Age Cutoff for Early‐Onset Parkinson's Disease: Recommendations from the International Parkinson and Movement Disorder Society Task Force on Early Onset Parkinson's Disease

ABSTRACT

Background

Early‐onset Parkinson's disease (EOPD)/young‐onset Parkinson's disease (YOPD) is defined as Parkinson's disease (PD) with an age at onset (AAO) after age 21 years but before the usual AAO for PD. Consensus is lacking, and the reported maximal age for EOPD/YOPD has varied from 40 to 60 years, leading to a lack of uniformity in published studies and difficulty in harmonization of data. EOPD and YOPD have both been used in the literature, somewhat interchangeably.

Objective

To define the nomenclature and AAO cutoff for EOPD/YOPD.

Methods

An extensive review of the literature and task force meetings were conducted. Conclusions were reached by consensus.

Results

First, the literature has seen a shift from the use of YOPD toward EOPD. This seems motivated by an attempt to avoid age‐related stigmatization of patients. Second, in defining EOPD, 56% of the countries use 50 or 51 years as the cutoff age. Third, the majority of international genetic studies in PD use an age cutoff of younger than 50 years to define EOPD. Fourth, many studies suggest that changes in the estrogen level can affect the predisposition to develop PD, making the average age at menopause of 50 years an important factor to consider when defining EOPD. Fifth, considering the differential impact of the AAO of PD on professional and social life, using 50 years as the upper cutoff for the definition of EOPD seems reasonable.

Conclusions

This task force recommends the use of EOPD rather than YOPD. It defines EOPD as PD with AAO after 21 years but before 50 years.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a number of defined clinical features such as bradykinesia with either 1 or both of rest tremor and rigidity as well as a variety of nonmotor symptoms. ¹ , ² , ³ , ⁴ Early‐onset PD (EOPD), also referred to as young‐onset PD (YOPD), has been defined as PD with an onset of motor symptoms after age 21 but before what is considered the usual age at onset (AAO) for PD. However, consensus is lacking, and the reported maximal age for EOPD/YOPD has varied from 40 to 60, ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ whereas onset at or before age 21 defines juvenile PD. ¹¹ , ¹⁶ Because of the effect of PD symptoms earlier in life, the interaction of symptoms with potentially more active roles in society, and the longer time horizon of disease, people with EOPD/YOPD face unique challenges compared with those with late‐onset PD. ¹⁷ , ¹⁸ International Parkinson and Movement Disorder Society (MDS) commissioned the Early Onset Parkinson Disease Task Force with the objectives of defining the best nomenclature for EOPD/YOPD and the AAO cutoff defining this condition as well as identifying unmet needs and unique challenges in patients with EOPD/YOPD to guide the harmonization of research and other initiatives. The task force recommendations were based on the nomenclature, epidemiology, geographic differences, genetics, role of sexual hormones, clinical features, impact, and social perceptions. All conclusions were reached by consensus.

Search Strategies and Selection Criteria

The task force chair was appointed by the MDS. The members of the task force, who are also the authors of the present publication, are PD specialists who were selected based on expertise in EOPD/YOPD, and were appointed by the task force chair. A systematic review of available literature was performed in PubMed up to January 2022 with the search terms early onset OR young onset OR early OR young AND Parkinson AND each of the following: definition, hormon*, menopause, social, and genetic. Articles were included if reporting on EOPD and written in English. Articles were excluded from this review if not available in English or published as editorials or letters. All abstracts were reviewed for relevance to the topic. Of the 2677 abstracts reviewed, 2625 were not considered relevant as the search terms were vague to capture the most abstracts possible and minimize the risk of missing a relevant study. A total of 52 abstracts were retained, and the corresponding full articles were carefully reviewed. Of these, 43 full articles were considered relevant and were included. PubMed links and references from these articles were also scrutinized to identify other relevant studies as suggested by the references' titles. Similar to the initial search, abstracts of potentially relevant references were reviewed and, if considered relevant, the corresponding full articles were reviewed. Thus, an additional 63 studies were included in this article, bringing the total of articles included to 106.

