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Article

Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson’s Disease

by
Diego Santos-García
1,*,
Ariadna Laguna
2,3,
Jorge Hernández-Vara
2,3,
Teresa de Deus Fonticoba
4,
Carlos Cores Bartolomé
1,
Maria J. Feal Painceiras
1,
Maria Cristina Íñiguez-Alvarado
1,
Iago García Díaz
1,
Silvia Jesús
3,5,
Maria Teresa Boungiorno
6,
Lluís Planellas
7,
Marina Cosgaya
8,
Juan García Caldentey
9,
Nuria Caballol
10,
Ines Legarda
11,
Iria Cabo
12,
Lydia López Manzanares
13,
Isabel González Aramburu
3,14,
Maria A. Ávila Rivera
15,
Víctor Gómez Mayordomo
16,
Víctor Nogueira
17,
Víctor Puente
18,
Julio Dotor García-Soto
19,
Carmen Borrué
20,
Berta Solano Vila
21,
María Álvarez Sauco
22,
Lydia Vela
23,
Sonia Escalante
24,
Esther Cubo
25,
Francisco Carrillo Padilla
26,
Juan C. Martínez Castrillo
27,
Pilar Sánchez Alonso
28,
Maria G. Alonso Losada
29,
Nuria López Ariztegui
30,
Itziar Gastón
31,
Jaime Kulisevsky
3,32,
Manuel Menéndez González
33,
Manuel Seijo
12,
Javier Rúiz Martínez
34,
Caridad Valero
35,
Mónica Kurtis
36,
Jessica González Ardura
37,
Ruben Alonso Redondo
38,
Carlos Ordás
39,
Luis M. López Díaz
29,
Darrian McAfee
40,
Pablo Martinez-Martin
3,
Pablo Mir
3,5 and
on behalf of the COPPADIS Study Group
†add Show full author list remove Hide full author list
1
Department of Neurology, CHUAC, Complejo Hospitalario Universitario de A Coruña, c/ As Xubias 84, 15006 A Coruña, Spain
2
Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain
3
CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), 19171 Madrid, Spain
4
CHUF, Complejo Hospitalario Universitario de Ferrol, 15405 Ferrol, Spain
5
Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
6
Hospital Universitari Mutua de Terrassa, 08221 Terrassa, Spain
7
Clínica del Pilar, 50006 Barcelona, Spain
8
Hospital Clínic de Barcelona, 08036 Barcelona, Spain
9
Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain
10
Consorci Sanitari Integral, Hospital Moisés Broggi, 08970 Sant Joan Despí, Spain
11
Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
12
Complejo Hospitalario Universitario de Pontevedra (CHOP), 36001 Pontevedra, Spain
13
Hospital Universitario La Princesa, 28006 Madrid, Spain
14
Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
15
Consorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, 08906 Barcelona, Spain
16
Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain
17
Hospital Da Costa, 27880 Burela, Spain
18
Hospital del Mar, 08003 Barcelona, Spain
19
Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain
20
Hospital Infanta Sofía, 28702 Madrid, Spain
21
Institut d’Assistència Sanitària (IAS)–Institut Català de la Salut, 17190 Girona, Spain
22
Hospital General Universitario de Elche, 03203 Elche, Spain
23
Fundación Hospital de Alcorcón, 28922 Madrid, Spain
24
Hospital de Tortosa Verge de la Cinta (HTVC), 43500 Tortosa, Spain
25
Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain
26
Hospital Universitario de Canarias, 38320 San Cristóbal de la Laguna, Spain
27
Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
28
Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain
29
Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), 36312 Vigo, Spain
30
Complejo Hospitalario de Toledo, 45007 Toledo, Spain
31
Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
32
Hospital de Sant Pau, 08025 Barcelona, Spain
33
Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
34
Hospital Universitario Donostia, 20014 Donostia, Spain
35
Hospital Arnau de Vilanova, 25198 Valencia, Spain
36
Hospital Ruber Internacional, 28034 Madrid, Spain
37
Hospital de Cabueñes, 33394 Gijón, Spain
38
Universitario Lucus Augusti (HULA), 27003 Lugo, Spain
39
Hospital Rey Juan Carlos, 28933 Madrid, Spain
40
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
 
