Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis

Introduction

Parkinson’s Disease (PD) is the most common neurodegenerative disorder and is characterised by resting tremor, rigidity and bradykinesia. It is a leading cause of disability worldwide^1–3. The prevalence of PD is rising with the increasing average age of the population, with a prevalence of 1903 per 100,000 in over 80 year olds compared to 41 per 100,000 in 40 to 49 year olds⁴. Studies suggest geographic variation, North America having the highest non-age adjusted prevalence (1,601 per 100,000) and Asia having the lowest prevalence (646 per 100,000), possibly due to genetic susceptibility^4,5, as well as the differing age profiles of the populations. The prevalence of PD is almost double in males compared to females, possibly due to a protective effect of female gonadal factors and the lack of a protective effect of male gonadal factors^6,7. Despite this, existing studies report increased mortality in females^6,7. Worldwide non-age adjusted mortality rate from PD has increased between 1994 and 2019 (1.76 per 100,000 in 1994 and 5.67 per 100,000 in 2019), which could be due to a variety of factors such as an ageing population and improved reporting³. In addition to PD being associated with a significant individual burden, PD is also associated with large economic burden³. In the United States (US) in 2017, there were 1 million people living with PD, incurring a total economic cost of $51.9 billion of direct and indirect healthcare costs, which is projected to increase substantially⁸.

There is a paucity of published data about the annual demographic trends in PD-related mortality in the US³. Therefore, the aim of this study was to examine the demographic trends in PD-related mortality using national data. Knowledge of these trends is important to monitor the growing population living with PD and improve end of life care services.

Methods

Results

Annual Trends for PD-Related Mortality

Between 1999 to 2020, there were a total 515,884 PD-related deaths. Overall CMR was 7.6 per 100,000 persons (95% CI 7.6-7.7) and AAMR was 7.1 per 100,000 persons (95% CI 7.1-7.2). CMR was 5.2 per 100,000 in 1999 (95% CI 5.1-5.3) and 12.1 per 100,000 in 2020 (95% CI 12.0-12.3). AAMR was 5.3 per 100,000 in 1999 (95% CI 5.2-5.4) and 9.8 per 100,000 in 2020 (95% CI 9.7-9.9). Using Joinpoint regression analysis, the APC in AAMR was 5.71 (95% CI 2.00-8.67) from 1999–2001, 1.44 (95% CI -0.07-1.85) from 2001–2013 and 4.25 (95% CI 3.34-5.62) from 2013–2020 (shown in Table 1 and Figure 1).

Table 1. Demographic trends in mortality by year.