In addition, for the geographic differences section, a list of all countries was created, and then a systematic search in the PubMed and Web of Science databases was conducted using the following search terms: early onset Parkinson* disease AND/OR young onset Parkinson* disease AND age AND the country's name. Articles in English were included. Of the 971 abstracts reviewed, 51 were retained, and the corresponding full articles were carefully reviewed.

Because 12 articles were redundant in both research strategies noted previously, the total number of articles included in this review was 145 (Fig. 1).

FIG. 1.

Search strategy.

Nomenclature

Authors who have first developed an interest in, and published on, this subgroup of PD have preferred the use of YOPD. ⁵ , ⁶ , ⁷ , ⁸ , ¹⁹ , ²⁰ However, there has been a shift toward the use of EOPD in the past 2 decades. ⁹ , ¹¹ , ¹⁵ , ²¹ , ²² The are no clear publications detailing the rationale behind this shift, but it seems motivated by an attempt to avoid age‐related stigmatization (Table 1). Thus, the recommendation of the Early Onset Parkinson Disease Task Force of the MDS is to use the term EOPD to designate PD with an onset of motor symptoms before the specific age that was agreed on.

TABLE 1.

Considerations for nomenclature

Young‐onset Parkinson's disease (YOPD) Might stigmatize younger patients further as being “too young” to develop Parkinson's disease. Might stigmatize patients who are older than the age cutoff as being old, while many are still in their 50s or early 60s, with the definition of “old” being constantly revised with the progress of medical care and increase in life expectation.

Early‐onset Parkinson's disease (EOPD) Delineates that Parkinson's disease developed earlier than average, without stigmatizing patients one way or the other.

Epidemiology

The prevalence of PD increases sharply with age, reaching 2.6% in people aged 85 to 89 years, ²³ , ²⁴ , ²⁵ , ²⁶ with a mean age of onset in the early to mid‐60s in the Western hemisphere. ²⁷ EOPD represents 3% to 7% of PD. ¹⁷ , ²⁸ The incidence of EOPD has been reported between 0.29 and 3.3 per 100,000 person‐years. ¹⁵ , ²⁰ , ²¹ , ²² , ²⁹

Geographical Differences

The age cutoff for the definition of EOPD varies from 1 country to another. An extensive review of the literature on this topic is presented in Table 2. Among the countries with a published age cutoff, 38% (n = 20) used a cutoff of 40 to 45 years, 56% (n = 29) used a cutoff of 50 or 51 years, and 6% (n = 3) used a cutoff of 55 years or older. More than 1 age cutoff has been used in some countries in different publications.

TABLE 2.

EOPD age cutoff (in years) by country

Country	Age cutoff for EOPD
Europe
Belarus	40 30
Belgium	50 31
Croatia	40
Czech Republic	40–45 32 , 33 , 34
Finland	55 21
Germany	50 35
Greece	50
Hungary	50 36
Iceland	50 37
Ireland	50 38
Italy	40–50 22 , 39
Kazakhstan	50 40
Luxembourg	50 41
Netherlands	40–50 18
Norway	45 42
Poland	40 43
Portugal	50 44
Russia	40 45 , 46
Serbia	50 47
Slovakia	40 48 , 49
Spain	50 50
Sweden	50 51
United Kingdom	40–50 11
Americas
Argentina	40 52
Brazil	20–45 53 , 54
Canada	40 55
Colombia	50 56
Ecuador	50 56
Mexico	45 57
United States	40–55 14 , 15 , 17 , 25
Asia‐Pacific
Middle East, North Africa, and South Asia: consensus from the MDS Task Force for the Middle East	50 58
Australia	50 59
China	40 60
French Polynesia	51 61
Guam	51 61
India	40–50 62 , 63 , 64
New Zealand	60 65
South Korea	40–50 66
Vietnam	50 67
Japan	40–50 28
Africa
Morocco	45 68
Nigeria	50 69
South Africa	50 70

There were no data published for countries not included in the table.