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remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
†
Membership of the COPPADIS Study Group is provided in the Supplementary Material.
J. Clin. Med. 2023, 12(4), 1329; https://doi.org/10.3390/jcm12041329
Submission received: 26 December 2022 / Revised: 31 January 2023 / Accepted: 1 February 2023 / Published: 7 February 2023
(This article belongs to the Special Issue Clinical Management of Parkinson's Symptoms)
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Abstract

:
Background and objective: Sex plays a role in Parkinson’s disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD. Patients and Methods: PD patients who were recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used. Results: At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Symptoms such as depression (p < 0.0001), fatigue (p < 0.0001), and pain (p < 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia (p < 0.0001), speech problems (p < 0.0001), rigidity (p < 0.0001), and hypersexuality (p < 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose (p = 0.002). Perception of quality of life was generally worse in females (PDQ-39, p = 0.002; EUROHIS-QOL8, p = 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males (p = 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females (p = 0.001). Conclusion: The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.

1. Introduction

Previously published data indicated that there are sex differences in many features of Parkinson’s disease (PD) [1,2]. Incidence and prevalence of PD are between 1.5 and 2 times higher in men than in woman and disease onset in women is slightly later than in men [3,4]. Clinically, males have more rigidity and speech problems, whereas females seem to have a greater prevalence of dyskinesia and motor and non-motor response fluctuations but more mild motor deterioration [5,6,7]. Regarding non-motor symptoms (NMSs), some studies have observed that symptoms such as fatigue, depression, anxiety, and sleep problems are more frequent in females, whereas other NMSs such as drooling, diurnal somnolence, urinary and sexual dysfunction, and cognitive problems are more prevalent in males [8,9,10]. However, the results are not consistent due to the great heterogeneity between the studies [2], including aspects such as the sample (e.g., differences in age, disease duration, or race), the type of evaluation conducted, or the follow-up period. Although several findings indicate that estrogens may play a role in PD and explain some sex differences, other mechanisms such as gene expression, neuroinflammation, oxidative stress, and lifestyle factors could be involved [11,12]. From a practical point of view, precise identification of the sex differences is important to tailor treatment, predict outcomes, and meet other individual and social needs in women and men with PD. In particular, it may be important to know sex differences in a specific population (i.e., in a province and/or a country) with the intention of developing global care strategies that can improve health care [13].
Although some epidemiological studies about PD have been conducted in Spain, the differences in motor and NMSs and disease progression between males and females in Spanish PD patients are unclear [14,15]. The aim of the present study was to analyze the main sex differences among Spanish patients with PD using data obtained from the COPPADIS cohort [16], the largest cohort of patients with PD studied in Spain to date. Specifically, we analyzed the differences between both sexes in terms of motor and NMSs, quality of life (QoL), autonomy, and disease progression.

2. Material and Methods

Patients with PD who were recruited from 35 centers of 14 Autonomous Communities of Spain from the COPPADIS cohort [16] from January 2016 to November 2017 were included in the present study. Methodology about the COPPADIS-2015 study can be consulted in https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0548-9 (accessed on 31 January 2023) [17]. This is a multi-center, observational, longitudinal-prospective, five-year follow-up study designed to analyze disease progression in a Spanish population of PD patients. All patients included were diagnosed according to UK PD Brain Bank criteria [18].
Specifically, the present study is a post hoc analysis with two parts. The first part included a cross-sectional analysis comparing data collected from the baseline visit (V0) regarding sex. The second was a longitudinal prospective analysis to compare the change between males and females in PD characteristics from the baseline visit (V0) to a follow-up visit at 24 months ± 1 month (V24M). For some variables, data about baseline visit, 12 months ± 1 month (V12M), and V24M were available.

