigment epithelial (RPE) cells, which lose the capacity to maintain the integrity of the function of neural cells, rods, and cones. AMD is therefore regarded as a neurodegenerative retinal disease.17,18 A number of molecular studies suggested that oxidative stress, chronic inflammation, impairment of the processing and degradation of dysfunctional cellular components, and alterations of neuronal homeostasis are common biological
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.09.026
pathways of age-associated neurodegenerative diseases.19–21 Therefore, the pathomechanisms contributing to late AMD may also be associated with the development of Parkinson disease because both may share similar pathways of pathogenesis and common risk factors. The aim of this study was to investigate the risk for Parkinson disease during a 3-year follow-up period after a diagnosis of neovascular AMD, compared to patients without neovascular AMD during the same period, in an ethnic Chinese population using a large, nationwide population-based dataset in Taiwan.
METHODS DATABASE:
After consulting with the director of the Institutional Review Board (IRB) of Taipei Medical University, this retrospective cohort study was exempt from full review by the IRB of Taipei Medical University because the LHID2000 consists of de-identified secondary data released to the public for research purposes. We retrieved data of sampled subjects for this study from the Taiwan Longitudinal Health Insurance Database (LHID2000). The LHID2000, which was created by the Taiwan National Health Research Institute (NHRI), includes all medical claims and registration files for 1 000 000 enrollees under the Taiwan National Health Insurance (NHI) program. These 1 000 000 enrollees of the LHID2000 were randomly selected from all enrollees listed in the 2000 Registry of Beneficiaries (n ¼ 23.72 million) under the NHI program. The Taiwan NHRI validated the representativeness of the LHID2000 relative to the entire population of NHI enrollees in terms of sex distribution. Some prior studies also demonstrated the high validity of the LHID2000.22,23
STUDY
SAMPLE: This retrospective cohort study included a study cohort and a comparison cohort. We first identified 1083 subjects who had received a first-time diagnosis of neovascular AMD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9CM] codes 362.42, 362.43, 362.52, or 362.53) between January 1, 2001 and December 31, 2008. We selected the date of receiving their first-time neovascular AMD diagnosis as the index date. Since incidences of neovascular _40 AMD and Parkinson disease are very low in subjects < years old, we excluded this age group of subjects (n ¼ 44). In addition, we further excluded all subjects who had ever received a diagnosis of Parkinson disease (ICD-9CM code 332), dementia (ICD-9-CM code 290, 294.1, or 331), or stroke (ICD-9-CM code 430-438) prior to the index date (n ¼ 162). As a result, 877 subjects with neovascular AMD were included in the study cohort. For the comparison cohort, we likewise retrieved subjects from the remaining enrollees of the LHID2000. We
VOL. 157, NO. 2
_40 years who had never received first identified all subjects > a diagnosis of neovascular AMD since initiation of the NHI program in 1995. We then randomly selected 8770 comparison subjects (10 comparison subjects per study patient) matched to the study subjects in terms of sex, age group (40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, and >79 years), urbanization level, and index year using the SAS program proc surveyselect (SAS System for Windows, ver. 8.2; SAS Institute, Cary, North Carolina, USA). In this study, we chose 10 comparison subjects per study subject on account of the very low prevalence of Parkinson disease. Furthermore, we matched the distribution of urbanization level between comparison subjects and study subjects in order to help assure that they were reasonably similar in terms of unmeasured neighborhood socioeconomic characteristics. For study subjects, the year of the index date was the year in which they had received their first diagnosis of neovascular AMD, while for comparison subjects, the year of the index date was simply a matched year in which comparison subjects had visited a physician. We assigned the date of their first visit to a physician that occurred during that matched year as the index date for comparison subjects. We also ensured that no selected comparison subjects had ever received a diagnosis of Parkinson disease, dementia, or stroke prior to the index date. Ultimately, there were 9647 subjects in this study. We then individually tracked each subject for 3 years following the subject’s index date to identify those subjects who subsequently received a diagnosis of Parkinson disease during that 3-year