Abbreviation: EOPD, early‐onset Parkinson's disease.

Genetics

It is beyond the scope of this article to comprehensively review the genetics of PD; however, it has been well recognized that the risk of genetic predisposition may increase with the younger AAO. ⁷¹ Indeed, a family history of PD is reported in 20% of patients with EOPD versus 6.9% of patients with later onset PD, and the age‐specific risk of PD is 7.8‐fold higher in the relatives of patients with EOPD compared with 2.9‐fold among the relatives of patients with later onset PD. ¹⁴ , ⁷² Most frequent genetic mutations associated with EOPD are located on parkin (PARK2), PINK1 (PARK 6), DJ‐1 (PARK7), ATP13A2 (PARK9), and PLA2G6 (PARK14). ¹⁷ Although some genetic studies use a cutoff of 40 years ⁷³ or 45 years, ⁷⁴ the vast majority of genetic studies in PD from various parts of the world use the age cutoff of younger than 50 years to define EOPD, ³⁸ , ⁴⁰ , ⁶⁷ , ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² supporting the recommendation to use that age cutoff for the definition of EOPD.

Role of Sexual Hormones

The incidence of PD is 1.5 to 2.0 times higher in men than in women, ⁸³ , ⁸⁴ with women being less susceptible ⁸⁵ , ⁸⁶ to the disease and developing it later in life. ⁸⁶ , ⁸⁷ In addition, the incidence and prevalence of PD have been reported as higher in postmenopausal than in premenopausal women of similar age in multiple epidemiological studies. ⁸⁸ , ⁸⁹ , ⁹⁰

Many experimental and human observations suggest that estrogen may have a protective as well as a dopaminergic effect in PD, ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ whereas a smaller number suggests no benefit. ⁹³ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ One cross‐sectional study of 579 women with PD, 497 of whom developed menopause before PD onset, reported that later age of menopause was associated with older AAO and better on medication Unified Parkinson's Disease Rating Scale motor score. ¹⁰⁸ In addition, a population‐based study using the Mendelian randomization method reported that each year of delay in age at menopause was associated with a 7% decrease in PD risk. ¹⁰⁹

Regarding estrogen supplementation, a few studies ¹¹⁰ , ¹¹¹ , ¹¹² have shown that estrogen postmenopausal hormone replacement therapy (HRT) improves motor disability in women with PD, and a metanalysis of 14 observational studies reported that estrogen HRT did not increase the risk of PD. ¹⁰⁷ On the other hand, progestin‐only HRT seems to increase the risk of PD 3‐fold in postmenopausal women. ¹¹³

Taken together, these studies suggest that changes in the estrogen level can affect the predisposition to develop PD, making the average age at menopause of 50 ¹¹⁴ another important factor to consider when defining the upper age cutoff for EOPD.

PD Clinical Features

Clinical features and their underlying biological mechanisms also need to be considered in the definition of the age cutoff for EOPD.

In a large retrospective study assessing the impact of AAO on clinical features and evolution of 593 patients, rigidity as the predominant initial symptom was more frequent in patients with EOPD (AAO < 50), whereas gait instability as the predominant initial symptom was more frequent in patients with older onset PD. ¹⁴ There was no statistically significant difference in the frequency of tremor or bradykinesia as the predominant initial symptom among the groups, confirming results of previous studies ¹¹⁵ while contrasting with others whose results indicated both an increased or decreased rate of tremor in patients with earlier onset. ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ Another series of 422 patients reported as well that rigidity was a more frequent presenting symptom in the younger group (AAO < 50). ¹²⁰ Dystonia has been suggested as a more frequent presenting symptom in EOPD (20% of patients with AAO < 45 vs. 3% of patients with AAO > 64) in a study of 358 patients. Within 2 years of onset, dystonia developed in an additional 11% of EOPD and 1% of late‐onset PD (LOPD). ¹¹⁵ Most studies agree that patients with EOPD tend to have a slower progression of motor symptoms than those with LOPD. ¹²¹ , ¹²² , ¹²³ , ¹²⁴ , ¹²⁵ , ¹²⁶ , ¹²⁷