PD Patient Assessment

In PD subjects, information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected at baseline (visit V0) and at 24 months ± 1 month (visit V24M). V0 and V24M evaluations included (1) motor assessment (Hoenh and Yahr [HY], Unified Parkinson’s Disease Rating Scale [UPDRS] part III and part IV [19], Freezing of Gait Questionnaire [FOGQ]), (2) NMSs (Non-Motor Symptoms Scale [NMSS], Parkinson’s Disease Sleep Scale [PDSS], Visual Analog Scale-Pain [VAS-Pain], Visual Analog Fatigue Scale [VAFS]), (3) cognition (PD-CRS), (4) mood and neuropsychiatric symptoms (BDI-II, Neuropsychiatric Inventory [NPI], Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale [QUIP-RS]), (5) disability (Schwab and England Activities of Daily Living Scale [ADLS]), and (6) health-related (the 39-item Parkinson’s disease Questionnaire [PDQ-39]) and global QoL (the EUROHIS-QOL 8-item index EUROHIS-QOL8]) [17]. At V12M, only the UPDRS, NMSS, and ADLS were assessed. In all the scales/questionnaires, a higher score indicates a more severe affectation except PD-CRS, PDSS, ADLS, and EUROHIS-QOL8, which is the opposite. Total score of the PDQ-39 (PDQ-39SI) and each domain of the NMSS and the PDQ-39 was expressed as a percentage: (score/total score) × 100 [20]. In patients with motor fluctuations, the motor assessment was made during the OFF state (without medication during the last 12 h) and during the ON state. The assessment was only performed without medication in patients without motor fluctuations. Non-motor assessment was conducted after taking medication.
The presence of motor fluctuations and dyskinesia was assessed according to the UPDRS-IV (items 39 and 32, respectively) [19]. FOG was defined according to the FOGQ-item 3 [21,22]. Motor phenotype was calculated based on a previously published formula [23,24]. Very severe NMS burden was defined as a NMSS total score >70 [20]. Patient with a score <81 on the PD-CRS were considered as with cognitive impairment [25,26]. Patients were classified as with major depression according to the DSM-IV criteria [27,28]. Impulse control disorder (ICD) (pathological gambling, compulsive shopping, hypersexuality, and compulsive eating behavior) and compulsive behavior (CB) (punding, hobbyism, and dopamine dysregulation syndrome) were defined according to the previously published cutoff points of the QUIP-RS: gambling ≥6, buying ≥8, sex ≥8, eating ≥7, hobbyism–punding ≥7 [28,29]. For dopamine dysregulation syndrome, we accounted for the investigator’s criterion since an established cutoff does not exist [30].

3. Data Analysis

Data were processed using SPSS 20.0 for Windows. Only PD patients with data available in both visits at V0 and at V24M were considered valid for the longitudinal analysis. For comparisons between males and females, Student’s t-test, the Mann–Whitney U test, chi-square test, or Fisher’s test, were used as appropriate (distribution for variables was verified by one-sample Kolmogorov–Smirnov test).
General linear model (GLM) repeated measure were used to test for changes in various scores (motor; NMS; QoL; autonomy for ADL) over time (V24M vs. V0 and/or V24M vs. V12M and V12M vs. V0) separately in each group (men vs. women) and test for differences between groups over time. Age at baseline, and levodopa equivalent daily dose (LEDD [31]) at baseline and at V24M were included as covariates. In the latter models, an interaction for visit and group was tested before testing for a group difference over time. Cohen’s d formula was applied for measuring the effect size in both groups, males and females. It was considered: <0.2–Negligible; 0.2–0.49–Small; 0.50–0.79–Moderate; ≥0.80–Large. The Bonferroni method was used to p value correction for multiple comparisons and a p ≤ 0.002 was considered significant.

