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. 2025 Jul 31;40(10):2220–2233. doi: 10.1002/mds.30310

Demographic and Clinical Profiles of Parkinson's Disease in India: Observations from a Nation‐Wide Multicenter Study

Asha Kishore 1,2,21,✉, Rupam Borgohain 3,4, Divya Kalikavil Puthenveedu 1, Roopa Rajan 5, Pramod Kumar Pal 6, Rukmini‐Mridula Kandadai 3,4, Ravi Yadav 6, Sahil Mehta 7, Hrishikesh Kumar 8, Niraj Kumar 9, Prashanth Lingappa Kukkle 10,11, Soaham Desai 12, Kuldeep Shetty 13, Pettarusp Wadia 14, Annu Aggarwal 15, Pankaj Ashok Agarwal 16, Mirza Masoom Abbas 17, Syam Krishnan 1, Divya Madathiparambil Radhakrishnan 5, Gurusidheswar Mahadevappa Wali 18, Achal Srivastava 5, Nitish Kamble 6, Teresa Maria D′ Costa Ferreira 19, Vivek Lal 7, Ashwin Ashok Kumar Sreelatha 20, Luis‐Giraldo Gonzalez‐Ricardo 20, Manas Chacko 1, Manu Sharma 20,✉
PMCID: PMC12553997  PMID: 40741694

Abstract

Background

Parkinson's disease (PD) phenotype may vary with genetic, ethno‐geographic, cultural, and environmental factors.

Objectives

The aim was to develop a clinical database of PD in India and assess the influence of age‐at‐onset (AAO), gender, and motor subtype on the clinical profile of PD.

Methods

A cross‐sectional study of PD was conducted across 18 Indian hospitals. Standardized assessments were performed by movement disorder specialists. Data were collected using uniform questionnaires during the recruitment visit. A total of 3300 age‐ and gender‐matched case–control pairs were analyzed for environmental exposures, habits, and co‐morbidities.

Results

We recruited 7918 PD cases with a mean AAO of 54.2 ± 11.8 years and a median disease duration of 5 years (interquartile range: 2–9). Subgroup analyses based on AAO, gender, and motor phenotype revealed significant differences in motor and non‐motor symptoms, exposures, habits, and co‐morbidities. Except coffee consumption, previously known associations were observed for exposure to insecticides/pesticides/fungicides (odds ratio [OR]: 1.67), head injury (OR: 3.11), coffee consumption (OR: 1.73), diabetes (OR: 1.48), hypertension (OR: 1.73), and smoking (OR: 0.74) in the Indian population.

Conclusions

This large pan‐Indian study highlights the clinical characteristics, environmental exposures, habits, and comorbid diseases associated with PD, which were broadly similar to those observed in European populations. The earlier AAO in Indian PD patients suggests a potentially higher genetic risk, warranting further investigation. A nationwide, community‐based, epidemiological study is needed to achieve a comprehensive understanding of all risk factors for PD in India and to validate the risk factors identified in this hospital‐based study. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinsons disease, Age at onset, Risk factors, Nonmotor symptoms, gender, Motor subtype

Parkinson's disease (PD), the second most common neurodegenerative disorder in the elderly, has seen a 21.7% increase in prevalence over the past two decades. 1 Most studies on the motor and non‐motor symptoms (NMS) in PD were conducted in European populations 2 , 3 , 4 , 5 The lack of adequate understanding of ethnic and racial differences in PD was highlighted in previous reports. 5 , 6 , 7 , 8 Limited healthcare access, inadequate diagnostic expertise, cultural influences, and the lack of standardized assessment tools present significant challenges to conducting multi‐ethnic and racial studies. An international study of NMS noted geographical differences in both the burden and the domains affected, with higher NMS scores in the Americas and lower scores in India and Japan. 9 However, the number of patients from India in the study was relatively small. Establishing comprehensive clinical repositories in underrepresented populations is crucial for understanding the heterogeneity of PD, developing biomarkers, and conducting clinical trials in diverse populations. Building a precision medicine program for PD, including prevention strategies, requires detailed data on the demographic, epidemiological, and clinical characteristics of the disease within specific populations.

Although PD is driven by a complex interplay of genetic and environmental factors, these remain poorly defined in the Indian context. To address these gaps and capture ethnic diversity in a global context, the Luxembourg‐German‐Indian Alliance on Neurodegenerative Diseases and Therapeutics (Lux‐GIANT) (www.lux-giant.com) was formed 10 to foster collaborative clinico‐genetic research. Under its aegis, a large, multicenter, hospital‐based, cross‐sectional study was conducted across India. The primary aim was to develop a database characterizing the clinical profile of PD in India and to assess the influence of age at onset (AAO), gender, and motor subtypes on the phenotype. A subset of matched case–control pairs was also analyzed to compare environmental exposures, habits, and comorbidities.

Subjects and Methods

Study Design

A multicenter (18 sites), hospital‐based, cross‐sectional study of PD was conducted across 18 Indian hospitals from November 2020 to November 2023. The detailed methodology was reported earlier. 10

Subjects

Consecutive PD patients, including both newly diagnosed individuals and those under regular follow‐up, were recruited and assessed at each site by a movement disorder specialist. A detailed neurological and systemic examination was conducted during the recruitment visit, by the movement disorder specialist of each center during the recruitment visit and fresh socio‐demographic data, clinical history, and treatment details were collected. To minimize recall bias, hospital records of prior diagnoses and clinical history were reviewed, and in cases of discrepancy, the information from hospital records was prioritized. Data were collected using a standardized proforma previously used by the Genetic Epidemiology of Parkinson's Disease (GEOPD) consortium 11 and entered into a dedicated Research Electronic Data Capture portal at one of the nodal sites.

Inclusion criteria for PD cases were: (1) diagnosis of PD based on the United Kingdom Parkinson's Disease Society Brain Bank criteria (including those with a family history of PD); 12 (2) age >21 years; and (3) Asian‐Indian ethnicity. Exclusion criteria included any suspicion of atypical and secondary parkinsonism. Family history was explored across at least two generations to identify relatives with PD or tremor. Familial PD was defined as having two or more, first‐ or second‐degree relatives with PD. A positive family history of tremor was recorded if any first‐ or second‐degree relative had hand tremor, resting or action, symmetric or asymmetric, without known PD symptoms.