	Variables	Year
		1999	2000	2001	2002	2003	2004	2005	2006	2007	2008	2009	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020	1999– 2020
Overall data	Number of deaths	14511	15591	16466	16857	17890	17898	19427	19431	19913	20320	20391	21835	22978	23664	25016	25972	27793	29494	31754	33596	35073	40014	515884
	Population (million)	2.8	2.8	2.9	2.9	2.9	2.9	3.0	3.0	3.0	3.1	3.1	3.1	3.1	3.1	3.2	3.2	3.2	3.2	3.3	3.3	3.3	3.3	6,746.4
	CMR ([95%CI]	5.2 [5.1- 5.3]	5.5 [5.5- 5.6]	5.8 [5.7- 5.9]	5.9 [5.8- 5.9]	6.2 [6.1- 6.3]	6.1 [6.0- 6.2]	6.6 [6.5- 6.7]	6.5 [6.4- 6.6]	6.6 [6.5- 6.7]	6.7 [6.6- 6.8]	6.6 [6.6- 6.7]	7.1 [7.0- 7.2]	7.4 [7.3- 7.5]	7.5 [7.4- 7.6]	7.9 [7.8- 8.0]	8.1 [8.0- 8.2]	8.6 [8.5- 8.7]	9.1 [9.0- 9.2]	9.7 [9.6- 9.9]	10.3 [10.2- 10.4]	10.7 [10.6- 10.8]	12.1 [12.0- 12.3]	7.6 [7.6- 7.7]
	AAMR [95%CI}	5.3 [5.2- 5.4]	5.7 [5.6- 5.7]	5.9 [5.8- 6.0]	6.0 [5.9- 6.0]	6.2 [6.1- 6.3]	6.1 [6.1- 6.2]	6.6 [6.5- 6.6]	6.4 [6.4- 6.5]	6.5 [6.4- 6.6]	6.5 [6.4- 6.6]	6.4 [6.3- 6.5]	6.8 [6.7- 6.9]	7.0 [6.9- 7.0]	7.0 [6.9- 7.1]	7.2 [7.1- 7.3]	7.3 [7.3- 7.4]	7.7 [7.6- 7.8]	8.0 [7.9- 8.1]	8.4 [8.3- 8.5]	8.6 [8.5- 8.7]	8.8 [8.7- 8.9]	9.8 [9.7- 9.9]	7.1 [7.1- 7.2]
Age	45-54 CMR	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.2	0.1	0.2	0.1	0.2	0.2	0.2	-
	55-64 CMR	1.0	1.1	1.2	1.2	1.2	1.2	1.4	1.2	1.1	1.1	1.3	1.3	1.3	1.4	1.4	1.4	1.5	1.6	1.7	1.7	1.8	2.0	-
	65-74 CMR	10.9	11.4	11.6	12.1	12.5	11.8	12.7	12	11.6	12.1	11.1	11.7	12.6	12.2	12.7	12.9	13.7	14.1	15.6	16	16.6	18.8	-
	75-84 CMR	57.9	61.6	64.3	63.4	67.3	67.1	70.7	69.2	71.1	70.7	70.3	74.3	75.7	75.8	78	78.8	81.9	85	89.1	90.5	92.8	104.7	-
	Over 85 CMR	123.7	131.2	136.4	141.4	144.9	144.3	155.4	156.9	156.2	156.6	156.2	164.7	167.6	171.4	177.2	181.1	189.7	197.7	205.1	213.5	214.5	236.2	-
Sex	Number of deaths	8,221	8,751	9,361	9,540	10,120	10,311	11,172	11,214	11,472	11,864	11,986	12,754	13,459	14,033	14,978	15,571	16,761	17,741	19,252	20,371	21,443	24,315	-
	Male AAMR	8.4	8.8	9.2	9.2	9.5	9.5	10.1	9.9	9.9	10	9.9	10.3	10.5	10.6	11	11.1	11.6	11.9	12.5	12.8	13.0	14.4	-
	Number of deaths	6,290	6,840	7,105	7,317	7,770	7,587	8,255	8,217	8,441	8,456	8,405	9,081	9,519	9,631	10,038	10,401	11,032	11,753	12,502	13,225	13,630	15,699	-
	Female AAMR	3.6	3.9	4.0	4.1	4.3	4.2	4.5	4.4	4.4	4.4	4.3	4.6	4.7	4.6	4.8	4.8	5.0	5.3	5.5	5.7	5.8	6.5	-
Race	Number of deaths	13,810	14,853	15,686	16,036	16,944	16,959	18,387	18,395	18,731	19,184	19,253	20,607	21,562	22,213	23,392	24,132	25,761	27,292	29,230	30,845	32,205	36,631	-
	White AAMR	5.6	6.0	6.2	6.3	6.6	6.5	7.0	6.9	6.9	6.9	6.9	7.3	7.4	7.5	7.7	7.8	8.2	8.6	9.0	9.2	9.4	10.5	-
	Number of deaths	502	532	546	555	624	622	705	673	791	731	717	795	881	918	1,031	1,149	1,183	1,367	1,527	1,688	1,667	2,075	-
	Black or African American AAMR	2.4	2.5	2.5	2.5	2.8	2.8	3.0	2.8	3.3	2.9	2.8	3.0	3.2	3.3	3.5	3.8	3.8	4.2	4.5	4.8	4.6	5.5	-
	Number of deaths	173	161	198	213	263	273	270	307	336	337	365	371	458	470	524	607	751	749	875	938	1,074	1,173	-
	Asian or Pacific Islander AAMR	3.4	2.9	3.2	3.3	3.8	3.7	3.4	3.7	3.8	3.5	3.7	3.5	4.0	3.9	4.0	4.3	4.9	4.7	5.0	5.1	5.6	5.8	-
	Number of deaths	26	45	36	53	59	44	65	56	55	68	56	62	77	63	69	84	98	86	122	125	127	135	-
	American Indian or Alaska Natives AAMR	2.8	4.1	3.0	4.4	4.9	3.6	4.8	4.2	3.9	4.7	3.3	3.8	4.2	3.4	3.4	4.0	4.3	3.4	4.9	4.7	4.5	4.3	-