4. Results

At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) were valid for the analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between both groups (males vs. females) in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Compared to males, to be single (11.1% vs. 4.4%; p < 0.0001) and living alone (15.6% vs. 7.6%; p < 0.0001) was more frequent in females (Table 1). To be taking antidepressant agents (33.3% vs. 18.1%; p < 0.0001), benzodiazepines (23.2% vs. 11.2%; p < 0.0001), and analgesics (31% vs. 19.8%; p = 0.002) was more frequent in females as well. Up to 91.1% of females were non-drinkers compared to 71.1% of males (p < 0.0001). Regarding antiparkinsonian treatment, LEDD (607.79 ± 432.61 vs. 503.71 ± 381.49; p = 0.002) was higher in males than in females.
Although no differences in the score of the motor scales (HY, UPDRS-III, UPDRS-IV, FOGQ) were observed between sexes (Table 2), sub-scores of the UPDRS-III (OFF) detected a greater severity in hypomimia, speech, and rigidity (p < 0.0001 for all analysis) in males compared to females (Table 3 and Figure 1A). Regarding NMSs, females had a higher score on the BDI-II (9.95 ± 7.89 vs. 7.95 ± 6.84; p = 0.001) and major depression almost doubled (22.9% vs. 12%; p < 0.0001) in females when compared to males. The scores on the VAS about pain and physical fatigue were higher also in females (Table 2). Although the frequency of ICD (12.2%) and CB (9.3%) was similar in both sexes (Table 3), hypersexuality was clearly more frequent in males (7.6% vs. 0.4%; p < 0.0001). There were no differences between males and females in the NMSS total score (43.49 ± 36.89 vs. 47.94 ± 39.52; p = 0.208) but by domains, a trend in significance was detected for a greater burden in sleep/fatigue (18.03 ± 16.72 vs. 15.35 ± 15.63; p = 0.041), mood/apathy (13.78 ± 17.96 vs. 9.79 ± 15.19; p = 0.003), and miscellaneous (16.98 ± 16.71 vs. 13.56 ± 14.49; p = 0.010) in females whereas in urinary symptoms (22.48 ± 22.22 vs. 20.29 ± 22.84; p = 0.047) in males (Table 3 and Figure 1B). The results regarding global, fronto-subcortical, and posterior cortical cognitive function as a whole were similar in both groups (Table 3).
The perception of health-related QoL (PDQ-39SI, 18.88 ± 13.76 vs. 16.05 ± 13.33; p = 0.002) was worse in females. “Emotional well-being” (25.64 ± 20.97 vs. 18.6 ± 18.72; p < 0.0001) and “Pain and discomfort” (33.76 ± 24.31 vs. 21.46 ± 20.2; p < 0.0001) were the domains of the PDQ-39 with the clearest differences with a greater severity in females (Table 3 and Figure 2A), but “Communication” was worse in males (11.99 ± 16.24 vs. 7.74 ± 13.52; p < 0.0001). With regard to the EUROHIS-QOL8, a trend in significance was detected for a worse perception in females in the total score (3.71 ± 0.56 vs. 3.82 ± 0.53; p = 0.009) and in “Quality of life” (3.73 ± 0.72 vs. 3.86 ± 0.7; p = 0.014), “Health status” (3.07 ± 0.87 vs. 3.23 ± 0.87; p = 0.020), and “Energy” (3.65 ± 0.88 vs. 3.84 ± 0.77; p = 0.004) (Table 3 and Figure 2B). No differences were detected between males and females in terms of autonomy for activities of daily living (ADL) (Table 2).
Although the score on the UPDRS-III increased significantly from V0 to V24M in both groups, males and females, the difference between them was not significant (p = 0.554) (Table 4 and Figure 3). However, hypomimia and speech impairment from V0 to V24M in males but not in females was highly significant (p < 0.0001) (Table 4). Collectively, we observed an impairment of NMS burden (NMSS total score) after the two-year follow-up in both groups (Table 4 and Figure 3), with a trend in significance in males than in females (Cohen’s d, 0.43 vs. 0.25; difference between groups, p = 0.012). From V0 to V24M, functional capacity for ADL (ADLS) was impaired in males (from 89.12 ± 9.08 to 85.23 ± 12.58; p < 0.0001) and females (from 87.91 ± 11.42 to 82.76 ± 14.69; p < 0.0001), but the effect was greater in females than in males (p = 0.001; Table 4). Although LEDD tended to be higher in males than in females in all visits (n = 470; V0, 624.37 ± 434.36 vs. 514.88 ± 379.45 [p = 0.006]; V12M, 702.06 ± 401.64 vs. 621.96 ± 432.72 [p = 0.010]; V24M, 808.55 ± 460.97 vs. 726.31 ± 460.68 [p = 0.017]) (Figure 3), similar results were detected after dividing LEDD by weight (males vs. females, n = 450; V0, 7.81 ± 5.52 vs. 7.74 ± 6.07 [p = 0.550]; V12M, 8.71 ± 4.97 vs. 9.47 ± 6.96 [p = 0.782]; V24M, 10.94 ± 6.16 vs. 10.58 ± 7.44 [p = 0.166]).
Finally, after comparison of all data of baseline visit (variables included in Table 1 and Table 2) between patients who were assessed at V24M (n = 496) and those patients who were lost to follow-up at V24M (n = 185), no significant differences were detected (only p < 0.005 in the PDSS total score, with a worse quality of sleep in patients who lost the follow-up; 108.87 ± 32.28 vs. 117.02 ± 24.47; p = 0.019).