Control Subjects

Healthy controls, matched for geographic and ethnic background, were recruited during the study period through advertisements in movement disorder clinics and hospital campuses. Investigators were encouraged to closely match controls with cases for age, gender, and education. Standard neurological examinations were conducted and detailed medical histories collected. Individuals with a family history of PD, tremor, or other neurodegenerative diseases were excluded.

Clinical Data Collection

AAO, disease duration, presence of motor symptoms and NMS at onset and at recruitment, were documented along with motor fluctuations and dyskinesias. These were verified with medical records. At the four university hospitals, patients were further assessed using the Unified Parkinson's Disease Rating Scale (UPDRS I–IV), Hoehn and Yahr staging, Montreal Cognitive Assessment (MoCA), and Beck Depression Inventory (BDI‐I). When possible, assessments were performed in the drug “OFF” state; otherwise, they were done in the “ON” state. Motor subtypes were determined from UPDRS II and III scores in the OFF state, and cases were classified into tremor‐dominant (TD), indeterminate (ID), or postural instability gait difficulty (PIGD) subtypes using an established method. 13 For all scales except MoCA, higher scores indicated greater symptom severity.

A GEOPD‐derived questionnaire 11 was used across all sites to assess NMS, psychosis, and impulse control disorders (ICDs). NMS queried included: cognitive impairment, psychosis, anxiety, depression, sweating abnormalities, seborrhea, rapid eye movement sleep behavior disorder (RBD), restless legs syndrome (RLS), periodic limb movements of sleep (PLMS), hyposmia/anosmia, orthostatic hypotension, constipation, dysphagia, and urinary urgency/incontinence.

Environmental and Lifestyle Data

The GEOPD questionnaire was also used to assess known risk factors, habits, and co‐morbid life style diseases associated with PD. 11 Subjects were asked about: (1) occupational or residential exposure to pesticides, herbicides, fungicides, insecticides, rodenticides, or fumigants; (2) lifetime smoking history of ≥100 cigarettes or >5 packs; (3) consumption of caffeinated coffee more than once weekly for at least 6 months; (4) history of head injury or concussion because of falls, sports, violence, or accidents; and (5) clinically confirmed co‐morbidities that included diabetes mellitus, hypertension, hypercholesterolemia, stroke, coronary artery disease, and cancer.

Self‐reported years of education, state of origin/domicile, and body mass index were documented for all participants. The study was approved by the Institutional Ethics Committees of all 18 participating centers. Written informed consent was obtained from all participants.

Statistical Methods

Categorical variables were presented as frequencies and percentages and compared using the χ2 test or Fisher's exact test. Continuous variables that followed a normal distribution were reported as mean and standard deviation (SD) and were compared using the t test or one‐way analysis of variance. For discrete and continuous variables not following a normal distribution, the median and interquartile range (IQR) (Q1 and Q3) were reported. Medians were compared using the Mann–Whitney U test and the Kruskal‐Wallis test. A P‐value less than 0.05 was considered statistically significant. Bonferroni correction was applied for adjusting P‐values in post hoc tests. A family‐wise error rate correction for multiple comparisons was not applied, as the analysis was descriptive in nature and was aimed at exploring a wide range of clinical characteristics. To ensure comparability between cases and controls for risk factors, a 1:1 exact matching was done based on gender and AAO in cases and 3300 pairs of cases and controls were generated. The strength of association was measured using the McNemar test, and McNemar's odds ratio with a 95% confidence interval (CI) was calculated. Conditional logistic regression was used to perform multivariable analysis. For stratification analyses, we defined an AAO threshold of <50 years to define early‐onset PD (EOPD) and ≥50 years as late‐onset PD (LOPD). 14 The analyses were performed using SPSS, STATA, and Python.

Data Sharing Statement

The data generated from this study are protected under the data protection regulations and guidelines of the Ministry of Health of the Government of India. The data‐sharing request can be made to the corresponding author and will be considered on a case‐by‐case basis. On approval, data access credentials will be provided.

Results

A total of 7918 PD cases were recruited. The male‐to‐female ratio was 2:1. The mean AAO was 54.2 ± 11.8 years, and the mean age at recruitment was 60.5 ± 11.3 years. The median disease duration was 5 years (IQR: 2–9). EOPD accounted for 32.8% of cases, whereas LOPD comprised 67.2%. Only 7.5% of cases had an AAO above 70 years. A family history of PD was reported in 9.3%, and a family history of tremor in 8.5% of cases. The predominant motor subtypes at recruitment were PIGD (47.1%) and TD (33.3%) (Table 1). The median education was 12 years (IQR: 9–15). The mean MoCA score was 23.7 ± 5.5, and the median BDI score was 9 (IQR: 5–13).

TABLE 1.