Abbreviations: AAMR – Age adjusted mortality rate; CI – Confidence interval; CMR – Crude mortality rate; PD – Parkinson’s Disease; SE – Standard error.

Figure 1. Joinpoint regression analysis by year.

Annual trends for PD-related mortality stratified by age

Older age categories had a consistently higher CMR throughout the 20 year period (Table 2 and Figure 2). CMR for patients aged over 85 was 7.6 (95% CI 172.8-174.3), compared to a CMR of 1.4 (95% CI 1.4-1.4) for patients aged 55–64 (shown in Figure 3).

Table 2. Mortality rate stratified by Census region, Census division and HHS region.

	Variables	AAMR [95%CI]
Census region	Census Region 1: Northeast	6.2 [6.1-6.2]
	Census Region 2: Midwest	7.7 [7.6-7.7]
	Census Region 3: South	7.2 [7.1-7.2]
	Census Region 4: West	7.4 [7.4-7.5]
Census division	Division 1: New England	6.8 [6.7-6.9]
	Division 2: Middle Atlantic	6.0 [5.9-6.0]
	Division 3: East North Central	7.5 [7.5-7.6]
	Division 4: West North Central	8.0 [7.9-8.1]
	Division 5: South Atlantic	7.0 [6.9-7.0]
	Division 6: East South Central	7.2 [7.1-7.3]
	Division 7: West South Central	7.5 [7.5-7.6]
	Division 8: Mountain	8.1 [8.0-8.2]
	Division 9: Pacific	7.1 [7.1-7.2]
HHS region	HHS Region #1	6.8 [6.7-6.9]
	HHS Region #2	5.3 [5.2-5.3]
	HHS Region #3	7.2 [7.1-7.2]
	HHS Region #4	7.0 [6.9-7.0]
	HHS Region #5	7.7 [7.6-7.7]
	HHS Region #6	7.6 [7.5-7.7]
	HHS Region #7	7.8 [7.7-7.9]
	HHS Region #8	8.1 [8.0-8.2]
	HHS Region #9	6.9 [6.9-7.0]
	HHS Region #10	8.4 [8.3-8.5]

Abbreviations: AAMR – Age adjusted mortality rate; CI – Confidence interval; HHS – Health and Human Services.

Figure 2. Crude mortality rate from 1999–2020 stratified by age.

Figure 3.

Joinpoint regression analysis by year stratified by 10 year age categories: A. 55–64, B. 65–74, C. 75–84, D. Over 85.

Annual trends for PD-related mortality stratified by sex

Male sex had a consistently higher AAMR (10.9 per 100,000 95% CI 10.8-0.9) than female sex (4.8 per 100,000 95% CI 4.7-4.8) across the study period (shown in Table 1). Using Joinpoint regression analysis, the APC in AAMR for males was 2.63 (95% CI 0.92-4.33) from 1999–2005, which then decreased to -0.17 (95% CI -1.61-3.91) from 2005–2009, increased to 2.71 (95% CI -0.36-3.48) from 2009–2018 and increased further to 6.14 (95% CI 2.93-7.90) from 2018–2020. The APC in AAMR for females was 4.61 (95% CI 2.01-9.44) from 1999–2002, 1.11 (95% CI -1.27-1.54) from 2002–2014, then 4.74 (95% CI 3.41-7.56) from 2014–2020 (shown in Figure 4 and Figure 5).