In addition, the prevalence of levodopa‐induced dyskinesia (LID) was reported to decrease with advancing AAO, with a higher frequency before age 50. In 1 population‐based study of 91 patients, the frequency of LID after 5 years of levodopa therapy was 40% in patients with PD onset before age 50, decreasing to 35.2% with an AAO between 50 and 69 years and 15.6% in patients with onset after 69 years. ¹²⁸ Another study suggested that the risk of dyskinesia was reduced by 20% to 30% for each 10 years of older AAO. ¹²⁹ In yet another series of 109 patients, the frequency of dyskinesia observed within 5 years of treatment was 80%, 26.7%, 22.7%, and 20% for onset between 40 and 49, 50 and 59, 60 and 69, and 70 and 79 years of age, respectively. ¹³⁰ Finally, in a large retrospective study of 593 patients, dyskinesia developed in 70% of the patients with EOPD (AAO < 50), 34.1% of the patients with middle‐onset PD (AAO 50–69), and 13% of the patients with LOPD (AAO > 69) (P < 0.001). ¹⁴ Similarly, treatment‐related dystonia was 2 to 4 times more frequent in patients with PD with AAO < 50 compared with later AAO in that cohort, ¹⁴ whereas another cohort of 358 patients suggested that the risk for dystonia was highest with AAO < 48. ¹¹⁵

Regarding nonmotor features, depression was reported twice as frequently in patients with EOPD (AAO < 50) than in patients with LOPD (AAO > 69). ¹⁴ Another controlled study similarly reported a higher rate of depression, worse emotional well‐being, and poorer quality of life with AAO ≤ 45 years of age. ¹³¹ Finally, 1 Norwegian cohort reported that patients with EOPD (AAO < 50) had a longer survival but a reduced life expectancy compared with patients with later onset PD. ¹³² However, these data were not confirmed in a North American population study reporting a longer life expectancy in EOPD overall compared with LOPD. ¹⁵

These clinical differences between EOPD and LOPD might have an anatomic substrate. Liu et al. ¹³³ compared the striatal patterns of dopaminergic degeneration between 40 EOPD (AAO ≤ 50) and 47 LOPD (AAO > 50), as examined with ¹¹C‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl) tropane positron emission tomography (PET). Although dopamine transporter (DAT) scans from patients with LOPD showed relatively uniform involvement of both the caudate and putamen, the DAT scans of patients with EOPD showed more sparing of the caudate compared with the putamen. Given the involvement of the caudate in complex cognitive functions, ¹³⁴ , ¹³⁵ , ¹³⁶ , ¹³⁷ this might provide an explanation for the lower prevalence of these nonmotor symptoms in EOPD compared with LOPD. ¹⁷ On the other hand, a PET and 18F‐fluorodopa scans study that included 27 patients aged 38 to 79 years reported a higher PD‐induced increase in dopamine turnover compared with the decrease in dopamine synthesis and storage rate in patients of younger age compared with older patients. The authors suggested that this implied greater alteration of dopamine turnover in EOPD that could lead to larger swings in synaptic dopamine levels, which has been suggested as a possible contributor to a greater risk of motor fluctuations. ¹³⁸

Regarding a potential biochemical substrate separating EOPD from LOPD, a controlled study including 76 patients with PD and 75 sex‐ and age‐matched controls reported that an AAO ≤ 50 was associated with lower levels of cerebrospinal fluid lactate and tau proteins, ¹³⁹ providing biochemical support for using 50 years as an age cutoff.

Overall, the clinical data and their suggested underlying biological mechanisms support the use of AAO < 50 for the definition of EOPD as well.