follow-up period (all Parkinson disease cases received a first-time Parkinson disease diagnosis between 2001 and 2011). This study only included Parkinson disease cases if their diagnosis consistently appeared in at least 2 medical claims on different dates in order to increase the diagnostic validity. We did not include Parkinson disease cases in which patients had received a diagnosis of dementia or stroke, or took antipsychotics during the study period, which may lead to Parkinson disease. Furthermore, subjects with Parkinson plus syndrome (ICD-9-CM code 333.0) were not included in our study. We also censored subjects who died during the 3-year follow-up period; 535 subjects had died, including 53 from the study cohort (6.0% of the study cohort) and 482 from the comparison cohort (5.5% of the comparison cohort) (P ¼ .357). STATISTICAL ANALYSIS:
We used the SAS statistical package (SAS System for Windows, ver. 8.2, Cary, North Carolina, USA) to conduct all statistical analyses performed in this study. We used the Kaplan-Meier method and log-rank test to examine differences in 3-year Parkinson disease–free survival rates between the study and comparison cohorts (time zero ¼ index date). We also used Cox proportional hazards regression (stratified by sex, age group, urbanization level, and the index year) to calculate the
AGE-RELATED MACULAR DEGENERATION AND PARKINSON DISEASE
465
3-year risk of subsequent Parkinson disease following a diagnosis of neovascular AMD. Before conducting the Cox proportional hazards regression analysis, we tested the proportional hazards assumption and found that this assumption was satisfied since the survival curves for both strata (subjects in the study cohort and comparison cohort) had hazard functions that were proportional over time by observing the plots. In this study, we also adjusted for the selected comorbidities including hypertension, diabetes, hyperlipidemia, and coronary heart disease in the regression model. Hazard ratios (HRs) along with 95% confidence intervals (CIs) were used to present the risk of Parkinson disease, with a 2-sided P value of _NT$25 001 Geographic region Northern Central Southern Eastern
294 290 503 259
33.5 33.1 57.4 29.5
2033 1785 4516 2219
506 247 124
57.7 28.2 14.1
4612 3096 1062
442 169 236 30
50.4 19.3 26.9 3.4
4110 2017 2406 237
%
P Value
23.2
To investigate the risk for Parkinson disease during a 3-year follow-up period after a diagnosis of neovascular age-related macular degeneration (AMD) using a nationwide population-based dataset in Taiwan. DESIGN: A retrospective matched-cohort study. METHODS: We identified 877subjects with neovascular AMD as the study cohort and randomly selected 8770 subjects for a comparison cohort. Each subject was individually followed for a 3-year period to identify those who subsequently developed Parkinson disease. Stratified Cox proportional hazard regressions were performed as a means of comparing the 3-year risk of subsequent Parkinson disease between the study and comparison cohorts. RESULTS: The incidence rate of Parkinson disease was 5.32 (95% confidence interval [CI]: 3.03-8.72) per 1000 person-years in patients with neovascular AMD and 2.09 (95% CI: 1.59-2.70) per 1000 person-years in comparison patients. The log-rank test indicated that subjects with neovascular AMD had a significantly lower 3-year Parkinson disease–free survival rate than comparison subjects (P < .001). After censoring cases in which patients died during the follow-up period and adjusting for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, and coronary heart disease, the hazard ratio of Parkinson disease during the 3-year follow-up period for subjects with neovascular AMD was 2.57 (95% CI: 1.42-4.64) that of comparison subjects. CONCLUSION: In this study, subjects with neovascular AMD were found to be at a significant risk of Parkinson disease during a 3-year follow-up period after their diagnosis among Taiwanese Chinese. Further study is needed to confirm our findings and explore the underlying
Accepted for publication Sep 25, 2013. From the Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei, Taiwan (S.D.C.); Sleep Research Center (S.D.C., H.C.L.) and Departments of Ophthalmology (J.D.H.) and Neurology (J.J.S.), Taipei Medical University Hospital, Taipei, Taiwan; Department of Ophthalmology, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan (C.C.H.); School of Medicine, Fu-Jen Catholic University, Hsingchuang, Taiwan (C.C.H.); and Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (J.J.S.). Inquiries to Dr Jau-Jiuan Sheu, Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan, 252 Wu-Hsing St, Taipei 110, Taiwan; e-mail: [email protected]
464
Ó
2014 BY
pathomechanism. (Am J Ophthalmol 2014;157: 464–469. Ó 2014 by Elsevier Inc. All rights reserved.)