Figure 4. Crude mortality rate from 1999–2020 stratified by sex.

Figure 5.

Joinpoint regression analysis by year stratified by sex: A. Male, B. Female.

Annual trends for PD-related mortality stratified by race/ethnicity

White patients had consistently higher AAMR (7.6 per 100,000 95% CI 7.6-7.6) than American Indians/Alaska Natives (4.4 per 100,000 95% CI 4.3-4.4), Asians/Pacific Islanders (4.1 per 100,000 95% CI 3.9-4.3) and Black/African Americans (3.4 per 100,000 95% CI 3.5-3.6) (shown in Table 1). Using Joinpoint regression analysis, the APC in AAMR for white patients was 5.58 (95% CI 2.16-8.28) from 1999–2001, 1.66 (95% CI 0.33-1.98) from 2001–2014 and 4.63 (95% CI 3.64-6.23) from 2014 to 2020. The APC in AAMR for American Indians/Alaska Natives was 0.75 (95% CI -0.58-2.11) from 1999–2020. The APC in AAMR for Asians/Pacific Islanders was 1.50 (95% CI -1.05-2.37) from 1999–2012 and 5.10 (95% CI 3.29-11.18) from 2012–2020. The APC in AAMR for Black/African Americans was 3.22 (95% CI 1.84-7.93) from 1999–2007, reducing to -1.56 (95% CI -3.84-8.46) from 2007–2010, then increasing to 6.07 (95% CI 2.72-8.47) from 2010–2020 (shown in Figure 6 and Figure 7).

Figure 6. Crude mortality rate from 1999–2020 stratified by race.

Figure 7.

Joinpoint regression analysis by year stratified by sex: A. White, B. Black/African American, C. American Indians/Alaska Natives, D. Asians/Pacific Islanders.

Discussion

To the best of our knowledge, this is the first study to investigate the trends in PD-related mortality in the US. There are several important findings. Firstly, PD-related mortality in the US has steadily increased over a 20 year period, with an AAMR of 5.3 per 100,000 in 1999 compared to 9.8 per 100,000 in 2020. Secondly, there are significant geographical differences in PD-related mortality, with Midwest regions associated with the highest mortality rate and top 3 states with highest AAMR being Utah, Idaho and Minnesota. Finally, there are significant differences in demographic trends in mortality, where older age, male sex and white race associated with higher AAMRs over the 20 year study period.

The average age of the population is increasing, and along with improved management of acute and chronic conditions, patients are living longer placing them at risk of chronic diseases¹⁹. Age is strongly associated with the development of PD, with a later age of diagnosis of PD linked to more severe motor deficit, postural instability and rapid disease progression²⁰. Ageing alters body homeostasis through its effect on cellular processes causing mitochondrial dysfunction, free radical production and oxidative stress, predisposing to neurodegeneration of the substantia nigra²¹. Furthermore, the iron content of the substantia nigra increases with age and is linked to their decrease in function²². The present analysis demonstrated that increasing age was associated with an increased AAMR. Previous studies have elicited this finding, with some displaying better overall prognosis and response to pharmacological treatment such as Levodopa therapy in younger patients^23,24.

This study reports sex differences in PD-related mortality. There are no studies that have analysed temporal trends in sex-related disparities in PD patients. Previous studies have reported an increased prevalence of PD in males, and increased likelihood of PD mortality in females^6,7. Increased prevalence in males may be due to findings of lack of protective effects of male gonadal factors, in contrast to female gonadal factors which are suspected to be protective for PD^6,7. Females have a higher likelihood of overall and earlier disease course-related mortality from PD compared to males²⁵. This could be due to a later age of diagnosis given the aforementioned protective factors, which is associated with more severe symptoms, lower responsiveness to guideline indicated treatment.