Impact of PD on Employment and Social Perception

One last variable to consider in the determination of the upper age limit for EOPD is the impact on social perception and employment. Although the retirement age is usually approximately 65 years in most countries, using that age as the upper limit for EOPD would not be appropriate as the typical AAO of PD is in the early to mid‐60s, ²⁷ thus placing a cutoff of 65 years quite late in the natural history of the disease. In addition, the development of PD 3 years from retirement is unlikely to have the same impact on professional development than a diagnosis made 15 years earlier. Indeed, a study comparing 75 patients with EOPD (AAO < 50) and 66 patients with LOPD (AAO ≥ 50) reported that, among those who retired, 97% of the patients with EOPD retired early versus 73% of those with LOPD (P = 0.003). ¹⁹ Other studies have found that 54% of patients with EOPD retire early, and 94% are likely to give up work within 10 years of disease onset, with patients with AAO < 45 years likely to stop working on average 6 to 7 years after diagnosis. ¹⁴⁰

In a retrospective cohort review of 88 Irish patients with PD with AAO < 65 years, men aged 55 to 64 years were twice as likely to be unemployed than the general population, whereas unemployment among women was not significantly affected by PD. The authors also found that the median time to loss of employment was 7 years, with 40% still employed after 5 years from onset and 14% after 10 years. Among those who were still working at the time of the study, 77% had made adjustments at work. Of those who had stopped working as a result of PD, 82% were dissatisfied with their unemployment status. ¹⁴¹

The burden of unemployment from EOPD goes beyond a financial cost, including social isolation, feelings of futility, lack of purpose and self‐esteem, and lack of daily structure. Many patients with PD are most bothered by the perception that others might have of their impairment than by their impairment itself. ¹⁴¹ , ¹⁴² This higher level of stigma in patients with EOPD ¹⁷ , ¹⁴³ seems to stem essentially from dysarthria, tremor, dyskinesia, and impact of the motor symptoms on activities of daily living such as eating and washing ¹⁴⁴ and can manifest as a reluctance to seek help and ask for adjustments at work, which in turn decreases the chances of staying employed.

In a prospective 50‐item survey aimed at clarifying patients' concerns in 222 individuals with PD, patients with EOPD (AAO < 50) reported significantly more concerns about difficulty with speaking (P = 0.003), washing and bathing (P = 0.04), or eating (P = 0.003) as well as with shaking (P = 0.005), dyskinesia (P = 0.001), low and/or depressed mood (P = 0.01), and anxiety and/or panic attacks (P < 0.001)—factors more likely to impact social or professional functioning—as greater concerns than typical‐onset patients with PD. ¹⁴⁴

Finally, EOPD may present a challenge to relationships. Marriages or relationships of shorter duration can be more vulnerable to the strain a chronic illness can impose than those of longer duration,¹⁴⁵ with significantly worse marital discord scores in couples with EOPD than in those with LOPD in 1 study comparing 75 patients with EOPD (<50 years) and 66 patients with LOPD. ¹⁹ The impact of the generational difference on these results cannot be excluded because of the absence of a healthy control. ¹⁸ A retrospective study comparing 272 patients with EOPD (AAO < 50) and 690 patients with LOPD (AAO > 70) reported less caregiver strain in the EOPD group. ¹²⁷ However, LOPD and their frequently similarly aged caregivers are each at greater risk of more medical comorbidities and financial strain, which are big contributors to caregiver strain and could be confounding factors.

In summary, considering the differential impact of the AAO of PD on professional and social life, using onset before age 50 years as the upper cutoff for the definition of EOPD seems reasonable (Fig. 2).

FIG. 2.

Interplay of factors leading to defining EOPD as AAO < 50. EOPD, early‐onset Parkinson's disease; AAO, age at onset; PD, Parkinson's disease.