Demographic factors, exposures, habits, and comorbidities in PD

Variables Gender comparison (n = 7918) Early versus late‐onset comparison (n = 7468) Motor subtype comparison (n = 1816)
Male 5367 (67.7%) Female 2551 (32.2%) P‐value Age at onset <50 y 2450 (32.8%) Age at onset ≥50 y 5018 (67.2%) P‐value TD 605 (33.3%) ID 355 (19.5%) PIGD 856 (47.1%) P‐value Adjusted P‐value (PIGD vs TD)
Age at onset (y), mean (SD) 54.6 (11.9) 53.5 (11.5) <0.001 40.9 (6.8) 60.7 (7.5) <0.001 52.4 (12.1) 53.6 (11.4) 54.0 (11.4) 0.0367 0.0343
Onset <50 y, n (%) 1591 (31.4) 858 (35.7) <0.001 NA NA NA 228 (38.1) 120 (34.1) 276 (32.5) 0.0867 0.0849
Onset <40 y, n (%) 565 (11.2) 268 (11.2) 0.9954 NA NA NA 92 (15.4) 37 (10.5) 87 (10.3) 0.008 0.0107
Age at recruitment (y), mean (SD) 60.9 (11.4) 59.7 (11.0) <0.001 48.8 (8.5) 66.0 (7.5) <0.001 57.1 (11.3) 59.3 (10.9) 60.7 (10.9) <0.001 <0.001
Duration of disease (y), median (IQR) 5.0 (2.0–9.0) 5.0 (2.0–9.0) 0.6474 6.0 (3.0–11.0) 4.0 (2.0–7.0) <0.001 4.0 (1.5–7.0) 5.0 (2.0–8.0) 6.0 (3.0–10.0) <0.001 <0.001
Male, n (%) 5367 (67.7) NA NA 1591 (65.0) 3473 (69.2) <0.001 452 (74.7) 247 (69.6) 535 (62.6) <0.001 <0.001
Body mass index, mean (SD) 24.3 (3.5) 24.2 (4.0) 0.2177 24.2 (3.7) 24.3 (3.6) 0.2923 24.4 (3.9) 24.0 (3.9) 24.2 (3.9) 0.3062 0.7605
Y of education, median (IQR) 12.0 (10.0–15.0) 10.0 (5.0–15.0) <0.001 12.0 (9.0–15.0) 12.0 (9.2–15.0) 0.002 11.0 (7.0–15.0) 10.0 (7.0–15.0) 11.0 (7.0–15.0) 0.8777 0.9999
Currently employed, n (%) 2816 (54.7) 943 (38.6) <0.001 1529 (64.3) 2107 (43.5) <0.001 406 (68.8) 242 (69.5) 521 (62.0) 0.0072 0.0244
Family history of PD, n (%) 486 (9.4) 223 (9.0) 0.6229 265 (10.9) 432 (8.7) 0.0021 68 (11.3) 42 (11.9) 71 (8.3) 0.0746 0.1741
Family history of tremor, n (%) 442 (8.9) 181 (7.7) 0.0762 222 (9.3) 395 (8.2) 0.1099 70 (11.8) 41 (12.1) 52 (6.2) <0.001 <0.001
Agriculture as a job, n (%) 906 (16.9) 246 (9.6) <0.001 349 (14.2) 770 (15.3) 0.211 140 (23.1) 80 (22.5) 143 (16.7) 0.004 0.007
Exposure to pesticide/insecticide/fungicide, n (%) 1154 (22.0) 382 (15.2) <0.001 453 (18.8) 1031 (20.9) 0.0365 155 (26.2) 81 (23.3) 144 (17.2) <0.001 <0.001
Head injury or concussion, n (%) 408 (8.1) 138 (5.7) <0.001 190 (8.1) 331 (7.0) 0.1009 57 (9.9) 32 (9.4) 74 (9.1) 0.8847 0.9999
Smoking, n (%) 869 (16.6) 33 (1.3) <0.001 263 (11.0) 583 (11.8) 0.2641 62 (10.6) 24 (7.0) 94 (11.3) 0.0815 0.9999
Coffee consumption, n (%) 1364 (26.2) 570 (22.9) 0.0019 600 (25.1) 1278 (26.1) 0.3551 112 (19.3) 56 (16.3) 134 (16.3) 0.2811 0.4052
Diabetes, n (%) 1145 (21.3) 427 (16.7) <0.001 274 (11.2) 1251 (24.9) <0.001 144 (23.8) 100 (28.2) 216 (25.3) 0.3229 0.9999
High cholesterol, n (%) 185 (3.4) 117 (4.6) 0.0134 75 (3.1) 223 (4.4) 0.0042 21 (3.5) 13 (3.7) 35 (4.1) 0.8192 0.9999
Hypertension, n (%) 1420 (26.5) 678 (26.6) 0.9101 378 (15.4) 1675 (33.4) <0.001 192 (31.7) 134 (37.7) 290 (33.9) 0.1648 0.9999
History of CAD, n (%) 149 (2.8) 31 (1.2) <0.001 20 (0.8) 156 (3.1) <0.001 11 (1.8) 4 (1.1) 22 (2.6) 0.2407 0.9999
Stroke, n (%) 50 (0.9) 23 (0.9) 0.8961 11 (0.4) 59 (1.2) 0.0022 3 (0.5) 4 (1.1) 12 (1.4) 0.26 0.2707
History of depression, n (%) 241 (4.5) 180 (7.1) <0.001 156 (6.4) 250 (5.0) 0.0132 35 (5.8) 28 (7.9) 74 (8.7) 0.1192 0.1196
History of anxiety, n (%) 279 (5.2) 123 (4.8) 0.4754 136 (5.6) 262 (5.2) 0.5513 46 (7.6) 31 (8.7) 62 (7.3) 0.6764 0.9999
Melanoma, n (%) 4 (0.1) 0 (0.0) 0.3124 2 (0.1) 2 (0.0) 0.6018 0 (0.0) 0 (0.0) 1 (0.1) 0.9999 0.9999
Prostate cancer, n (%) 12 (0.2) NA NA 0 (0.0) 8 (0.2) 0.0595 0 (0.0) 1 (0.3) 2 (0.2) 0.4364 0.9999
Other cancers, n (%) 31 (0.6) 32 (1.3) 0.0015 10 (0.4) 52 (1.0) 0.005 7 (1.2) 3 (0.8) 11 (1.3) 0.8821 0.9999
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Note: In the comparison of EOPD and LOPD, 450 cases with missing data were removed. Motor subtyping could be done only in cases that underwent detailed UPDRS assessment in the university hospitals in OFF state.

Abbreviations: PD, Parkinson's disease; ID, indeterminate type PD; TD, tremor dominant PD; PIGD, postural instability gait difficulty type PD; SD, standard deviation; IQR, interquartile range; CAD, coronary artery disease; EOPD, early‐onset PD; LOPD, late‐onset PD; UPDRS, Unified Parkinson's Disease Rating Scale.

Motor and NMS of All PD

The most frequent motor symptoms at both onset and recruitment were rest tremor, slowness, and rigidity, followed by postural tremor, reduced arm swing, slow gait, reduced hand dexterity, and micrographia.

The NMS burden was greater at recruitment, with a significant increase in frequency compared to onset, for constipation (29.5% vs. 40.5%), RBD (15.3% vs. 26.2%), insomnia (16.1% vs. 20.2%), urinary urgency/incontinence (12.6% vs. 19.5%), depression (8.0% vs. 16.0%), and cognitive symptoms (7.8% vs. 12.7%) (P < 0.05 for all comparisons).