5. Discussion

The present study analyzes the differences between Spanish males and females with PD in motor features, NMSs, QoL, and autonomy for ADL. This is the first study carried out in Spain that analyzes sex differences in a large cohort and one of the largest studies with longitudinal data and detailed evaluations carried out to date. Depression, fatigue, pain, and a worse QoL were more frequent in females whereas hypomimia, speech problems, and hypersexuality were associated with the male sex. In the short-term, males showed a tendency to develop a greater NMS burden impairment, but females deteriorated more in their functional capacity to perform their ADL. To know the differences in PD progression by sex is important because it allows for more personalized medicine, considering age, race, sex, and cultural context has become the vanguard of delivery of care [32].
Multiple studies analyzing sex differences in PD have been published to date. Many of them have been case-control, retrospective, or cross-sectional studies, and lack consistent findings [2]. In our cross-sectional analysis, we detected many differences between males and females but not in age and time from symptoms onset, so both groups were appropriate to compare. Aligning with our results, previous studies observed that women are more likely to live alone; however, while a spouse or partner is the most likely individual to serve as a caregiver, homebound women are more likely to be single or widowed compared to men [33]. Additionally, in our cohort, primary education, to receive more drugs for other diseases, and assistance to a PD association tended to be more frequent in women, as opposed to harmful habits (smoking and alcohol consumption), which were significantly more frequent in males. Although lifestyle factors are important in PD [34], reviews about the differences in PD by sex lack information about these factors and focus more other aspects [1,2,11,35,36,37,38,39].
Sex-related differences have been documented in several aspects of PD, including motor features, response to levodopa, NMSs, and QoL, among others [1,2,4,5,6,7,8,9,10,11,35,36,37,38,39]. Motor symptoms emerge later in women, including specific characteristics such as reduced rigidity [6,40,41] but also more risk of falling [11,41], as we found. On the contrary, speech problems, in line with our findings, freezing of gait, and drooling are more associated with male sex [1,2,11,42,43]. Although the frequency of hypomimia seems to be no different between sexes [44], we identified it as more severe in males. In fact, both axial signs, hypomimia, and speech problems were impaired after a two-year follow-up in males but not in females. Other axial symptoms such as camptocormia have been related to male sex as well [45]. Although the score on the UPDRS-III during the OFF state was higher in males from our cohort in all visits compared to females, the differences were not significant, nor was motor progression in both groups at the follow-up. Using data from the PPMI cohort, Picillo et al. [5] detected in a five-year longitudinal analysis that men had more longitudinal progression in clinician-assessed motor features in the ON medication state but a similar increase over time of MDS-UPDRS part III OFF scores in both sexes. Other studies suggests that women with PD have milder motor symptoms compared to men with PD [46]. However, Abraham et al. [47] observed similar rates of progression between males and females until 20 years post-diagnosis, and only women had a quicker rate of progression after this period. A prior study with a ten-year follow-up had found that females had slower initial but faster later impairment progression [48]. Thus, this point is not clear, being an important research area to understand underlying reasons for this heterogeneity in PD progression [49]. Specifically, different genetic, hormonal, neuroendocrinal, and molecular players contribute towards the differences in PD pathogenesis [12,13]. Regarding motor complications, several studies reported a high incidence in females [50,51,52]. We did not find differences in the frequency of motor fluctuations and dyskinesia at baseline between males and females. Additionally, although the UPDRS-IV score was impaired after a two-year follow-up more in females, only a trend in significance was detected. Despite this difference observed in many studies, women with PD did not receive different treatments compared with men, suggesting that non-motor fluctuations in women remain mostly undertreated [53]. In our analysis, LEDD was lower in females at baseline (all cohort) and tended to be lower in all visits (subgroup with data available in all visits), which has been previously reported [5]. However, no differences between both groups were detected when LEDD was divided by weight, which could suggest a similar management in terms of dose requirement. Interestingly, tremor was the only motor sign that decreased after the two-year follow-up in both groups in our cohort. It is well known that motor PD subtype is instable and some cases with tremor-dominant type change to non-tremor subtype in the short-term [23].