P
ARKINSON DISEASE IS A NEUROLOGIC SYNDROME
characterized by movement difficulties including a slowing of movements, rigidity, tremors, and postural instability. Risk factors include drug, substance, or toxin exposure;1–3 infections;4 and vascular insults.5 Vascular Parkinson disease, an important cause of Parkinson disease, commonly occurs in older people with vascular risk factors such as hypertension, diabetes, and hyperlipidemia.5,6 Idiopathic Parkinson disease, the second most common neurodegenerative disorder, is a parkinsonian syndrome without an obvious known cause. As no specific underlying cause has been identified, Parkinson disease is regarded as an age-related neurodegenerative disorder that develops from interactions among aging, a genetic predisposition, and environmental exposure, which trigger neurodegeneration.7 Age-related macular degeneration (AMD) is a leading cause of visual loss in aged people in the Western world and also a common eye disorder in elderly ethnic Chinese people in Taiwan.8,9 Although Chinese people were reported to have lower prevalence rates for early and late AMD compared to Western populations,10,11 Chinese individuals in Taiwan were found to have a similar prevalence of AMD compared to other ethnic groups.9,12 Epidemiologic studies have reported the modifiable risk factors of late AMD, including cardiovascular disease and cardiovascular risk factors.13–15 AMD is characterized by the presence of drusen and retinal pigmentary abnormalities in the macula in the early stage and geographic atrophy or choroidal neovascularization in the late stage.16 Like Parkinson disease, the pathogenesis of AMD is still not fully understood and is attributed to a complicated interplay of aging, genetic, and environmental factors.16 The core element of the pathophysiology of AMD is senescence of retinal pigment epithelial (RPE) cells, which lose the capacity to maintain the integrity of the function of neural cells, rods, and cones. AMD is therefore regarded as a neurodegenerative retinal disease.17,18 A number of molecular studies suggested that oxidative stress, chronic inflammation, impairment of the processing and degradation of dysfunctional cellular components, and alterations of neuronal homeostasis are common biological
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.09.026
pathways of age-associated neurodegenerative diseases.19–21 Therefore, the pathomechanisms contributing to late AMD may also be associated with the development of Parkinson disease because both may share similar pathways of pathogenesis and common risk factors. The aim of this study was to investigate the risk for Parkinson disease during a 3-year follow-up period after a diagnosis of neovascular AMD, compared to patients without neovascular AMD during the same period, in an ethnic Chinese population using a large, nationwide population-based dataset in Taiwan.
METHODS DATABASE:
After consulting with the director of the Institutional Review Board (IRB) of Taipei Medical University, this retrospective cohort study was exempt from full review by the IRB of Taipei Medical University because the LHID2000 consists of de-identified secondary data released to the public for research purposes. We retrieved data of sampled subjects for this study from the Taiwan Longitudinal Health Insurance Database (LHID2000). The LHID2000, which was created by the Taiwan National Health Research Institute (NHRI), includes all medical claims and registration files for 1 000 000 enrollees under the Taiwan National Health Insurance (NHI) program. These 1 000 000 enrollees of the LHID2000 were randomly selected from all enrollees listed in the 2000 Registry of Beneficiaries (n ¼ 23.72 million) under the NHI program. The Taiwan NHRI validated the representativeness of the LHID2000 relative to the entire population of NHI enrollees in terms of sex distribution. Some prior studies also demonstrated the high validity of the LHID2000.22,23
STUDY
SAMPLE: This retrospective cohort study included a study cohort and a comparison cohort. We first identified 1083 subjects who had received a first-time diagnosis of neovascular AMD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9CM] codes 362.42, 362.43, 362.52, or 362.53) between January 1, 2001 and December 31, 2008. We selected the date of receiving their first-time neovascular AMD diagnosis as the index date. Since incidences of neovascular _40 AMD and Parkinson disease are very low in subjects < years old, we excluded this age group of subjects (n ¼ 44). In addition, we further excluded all subjects who had ever received a diagnosis of Parkinson disease (ICD-9CM code 332), dementia (ICD-9-CM code 290, 294.1, or 331), or stroke (ICD-9-CM code 430-438) prior to the index date (n ¼ 162). As a result, 877 subjects with neovascular AMD were included in the study cohort. For the comparison cohort, we likewise retrieved subjects from the remaining enrollees of the LHID2000. We