The present study reports important racial differences in PD-related mortality, with white race associated with the highest AAMR. This could be because PD is most prevalent in white populations, possibly due to genetic susceptibility⁵. Several studies state black patients have a higher risk of mortality than white patients^26–28. Common reasons for poor outcomes in black patients could be multifactorial. There are several social determinants of health that could mediate outcomes in black populations which have been demonstrated across many different studies involving the US, including geographic location, socioeconomic status and access to healthcare^29–31. State-level disparities in the context of US healthcare in particular could be due to varying levels of accessibility to services and affordability³². Furthermore, certain regions of the US such as the Midwest have a higher proportion of individuals who are holder and white race³³. This could explain increased AAMR in the Midwest region and associated states.

Admissions to hospital in patients with PD in the US have been steadily increasing. An analysis using the National Inpatient Sample demonstrated that from 2002–2016, admissions in patients with PD rose from 212,070 to 312,980³⁴. Mortality as an inpatient during this time decreased from 4.8% in 2002–2004 to 3.6% in 2014–2016³⁴. In the present study, PD-related AAMR increased over the study period, suggesting patients with PD are likely die outside of hospital, as this analysis also demonstrates. Previous studies have demonstrated a similar trend. An analysis of the World Health Organisation Mortality Database from 1994–2019 showed that mortality rate in 1994 was 1.76 per 100,000, rising to 5.67 per 100,000 in 2019. Mortality rate was higher in males and in European countries and the United States³. Another study similar to the present study where AAMR from PD increased from 5.4 per 100,000 to 8.8 per 100,000 in a 20 year period³⁵. The present study observed a similar trend, with AAMR 5.3 per 100,000 in 1999 and 9.8 per 100,000 in 2020.

There are several important clinical implications of this study. This study demonstrates that PD is present as an underlying cause in a significant number of deaths in the US. Knowledge of trends in PD-related mortality is fundamental to building healthcare infrastructure around the growing needs of the increasing population living with PD. This study reports significant differences in demographic trends in PD-related mortality. Increasing age, male sex and white race were associated with the highest AAMR. This supports increased focus into the underlying reasons for these disparities and research into how these disparities can be addressed and managed.

There are several limitations to this study inherent to the dataset used. Firstly, routinely collected data from death certificates may be subject to coding inaccuracies, although there is no reason to believe this would bias findings in one direction or another, it may decrease precision. Secondly, data on overall prevalence, pharmacotherapy, co-morbidities and procedures that could have mediated outcomes are not available on the dataset, and therefore, we were not able to consider the rate of deaths allowing for the underlying rate of disease or the pathway from diagnosis to death. Finally, with this dataset we cannot ascertain the exact primary cause of death (e.g. cardiovascular disease, respiratory disorders, trauma), although arguably this is not the question at hand if PD is underlying this primary cause of death. This study records PD as an underlying cause of death where it is recorded on the death certificate of the deceased patient.

Future research could investigate underlying reasons behind disparities in mortality. Given the present study confirms populations with the highest prevalence of PD (older, male and white), also have the highest AAMR, further work must be completed to determine underlying reasons behind poor outcomes in female sex and non-white groups discovered in other studies. Knowledge of the factors contributing to poor outcomes could be fundamental to identify at-risk individuals. These individuals can be targeted for risk factor optimisation with the aim to reduce downstream adverse outcomes. Further research could also investigate the interplay between the aforementioned social determinants, age of diagnosis, onset of symptoms, comorbidities and how these impact demographic differences in PD-related mortality.

Conclusions

In conclusion, there are significant differences in demographic trends in PD-related mortality in the US. PD accounts for a greater number of deaths per head of population at older ages, in males, people of white race and in the Midwest. Knowledge of these trends is important to build healthcare services around this growing population. Further research must focus on addressing these differences to optimise management and development of appropriate healthcare infrastructure around this growing, at-risk population.

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