Gender Differences in PD

Among all the 7918 cases analyzed, 67.7% were men and 32.2% women (Table 2). The mean age of men was higher than that of women by 1 year, both at onset and recruitment, while the median disease duration was similar. The predominant motor symptoms at onset and recruitment were largely similar, except for micrographia, which was significantly more common in men. At recruitment, men reported a higher frequency of both reduced facial expression and hand dexterity and motor fluctuations, whereas falls and dyskinesias were more frequent in women. There were no significant differences in UPDRS I–IV or Hoehn and Yahr scores (in OFF or ON states) between the genders, in the subset of cases.

TABLE 2.

Comparisons of motor and non‐motor symptoms based on gender, AAO, and motor subtype of PD

Variables, n (%) Men vs. women with PD (n = 7918) EOPD vs. LOPD (n = 7468) Motor subtypes of PD (n = 1816)
Male 5367 (67.7%) Female 2551 (32.2%) P‐value AAO <50 y 2450 (32.8%) AAO ≥50 y 5018 (67.2%) P‐value TD 605 (33.3%) ID 355 (19.5%) PIGD 856 (47.1%) P‐value Adjusted P‐value (TD vs. PIGD)
Motor symptoms at onset, n (%)
Rest tremor 3215 (59.9) 1514 (59.3) 0.6387 1454 (59.3) 3196 (63.7) <0.001 446 (73.7) 217 (61.1) 363 (42.5) <0.001 <0.001
Bradykinesia 2045 (38.1) 1004 (39.4) 0.2839 1006 (41.1) 1986 (39.6) 0.2193 172 (28.4) 162 (45.6) 422 (49.4) <0.001 <0.001
Rigidity 1603 (29.9) 811 (31.8) 0.0823 765 (31.2) 1573 (31.3) 0.9145 55 (9.1) 58 (16.3) 184 (21.5) <0.001 <0.001
Postural/action 1338 (24.9) 617 (24.2) 0.4734 583 (23.8) 1332 (26.5) 0.0107 189 (31.2) 95 (26.8) 194 (22.7) 0.0012 <0.001
Reduced dexterity 622 (11.6) 285 (11.2) 0.5859 329 (13.4) 569 (11.3) 0.0091 23 (3.8) 21 (5.9) 107 (12.5) <0.001 <0.001
Micrographia 356 (6.6) 119 (4.7) <0.001 169 (6.9) 300 (6.0) 0.1241 30 (5.0) 15 (4.2) 53 (6.2) 0.3234 0.9402
Reduced arm swing 1080 (20.1) 512 (20.1) 0.9566 576 (23.5) 996 (19.8) <0.001 56 (9.3) 49 (13.8) 194 (22.7) <0.001 <0.001
Gait disorder 781 (14.6) 368 (14.4) 0.8816 298 (12.2) 807 (16.1) <0.001 13 (2.1) 18 (5.1) 60 (7.0) <0.001 <0.001
Freezing 373 (6.9) 177 (6.9) 0.9851 143 (5.8) 397 (7.9) 0.0012 1 (0.2) 4 (1.1) 21 (2.5) 0.0012 0.0012
Falls 171 (3.2) 96 (3.8) 0.1837 67 (2.7) 194 (3.9) 0.0124 0 (0.0) 2 (0.6) 10 (1.2) 0.0145 0.0205
Non‐motor symptoms at onset, n (%)
Constipation 930 (17.3) 417 (16.3) 0.2773 282 (11.5) 1031 (20.5) <0.001 85 (14.0) 63 (17.7) 150 (17.5) 0.1557 0.2205
Insomnia 403 (7.5) 195 (7.6) 0.8315 191 (7.8) 392 (7.8) 0.9807 73 (12.1) 37 (10.4) 79 (9.2) 0.2194 0.2445
RLS 573 (10.7) 259 (10.2) 0.4778 203 (8.3) 620 (12.4) <0.001 38 (6.3) 35 (9.9) 67 (7.8) 0.1315 0.7715
Urinary urgency 301 (5.6) 159 (6.2) 0.2669 109 (4.4) 335 (6.7) <0.001 22 (3.6) 21 (5.9) 54 (6.3) 0.0702 0.0695
Hyperhidrosis 45 (0.8) 36 (1.4) 0.0179 43 (1.8) 38 (0.8) <0.001 9 (1.5) 3 (0.8) 5 (0.6) 0.2061 0.2436
Anosmia/hyposmia 115 (2.1) 42 (1.6) 0.1388 37 (1.5) 119 (2.4) 0.0145 7 (1.2) 8 (2.3) 12 (1.4) 0.3841 0.9999
Cognitive symptoms 220 (4.1) 73 (2.9) 0.0064 71 (2.9) 191 (3.8) 0.0452 17 (2.8) 11 (3.1) 30 (3.5) 0.751 0.9999
Motor symptoms at recruitment, n (%)
Rest tremor 3502 (65.3) 1608 (63.0) 0.054 1696 (69.2) 3315 (66.1) 0.0063 565 (93.4) 315 (88.7) 594 (69.5) <0.001 <0.001
Postural/action tremor 2097 (39.1) 973 (38.1) 0.4273 1100 (44.9) 1915 (38.2) <0.001 476 (78.7) 279 (78.6) 571 (66.8) <0.001 <0.001
Bradykinesia 3369 (62.8) 1558 (61.1) 0.1452 1703 (69.5) 3163 (63.0) <0.001 510 (84.3) 321 (90.4) 776 (90.8) <0.001 <0.001
Rigidity 3076 (57.3) 1430 (56.1) 0.2913 1626 (66.4) 2787 (55.5) <0.001 462 (76.4) 296 (83.4) 721 (84.3) <0.001 <0.001
Reduced facial expression 1685 (31.4) 715 (28) 0.002 803 (32.8) 1570 (31.3) 0.195 351 (58) 240 (67.6) 525 (61.3) 0.013 0.608
Reduced hand dexterity 1612 (30) 693 (27.2) 0.009 812 (33.1) 1473 (29.4) 0.001 235 (38.8) 152 (42.8) 427 (49.9) <0.001 <0.001
Gait disorder 2017 (37.6) 945 (37.0) 0.6443 1032 (42.1) 1892 (37.7) <0.001 356 (58.8) 258 (72.7) 661 (77.3) <0.001 <0.001