There is currently a large amount of evidence available on the sex differences in the spectrum of NMSs in PD patients [11]. However, there are many scales validated to assess different NMSs in PD and this could contribute to heterogeneous results in some respects [2]. PD women have more depression, sleep problems, fatigue, and pain [1,2,8,11,54,55,56,57,58,59]. However, urinary symptoms and sexual dysfunction seem to be more prevalent in men [1,2,8,58,60]. In our cohort, depression was double in women than men. Women also were receiving more frequent antidepressant agents, benzodiazepines, and analgesics. When considering NMSs as a whole, the results were inconsistent. According to Solla et al. [61], women had higher scores on the NMSS, including severe sleep difficulties, increased fatigue, and mood disorders, such as apathy, anxiety, sadness, depression, and lack of motivation, whereas men had higher sexual dysfunction levels. However, Nicoletti et al. [62] reported that the presence of NMSs was more strongly associated with male sex in a cross-sectional study conducted in 585 PD patients, but no differences were detected in another cross-sectional study conducted in 415 PD patients by Kang et al. [46]. In all these studies, the NMS burden was assessed with the same scale we used, the NMSS. Some studies suggest a greater NMS burden in males [61]. In particular, Picillo et al. [62] observed that men complained of a greater number of NMSs as compared to women in a two-year follow-up study as well. Here, we detected only a trend in significance after applying the Bonferroni test (p = 0.012) for a greater NMS burden increase in males after a two-year follow-up, without significant differences by sex in the change of the score of all domains of the NMSS. Although some studies reported that male PD patients have worse general cognitive abilities and that male sex is the primary predictive factor for mild cognitive impairment and its rapid progression in the severe stage of the disease [7,9,10,11,63], we did not find significant differences in the neuropsychiatric symptoms. Regarding ICD and/or CB, the frequency was according to the literature [64] and hypersexuality was the only ICD significantly more frequent in males, being present in 7.6% of them. A recent review reported a mean prevalence of hypersexuality of 3.5% in PD patients and quite convincing demographic data indicating that patients are often males on dopamine agonists [65]. Finally, females have significantly less social support, more psychological distress, and worse self-reported disability and health-related QoL compared to males [47,66,67,68]. In our analysis, we detected differences with a worse perception by females, especially in emotional well-being, pain, and discomfort. Few studies have analyzed differences in the changes over time to develop the ADL in PD between sexes. We detected an impairment in the functional capacity in both sexes after the two-year follow-up conducted, but more significantly in women, as Sperens et al. [69] reported in an eight-year follow-up study conducted in 129 PD patients, with a worse impairment in women in domains such as shopping and cleaning. Other studies emphasize the importance of the progressive disability of women with PD, influencing aspects, such as polypharmacy or comorbidities, that translate into a consumption of health resources [56].
The present study has some limitations. Our findings may not be applicable to all PD patients in the community clinical setting because PD patients enrolled in the COPPADIS study represent a selected population with less disability at baseline than the general population (e.g., no older than 75 years old, not being under a second-line therapy, etc.). For some variables, the information was not collected in all cases and the data in the follow-up were obtained in 496 patients of 681 initially included in the baseline analysis (72.8%), so they could influence the results. However, this percentage is even higher in other longitudinal prospective studies [70] and a bias of withdrawals of more affected patients was excluded after comparing subjects who were lost to follow-up vs. those who were not. Another important aspect is that, due to the large sample size, some differences observed could be statistically significant but not a minimum clinically important difference (e.g., differences detected in motor aspects such as hypomimia, speech, and rigidity) [71], so it is necessary to be cautious about the relevance of some differences detected. Moreover, the observational nature of the study does not provide support for a cause–effect relationship but can only suggest correlation between variables. Furthermore, the medication dose was not adjusted for the body mass index because these data were not collected, but we did do so by weight. On the other hand, and with the intention to reduce the instance of a false positive, we applied the Bonferroni test with a significant p value definition of ≤ 0.002. Finally, we described the differences between men and women with PD in our cohort, but we did not analyze other markers in this manuscript that could explain the reason for them [72]. Nonetheless, the strengths of our study include a large sample size, a very thorough assessment, a prospective longitudinal follow-up design, and the extensive clinical and demographic information recorded.
In conclusion, the present study supports the idea that there are sex differences in PD. Symptoms such as depression, fatigue, or pain seem to be more frequent and/or severe in females, whereas others such as hypomimia, speech problems, rigidity, or hypersexuality were more common in males. Moreover, women could have a worse perception of their QoL. All in all, more studies are needed to better understand the differences between males and females with PD, especially in the long-term follow-up, and their causes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12041329/s1, Coppadis Study Group.