Conclusion

After careful review of the available literature and deliberation, the Early Onset Parkinson Disease Task Force created by the MDS recommends the use of early‐onset Parkinson's disease instead of young‐onset Parkinson's disease. Furthermore, after considering hormonal, clinical, and genetic factors as well as the differential impact of the AAO of PD on professional and social life, this task force recommends using an AAO before 50 years for the definition of EOPD. This task force hopes that these recommendations regarding nomenclature and definition will help uniformize future research on the specific challenges and unmet needs of this subset of patients with PD as well as guide and harmonize future research and other initiatives.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

R.M.: 1A, 1B, 1C, 2A, 2B

K.S.: 2A, 2B

J.F.: 2B

B.P.: 2B

T.H.: 2B

M.E.P.P.: 2B

K.R.K.: 2B

V.M.: 2B

B.Z.: 2B

E.‐K.T.: 2B

R.S.: 1A, 1B, 2B

Disclosures

Ethical Compliance Statement: Because this work was a review of the literature and task force deliberation, no approval from an institutional review board was necessary. Similarly, informed patient consent was not necessary for this work. All authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: Raja Mehanna is on the speaker bureau for TEVA, Adamas Pharmaceuticals, Kyowa Kirin, and Sunovion. He has received research grants from Global Kinetic Corporation, Northera, Neurocrine, and Cerevel. Katarzyna Smilowska has nothing to disclose. Jori Fleisher has received royalties from Wolters Klewer Health/UpToDate and honoraria from the Parkinson's Foundation and the Davis Phinney Foundation. She also has the following research support: National Institute of Neurological Disorders and Stroke (NINDS; 1K23NS097615‐01A1 [principal investigator, PI: Fleisher], 5U01NS100610‐05/737SUB U01NS100610 [PI: Leverenz; role: site PI]), National Institute on Aging (NIA; 5P30AG064200‐02 [PI: Hepburn; role: pilot study PI]), Parkinson's Foundation (PF‐COE‐PC‐920660 [role: site palliative care champion], PF‐CORE_2004 [PI: Fleisher], PF‐CORE‐856255 [PI: Fleisher]), PCORI (15963‐PF PCORI [PI: Schroeder, role: collaborative member]), Rush University (Leslie Nan Burridge Faculty Scholar in Parkinson's Disease Research Endowment [PI: Fleisher]; Rush University Center for Excellence in Aging Pilot Grant [PI: Labuschagne; role: coinvestigator]; Rush University Movement Disorders Pilot Grant [PI: Shah‐Zamori; role: coinvestigator]), and private philanthropic support. Bart Post has nothing to disclose. Taku Hatano is employed at Juntendo University School of Medicine and received a grant from the Japan Agency for Medical Research and Development under grant numbers 20dm0107156, 21wm0425015, 21ak0101112, and 21dk0207055; the Japan Society for the Promotion of Science under grant number 21K07424; a grant from Setsuro Fujii Memorial Foundation; TaNeDS; research funds from Daiichi Sankyo TaNeDS Funding Program; speaker's honoraria from Dainippon Sumitomo; Takeda Pharmaceutical Company Co., Ltd.; FP Pharmaceutical Corporation; Kyowa Kirin Co., Ltd.; Ono Pharmaceutical Co., Ltd.; AbbVie GK; Eisai Co., Ltd.; Sanofi K.K.; and Otsuka Pharmaceutical Co., Ltd. Maria Elisa Pimentel Piemonte has nothing to disclose. Kishore Raj Kumar received honoraria from Seqirus, AbbVie Pty Ltd, Research Review Australia Pty Limited; grant funding from the Paul Ainsworth Family Foundation, The Michael J. Fox Foundation, and GP2 (unrelated to the current study); is employed by New South Wales (NSW) Health; and receives royalties from Oxford University Press for Neurogenetics (What Do I Do Now) first edition. Victor McConvey has nothing to disclose. Baorong Zhang M has nothing to disclose. Eng‐King Tan received honoraria for editorial duties for Clinical Parkinsonism Related Disorders and grant support from the National Medical Research Council, Singapore. Rodolfo Savica received research support from the NIA, the NINDS, and the Mayo Clinic Small Grants Program National Center for Advancing Translational Sciences and an unrestricted research grant from Acadia Pharmaceuticals Inc.