Falls 460 (8.6) 264 (10.3) 0.0103 274 (11.2) 435 (8.7) <0.001 22 (3.6) 27 (7.6) 187 (21.9) <0.001 <0.001
Freezing 827 (15.4) 393 (15.4) 0.997 508 (20.7) 702 (14.0) <0.001 36 (6.0) 49 (13.8) 245 (28.7) <0.001 <0.001
Dyskinesias 773 (14.4) 454 (17.8) <0.001 632 (25.8) 580 (11.6) <0.001 58 (9.6) 41 (11.5) 201 (23.5) <0.001 <0.001
Motor fluctuation 810 (15.1) 334 (13.1) 0.018 505 (20.6) 636 (12.7) <0.001 41 (6.8) 23 (6.5) 160 (18.7) <0.001 <0.001
Non‐motor symptoms at recruitment, n (%)
Psychosis 116 (2.2) 61 (2.4) 0.5179 47 (1.9) 128 (2.6) 0.0898 7 (1.2) 5 (1.4) 32 (3.7) 0.0026 0.0076
Depression 535 (10.0) 344 (13.5) <0.001 359 (14.7) 503 (10.0) <0.001 23 (3.8) 28 (7.9) 106 (12.4) <0.001 <0.001
RBD 1053 (19.6) 467 (18.3) 0.1655 440 (18.0) 1065 (21.2) <0.001 78 (12.9) 61 (17.2) 183 (21.4) <0.001 <0.001
RLS 208 (3.9) 131 (5.1) 0.0097 89 (3.6) 247 (4.9) 0.0116 17 (2.8) 18 (5.1) 54 (6.3) 0.0093 0.0065
Anosmia/hyposmia 270 (5.0) 132 (5.2) 0.7855 126 (5.1) 273 (5.4) 0.5914 33 (5.5) 19 (5.4) 52 (6.1) 0.8291 0.9999
Cognitive impairment 564 (10.5) 232 (9.1) 0.0505 229 (9.3) 517 (10.3) 0.1958 51 (8.4) 36 (10.1) 132 (15.4) <0.001 <0.001
EDS 255 (4.8) 83 (3.3) 0.0021 114 (4.7) 223 (4.4) 0.6828 35 (5.8) 24 (6.8) 74 (8.7) 0.1051 0.1196
Insomnia 885 (16.5) 485 (19.0) 0.0056 485 (19.8) 852 (17.0) 0.0029 136 (22.5) 86 (24.2) 226 (26.4) 0.22 0.2545
Orthostasis 84 (1.6) 49 (1.9) 0.2498 37 (1.5) 85 (1.7) 0.5566 18 (3.0) 8 (2.3) 36 (4.2) 0.1785 0.6538
Hyperhidrosis 102 (1.9) 75 (2.9) 0.0035 87 (3.6) 89 (1.8) <0.001 27 (4.5) 17 (4.8) 45 (5.3) 0.7791 0.9999
Seborrhea 90 (1.7) 28 (1.1) 0.0468 46 (1.9) 69 (1.4) 0.0978 20 (3.3) 17 (4.8) 28 (3.3) 0.3937 0.9999
Constipation 1877 (35.0) 762 (29.9) <0.001 685 (28.0) 1893 (37.7) <0.001 188 (31.1) 138 (38.9) 383 (44.8) <0.001 <0.001
Urinary incontinence 872 (16.2) 354 (13.9) 0.0064 339 (13.8) 846 (16.9) <0.001 97 (16.0) 84 (23.7) 235 (27.5) <0.001 <0.001
MoCA score, mean (SD) 24.1 (5.2) 22.8 (6.2) <0.001 24.2 (5.5) 23.5 (5.5) <0.001 25.3 (6.1) 24.8 (6.0) 24.2 (5.8) 0.0054 0.0039
BDI score, median (IQR) 8.0 (5.0–13.0) 9.0 (6.0–14.0) <0.001 9.0 (6.0–14.0) 8.0 (5.0–13.0) <0.001 8.0 (4.0–12.0) 9.0 (5.0–13.0) 9.0 (6.0–14.0) <0.001 <0.001
Drug OFF state
H & Y stage I–III, n (%) 1642 (94.4) 795 (93.4) 0.3377 783 (92.6) 1564 (94.7) 0.0302 588 (98.3) 338 (96.3) 769 (90.7) <0.001 <0.001
H & Y stage IV–V, n (%) 98 (5.6) 56 (6.6) 63 (7.4) 87 (5.3) 10 (1.7) 13 (3.7) 79 (9.3)
UPDRS III‐OFF, median (IQR) 38.0 (27.0–46.0) 37.0 (26.0–46.0) 0.3854 38.0 (27.0–47.0) 37.0 (27.0–46.0) 0.6416 35.0 (25.0–46.0) 39.0 (31.0–46.0) 39.0 (28.0–48.0) 0.0013 0.002
Drug ON state
H & Y stage I–III, n (%) 2537 (95.8) 1200 (95.4) 0.584 1260 (96.1) 2400 (95.5) 0.3518 NA NA NA NA NA
H & Y stage IV–V, n (%) 112 (4.2) 58 (4.6) 51 (3.9) 114 (4.5) NA NA NA
UPDRS III‐ON, median (IQR) 21.0 (13.0–30.0) 20.0 (13.0–29.0) 0.0582 20.0 (12.0–28.0) 21.0 (13.0–30.0) 0.0038 NA NA NA NA NA
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Abbreviations: AAO, age at onset; PD, Parkinson's disease; EOPD, early‐onset PD; LOPD, late‐ onset PD; TD, tremor dominant PD; ID, indeterminate type PD; PIGD, postural instability gait difficulty type PD; RLS, restless leg syndrome; RBD, rapid eye movement sleep behavior disorder; EDS, excessive daytime sleepiness; MoCA, Montreal Cognitive Assessment score; SD, standard deviation; BDI, Becks Depression Inventory; IQR, interquartile range; H & Y, Hoehn and Yahr stage; NA, not applicable as motor subtyping could be done only of cases assessed in drug OFF; UPDRS III, Unified Parkinson's Disease Rating Scale part III.

Among NMS at onset, cognitive symptoms were more frequent in men, whereas RLS and hyperhidrosis were more common in women. At recruitment, constipation, urinary urgency/incontinence, and excessive daytime sleepiness (EDS) were more frequent in men, whereas RLS, insomnia, hyperhidrosis, and depression were more frequent in women (Table 2, Figure 1). Compared to men, women had slightly worse BDI and MoCA scores, and their median education was 2 years lower than men.