VOL. 157, NO. 2
_40 years who had never received first identified all subjects > a diagnosis of neovascular AMD since initiation of the NHI program in 1995. We then randomly selected 8770 comparison subjects (10 comparison subjects per study patient) matched to the study subjects in terms of sex, age group (40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, and >79 years), urbanization level, and index year using the SAS program proc surveyselect (SAS System for Windows, ver. 8.2; SAS Institute, Cary, North Carolina, USA). In this study, we chose 10 comparison subjects per study subject on account of the very low prevalence of Parkinson disease. Furthermore, we matched the distribution of urbanization level between comparison subjects and study subjects in order to help assure that they were reasonably similar in terms of unmeasured neighborhood socioeconomic characteristics. For study subjects, the year of the index date was the year in which they had received their first diagnosis of neovascular AMD, while for comparison subjects, the year of the index date was simply a matched year in which comparison subjects had visited a physician. We assigned the date of their first visit to a physician that occurred during that matched year as the index date for comparison subjects. We also ensured that no selected comparison subjects had ever received a diagnosis of Parkinson disease, dementia, or stroke prior to the index date. Ultimately, there were 9647 subjects in this study. We then individually tracked each subject for 3 years following the subject’s index date to identify those subjects who subsequently received a diagnosis of Parkinson disease during that 3-year follow-up period (all Parkinson disease cases received a first-time Parkinson disease diagnosis between 2001 and 2011). This study only included Parkinson disease cases if their diagnosis consistently appeared in at least 2 medical claims on different dates in order to increase the diagnostic validity. We did not include Parkinson disease cases in which patients had received a diagnosis of dementia or stroke, or took antipsychotics during the study period, which may lead to Parkinson disease. Furthermore, subjects with Parkinson plus syndrome (ICD-9-CM code 333.0) were not included in our study. We also censored subjects who died during the 3-year follow-up period; 535 subjects had died, including 53 from the study cohort (6.0% of the study cohort) and 482 from the comparison cohort (5.5% of the comparison cohort) (P ¼ .357). STATISTICAL ANALYSIS:
We used the SAS statistical package (SAS System for Windows, ver. 8.2, Cary, North Carolina, USA) to conduct all statistical analyses performed in this study. We used the Kaplan-Meier method and log-rank test to examine differences in 3-year Parkinson disease–free survival rates between the study and comparison cohorts (time zero ¼ index date). We also used Cox proportional hazards regression (stratified by sex, age group, urbanization level, and the index year) to calculate the
AGE-RELATED MACULAR DEGENERATION AND PARKINSON DISEASE
465
3-year risk of subsequent Parkinson disease following a diagnosis of neovascular AMD. Before conducting the Cox proportional hazards regression analysis, we tested the proportional hazards assumption and found that this assumption was satisfied since the survival curves for both strata (subjects in the study cohort and comparison cohort) had hazard functions that were proportional over time by observing the plots. In this study, we also adjusted for the selected comorbidities including hypertension, diabetes, hyperlipidemia, and coronary heart disease in the regression model. Hazard ratios (HRs) along with 95% confidence intervals (CIs) were used to present the risk of Parkinson disease, with a 2-sided P value of _NT$25 001 Geographic region Northern Central Southern Eastern
294 290 503 259
33.5 33.1 57.4 29.5
2033 1785 4516 2219
506 247 124
57.7 28.2 14.1
4612 3096 1062
442 169 236 30
50.4 19.3 26.9 3.4
4110 2017 2406 237
%
P Value
23.2