FIG. 1.

FIG. 1

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Shows the distribution of non‐motor symptoms (NMS) that were significantly different in comparisons between men and women, EOPD and LOPD, and Parkinson's disease (PD) subtypes. EOPD, early onset of PD (age <50 years); LOPD, late onset of PD (age >60 years); TD, tremor‐dominant; PIGD, postural instability and gait difficulty. *Significant at the 0.05 level (2‐tailed).

The frequency of agricultural jobs and exposure to insecticides/herbicides/fungicides was higher in men (Table 1). Similarly, smoking, caffeinated coffee consumption, diabetes mellitus, and coronary artery disease were more common in men. In contrast, cancers (excluding prostate cancer) were more prevalent in women. A family history of PD (9.4% vs. 9.0%, P = 0.65) and tremor (8.9% vs. 7.7%, P = 0.08) was comparable between genders (Table 1).

Early Versus Late‐Onset PD

From the total of 7918 cases, 450 cases with missing data were excluded for this analysis. In EOPD, the mean ages at onset and recruitment were 40.9 ± 6.8 years and 48.8 ± 8.5 years, respectively, and in LOPD, 60.7 ± 7.5 years and 66.0 ± 7.5 years. At recruitment, the median disease duration was 6 years (IQR: 3–11) in EOPD and 4 years (IQR: 2–7) in LOPD.

At onset, rest tremor, postural tremor, freezing, falls, and gait difficulty were significantly more frequent in LOPD, whereas bradykinesia was more frequent in EOPD, and rigidity was similar in both groups. At recruitment, all motor symptoms, including motor fluctuations and dyskinesia, were more frequent in EOPD. UPDRS I–III scores in OFF were similar between groups, but UPDRS III scores in ON were slightly better in EOPD. UPDRS IV‐A and IV‐B scores were comparable in subjects assessed in both groups (Table 2).

RLS, RBD, hyposmia, constipation, and urinary symptoms were more frequent in LOPD, whereas hyperhidrosis was more common in EOPD. At recruitment, LOPD reported higher frequencies of constipation, RBD, RLS, and urinary symptoms, whereas impulsive‐compulsive symptoms, hyperhidrosis, insomnia, and depression were more frequent in EOPD (Table 2, Fig 1). MoCA scores were worse in LOPD and BDI scores worse in EOPD though median education levels were similar (Table 1).

Among queried factors, exposure to insecticides/pesticides/fungicides was significantly more common in LOPD, although the frequency of agricultural jobs was similar between groups (Table 1). Co‐morbidities such as stroke, diabetes, hypertension, hypercholesterolemia, and coronary artery disease were significantly more frequent in LOPD. A family history of PD was more frequent in EOPD (10.8% vs. 7.7%, P = 0.002), but not that of tremor (P = 0.31).

Predominant Motor Subtypes and Difference

Of the 1816 cases with UPDRS II and III scores available in the drug OFF state for motor subtyping, 47.1% were PIGD, 33.3% TD, and 19.6% ID. Although P‐values were adjusted for multiple comparisons among the three motor subtypes, only the comparison between the TD and PIGD is presented, these being the predominant subtypes (Table 2). The mean AAO was similar (54 years) and the mean disease duration was 2 years longer in PIGD than TD (6 vs. 4 years, P < 0.001). As expected, tremor at onset was more frequent in TD, whereas generalized bradykinesia, rigidity, freezing, gait difficulty, and falls were more common in PIGD. These differences persisted at recruitment. Additionally, motor fluctuations and dyskinesias were significantly more frequent in PIGD. Severe disease (Hoehn and Yahr stages IV + V in OFF) was more common in PIGD than in TD. UPDRS I–III scores in the OFF were also higher in PIGD.

NMS at onset were similar between subtypes, but at recruitment, depression, psychosis, RBD, RLS, constipation, and urinary symptoms were more frequent in PIGD (Table 2, Fig. 1). MoCA and BDI scores were slightly worse in PIGD than TD, despite similar education levels. A positive family history of PD was similar between subtypes (P = 0.1), but a family history of tremor was significantly more frequent in TD than PIGD (11.8% vs. 6.2%, P < 0.001).

Risk Factors for PD

A total of 3300 pairs each of age‐ and gender‐matched (1:1), cases and controls were selected from the total PD cases (n = 7918) and controls (n = 4000) for this analysis (Table 3). The independent associations (Table 4) were (1) exposure to insecticides/pesticides/fungicides (OR: 1.67, 95% CI: 1.41–1.99), head injury (OR: 3.11, 95% CI: 2.36–4.11), coffee consumption (OR: 1.73, 95% CI: 1.51–1.98), diabetes (OR: 1.48, 95% CI: 1.26–1.74), hypertension (OR: 1.73, 95% CI: 1.5–2.0). Smoking showed an inverse association with PD (OR: 0.74, 95% CI: 0.62–0.88). Agricultural jobs and coronary artery disease were not significant in multivariable analysis (P > 0.05 for each). Anxiety and depression, now considered as pre‐motor symptoms of PD, were excluded from the model, but showed higher frequency in cases and controls (Table 3).

TABLE 3.

Comparison between age‐ and gender‐matched PD cases‐control pairs

Variables Cases (3320) Control (3320) P‐value
Age at onset (y), mean (SD) 50.0 (12.6) 50.0 (12.6) 0.9999
Male, n (%) 2090 (63) 2090 (63) 0.9999
Duration of disease (y), median (IQR) 5.0 (3.0–10.0) NA NA
Body mass index, mean (SD) 24.2 (3.7) 25.0 (3.8) <0.001
Y of education, median (IQR) 12.0 (8.0–15.0) 12.0 (9.0–15.0) 0.0149
Family history of tremor, n (%) 277 (8.5) NA NA
Family history of dementia, n (%) 70 (2.2) NA NA
Exposure to pesticide/insecticide/fungicide, n (%) 613 (18.5) 378 (11.4) <0.001
Agriculture as a job, n (%) 502 (15.1) 383 (11.5) <0.001
Head injury or concussion, n (%) 257 (7.8) 79 (2.4) <0.001
Smoking, n (%) 330 (9.9) 360 (10.8) 0.2486
Coffee consumption, n (%) 763 (23.0) 486 (14.7) <0.001
Diabetes, n (%) 622 (18.7) 383 (11.5) <0.001
Hypertension, n (%) 832 (25.1) 487 (14.7) <0.001
History of CAD, n (%) 40 (1.2) 22 (0.7) 0.0301
Stroke, n (%) 26 (0.8) 11 (0.3) 0.21
History of depression, n (%) 179 (5.4) 9 (0.3) <0.001
History of anxiety, n (%) 184 (5.5) 15 (0.5) <0.001
Melanoma, n (%) 1 (0.0) 1 (0.0) 0.9999
Prostate cancer, n (%) 1 (0.0) 0 (0.0) 0.9999
Other cancers, n (%) 22 (0.7) 16 (0.5) 0.416
MoCA, mean (SD) 23.8 (5.9) 25.4 (3.8) <0.001
BDI, median (IQR) 9 (5–13) 4 (1–7) <0.001
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Note: Family history of PD or tremor was exclusion criteria for controls.

Abbreviations: PD, Parkinson's disease; SD, standard deviation; IQR, interquartile range; NA, not applicable; CAD, coronary artery disease; MoCA, Montreal Cognitive Assessment score; BDI, Becks Depression Inventory.

TABLE 4.

Independent association of environmental exposures, habits, and co‐morbid life style disease with PD

N = 6640 (cases = 3320, controls = 3320) McN OR (95% CI) P‐value Adjusted OR a (95% CI) P‐value
Agricultural job 1.36 (1.18–1.57) <0.001* 1.09 (0.91–1.3) 0.361
Life time direct exposure to pesticide/insecticide/fungicide 1.76 (1.53–2.03) <0.001* 1.67 (1.41–1.99) <0.001*
Smoked 100 or more cigarettes 0.91 (0.78–1.07) 0.258 0.74 (0.62–0.88) 0.001*
Regular consumption of caffeinated drinks for >6 months 1.75 (1.54–1.99) <0.001* 1.73 (1.51–1.98) <0.001*
Head injury/concussion 3.63 (2.78–4.75) <0.001* 3.11 (2.36–4.11) <0.001*
Diabetes 1.82 (1.58–2.1) <0.001* 1.48 (1.26–1.74) <0.001*
Hypertension 1.99 (1.75–2.26) <0.001* 1.73 (1.5–2) <0.001*
History of CAD 1.86 (1.09–3.16) 0.022* 1.29 (0.71–2.33) 0.404
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a

Conditional logistic regression—age‐ and gender‐matched.

*

Significant at the 0.05 level (2‐tailed).

Abbreviations: PD, Parkinson's disease; McN OR, McNemar's odds ratio; CI, confidence interval; OR, odds ratio; CAD, coronary artery disease.

Discussion

This pan‐Indian, hospital‐based, cross‐sectional study of PD, in which diagnostic and clinical assessments were performed by movement disorder specialists to enhance diagnostic accuracy and symptom interpretation, provides the largest PD database from the subcontinent. Direct comparison of our results with multi‐ethnic studies is challenging because of methodological differences, varied objectives, and conflicting results among previous reports. 9 , 15 , 16 The most notable demographic difference in our study is the lower mean AAO of PD in India, which is nearly a decade earlier than in European, 17 African, 18 and East Asian populations, 19 , 20 but similar to Latin American populations. 21 Inaccuracies in self‐reported age and recall bias in reporting AAO cannot be fully eliminated, even when cross verified using age from the national identity cards and disease duration from medical records. Additionally, younger PD cases with better health seeking behaviors are likely to present to tertiary care hospitals. Alternatively, the lower AAO by a decade could be because of the high prevalence of EOPD in India 22 and a higher genetic burden of PD shown in a genome‐wide association study of PD in India (pre‐print). 23 These converging lines of evidence support the hypothesis that earlier an AAO of PD in some of these populations could be a true epidemiological characteristic rather than a result of age‐reporting inaccuracies and suggest an influence of genetic and environmental influence on AAO in non‐European populations.

The prevalence of PD is known to be higher in men 24 , 25 , 26 , 27 , 28 and this was also consistently seen across all cases and PD subtypes in our study population. Gender differences in motor symptoms and NMS are reported in early and mild to moderate PD. 24 More tremor and fall risk in women, and more rigidity and freezing in men were reported earlier. 25 Our results showed that motor symptoms were broadly similar across both genders. However, dyskinesia was more frequent in women and motor fluctuations in men, despite comparable AAO and disease duration. Women are reportedly, approximately three times more likely to develop dyskinesias, and at an earlier stage, which could be because of higher levodopa bioavailability, lower renal clearance, higher weight‐adjusted dosing, estrogen effects, and higher striatal D1/D2 receptor ratios in them. 25 , 29 Men, on the other hand, have faster disease progression and, therefore, develop fluctuations earlier. 30

Gender‐related differences in NMS are widely recognized. 24 , 25 , 26 , 27 Anxiety, depression, fatigue, dysphagia, constipation, and pain are more common in women, whereas sialorrhea, ICDs, urinary dysfunction, orthostatic hypotension, RBD, and daytime sleepiness are more common in men. 27 In our study, at onset, RLS and PLMS were more frequent in women, whereas cognitive symptoms were more often reported by men. At recruitment, depression, RLS, insomnia, and hyperhidrosis were more common in women and constipation, urinary urgency/incontinence, and EDS were more frequent in men, while. Our findings broadly align with earlier reports.

Gender differences in cognitive patterns and in the risk of conversion from mild cognitive impariment to PD dementia, typically higher in men, are already known. 31 , 32 Although we found slightly lower MoCA scores in women, this could be influenced by their lower educational levels. A comprehensive cognitive evaluation, adjusted for education and other variables, would be needed to confirm whether gender independently influences cognitive and depression in PD.

AAO significantly influences PD phenotype. In a study of 422 patients, older AAO was associated with more severe motor and non‐motor phenotypes, reduced dopaminergic function, and lower cerebrospinal fluid α‐synuclein and tau levels. 33 In our cohort, tremor, gait difficulty, freezing, and falls were more common at onset in LOPD, whereas motor fluctuations and dyskinesias were more frequent in EOPD, consistent with prior findings. 31 , 34 , 35

NMS patterns also varied with AAO. At onset, RBD, RLS, and urinary symptoms were more frequent in LOPD. At recruitment, impulsivity, depression, and insomnia were more prevalent in EOPD, with only RBD remaining more frequent in LOPD. Cognitive scores were worse in LOPD, whereas BDI scores were higher in EOPD. The greater NMS burden in LOPD may reflect aging, more severe dopaminergic degeneration, α‐synuclein pathology (and the higher frequency of co‐morbidities, as seen in this study). Several studies have shown that EOPD is more likely to have a family history of PD, including one from India suggesting a stronger genetic predisposition. 36 , 37 , 38 Monogenic forms of PD (eg, Parkin mutations), which predominantly present as EOPD, 9 are associated with primarily nigral pathology, accounting for the milder NMS burden in them. 39

Motor subtypes likely represent a spectrum and are influenced by multiple factors and various subtyping methods exist, making comparisons with previous studies difficult. The severity and burden of both motor and NMS are reported to be greater in PIGD compared to TD, with higher cognitive impairment in PIGD, particularly in the later stages. 40 , 41 , 42 Another study found that NMS burden was greater in the non‐TD subtype, regardless of disease duration. Our findings are consistent with these observations. 43 Apart from tremor, all motor and NMS were more frequent in the PIGD subtype, with fewer cases in Hoehn and Yahr stage IV–V in TD (1.7% vs. 9.3%), as reported earlier. 43 Structural imaging studies show greater grey matter loss in motor, limbic, and cognitive areas in PIGD, which may underlie the clinical differences. 44

A family history of tremor was more frequent in the TD subtype in our study, consistent with earlier reports linking action tremor to TD. 43 However, whether this reflects an isolated manifestation of TD or an overlap with essential tremor or a shared genetic susceptibility to tremor disorders, remains unclear.

Most of the risk factors identified in our study are largely consistent with observations in prior European studies 45 , 46 , 47 , 48 Contrasting to previous evidence of a negative association with caffeine intake in most studies, 49 we found a positive association with coffee drinking habit, which was unexpected. In our study, the questionnaire used did not include queries on the quantify caffeine consumption, the type of coffee (filtered or unfiltered, and black or with cream), intake of other caffeinated beverages, the induction time or the urban–rural differences in coffee‐drinking habits. Future studies are required to confirm or refute this association in Indian PD that is contrary to several reports in other populations.

Strengths and Limitations

A major strength of our study is the large sample size and the uniform clinical assessments conducted by movement disorder specialists, enabling detailed characterization of both motor and NMS of PD. Although efforts were made to cross‐verify data with medical records, recall bias could not be entirely eliminated. In the case–control analysis, differential recall bias may exist, as cases reported exposures retrospectively from disease onset while controls provided information based on their current age. The hospital‐based design may have contributed to the lower age of cases observed as younger individuals with better health seeking behaviors are more likely to present to referral hospitals. Despite efforts to recruit older controls across the centers, recruiting from volunteers who responded to hospital advertisements likely resulted in a control group with a lower mean age than the cases. This could have led to the exclusion of older PD cases, from the age matched case‐control risk factor analysis, even if only a small proportion (7.5%) had age at onset above 70 years. These excluded individuals may have had different exposure patterns. Additionally, as a hospital‐based, cross‐sectional study, our findings may not fully capture rural–urban differences and, therefore, do not represent the heterogeneous exposure or risk factor profile in the population at large. Detailed cognitive evaluations, the use of specific NMS scales, and quantitative assessments of environmental exposures were beyond the scope of this large‐scale study. Instead, we adopted the standardized questionnaire used by the GEOPD consortium, which provides a broad overview.

Conclusion

This is the largest, well‐characterized clinical dataset on PD from a South Asian country and demonstrates broad similarities to PD and its subtypes as reported in European populations, with the notable exception of an earlier AAO in India. Future clinical trials of symptomatic therapies in PD should consider the differences in motor and NMS, based on age, gender, and motor subtype. This is a cross‐sectional study, and the risk factor analysis is exploratory in nature. No causal inferences can be made as the temporal relationship between exposures, habits, or comorbidities and disease onset is unverified and is a limitation inherent in cross sectional study designs. Therefore, interpretation of these associations should be approached with caution. These findings need validation in a future longitudinal study that includes rural populations, and quantitative assessments of environmental exposures, for a more comprehensive understanding of the PD risk profile in the Indian population.

Author Roles

(1) A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, LGR, B. Execution, Review and Critique; (3) Manuscript Preparation: A. Writing First Draft, B. Review and Critique.

A.K.: 1A, 1B, 2A, 3A, 3B.

R.B.: 1C, 3B.

D.K.P..: 1C, 3B.

R.R.: 1C, 3B.

P.K.P.: 1C, 3B.

R.M.K.: 1C, 3B.

R.Y.: 1C, 3B.

S.M.: 1C, 3B.

H.K.: 1C, 3B.

N.K.: 1C, 3B.

P.L.K.: 1C, 3B.

S.D.: 1C, 3B.

K.S.: 1C, 3B.

P.W.: 1C, 3B.

A.A.: 1C, 3B.

P.A.A.: 1C, 3B.

M.M.A.: 1C, 3B.

S.K.: 1C, 3B.

D.M.K.: 1C, 3B.

G.M.W.: 1C, 3B.

A.S.: 1C, 3B.

N.K.: 1C, 3B.

T.D.F.: 1C, 3B.

V.L.: 1C, 3B.

A.A.S.:3B.

L.G.R.: 1C, 2A, 3B.

M.C.: 2A, 2C,3B.

M.S.: 1A, 1B, 2C, 3B.

Financial Disclosures

None of the authors have any financial disclosures to make.

Acknowledgments

We thank all the participants of the study and The Michel J. Fox foundation for the generous funding for the study.

Asha Kishore and Manu Sharma are joint senior authors.

Relevant conflicts of interest/financial disclosures: None.

Funding agency: The Michel J. Fox Foundation (grant proposal reference number: 009411).

Contributor Information

Asha Kishore, Email: asha.kishore@asterdmhealthcare.in.

Manu Sharma, Email: manu.sharma@uni-tuebingen.de.

Data Availability Statement

The data that support the findings of this study are available from Government of India. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Government of India.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from Government of India. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Government of India.

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