Author Contributions

Conception, organization, and execution of the project; statistical analysis; writing of the first draft of the manuscript; recruitment and/or evaluation of participants: D.S.-G.; collaboration in the preparation of the manuscript, review and critique: A.L., J.H.-V., C.C.B., M.J.F.P., I.G.D. and M.C.Í.-A.; review and critique; recruitment and/or evaluation of participants: J.H.-V., T.d.D.F., S.J., M.T.B., L.P., M.C., J.G.C., N.C., I.L., I.C., L.L.M., I.G.A., M.A.Á.R., V.G.M., V.N., V.P., J.D.G.-S., C.B., B.S.V., M.Á.S., L.V., S.E., E.C., F.C.P., J.C.M.C., P.S.A., M.G.A.L., N.L.A., I.G., J.K., M.M.G., M.S., J.R.M., C.V., M.K., J.G.A., R.A.R., C.O., L.M.L.D. and P.M.; recruitment and/or evaluation of participants: COPPADIS Study Group; review and critique, review of English style: D.M.; review and critique, supervision: P.M.-M. All authors have read and agreed to the published version of the manuscript.

Funding

COPPADIS and the present study were developed with the help of Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético ( https://fundaciondegen.org/) and Alpha Bioresearch (www.alphabioresearch.com). Also, we received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017–2020 por el proyecto “PROGRESIÓN NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and ap-proved by Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 2/DEC/2014).

Informed Consent Statement

For this study, we received approval from the Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 02/DEC/2014) and written informed consents from all participants in this study were obtained. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. Written informed consent from all participants in this study were obtained before the start of the study.

Data Availability Statement

The protocol and the statistical analysis plan are available on request. Deidentified participant data are not available for legal and ethical reasons.

Acknowledgments

We would like to thank all patients and their caregivers who collaborated in this study. Many thanks also to Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético (https://fundaciondegen.org/, accessed on 31 January 2023), Alpha Bioresearch (www.alphabioresearch.com, accessed on 31 January 2023), Instituto de Salud Carlos III, and other institutions for helping us.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Activities For Daily LivingADL
Schwab and England Activities of Daily Living ScaleADLS
Beck Depression Inventory-IiBDI-II
Caregiver Strain IndexCSI
Freezing Of Gait QuestionnaireFOGQ
Levodopa Equivalent Daily DoseLEDD
Non-Motor Symptoms; Non-Motor Symptoms ScaleNMS
Neuropsychiatric InventoryNPI
Parkinson’s DiseasePD
Parkinson’s Disease Cognitive Rating ScalePD-CRS
The 39-Item Parkinson’s Disease Questionnaire Summary IndexPDQ-39
Parkinson’s Disease Sleep ScalePDSS
Quality Of LifeQoL
Questionnaire For Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating ScaleQUIP-RS
Unified Parkinson’s Disease Rating ScaleUPDRS
Visual Analogue ScaleVAS

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Figure 1. (A) Mean score of sub-scores of the UPDRS-III-OFF at baseline in PD males vs. females; *, p < 0.0001. (B) Mean score on each domain of the NMSS at baseline in PD males vs. females; *, p < 0.05; Sleep/fatigue, p = 0.041; Mood/apathy, p = 0.003; Urinary symptoms, p = 0.047; Miscellaneous, p = 0.010.
Figure 1. (A) Mean score of sub-scores of the UPDRS-III-OFF at baseline in PD males vs. females; *, p < 0.0001. (B) Mean score on each domain of the NMSS at baseline in PD males vs. females; *, p < 0.05; Sleep/fatigue, p = 0.041; Mood/apathy, p = 0.003; Urinary symptoms, p = 0.047; Miscellaneous, p = 0.010.
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Figure 2. (A) Mean score of each domain of the PDQ-39 at baseline in PD males vs. females; *, p < 0.05; Mobility, p = 0.01; ADL, Activities of daily living, p = 0.034; Emotional well-being, p < 0.0001; Social support, p = 0.046; Communication, p < 0.0001; Pain and discomfort, p < 0.0001. ADL: Activities of daily living (ADL): (B) Mean score on each domain of the EUROHIS-QOL8 at baseline in PD males vs. females; *, p < 0.05; Quality of life, p = 0.014; Health status, p = 0.020; Energy, p = 0.04.
Figure 2. (A) Mean score of each domain of the PDQ-39 at baseline in PD males vs. females; *, p < 0.05; Mobility, p = 0.01; ADL, Activities of daily living, p = 0.034; Emotional well-being, p < 0.0001; Social support, p = 0.046; Communication, p < 0.0001; Pain and discomfort, p < 0.0001. ADL: Activities of daily living (ADL): (B) Mean score on each domain of the EUROHIS-QOL8 at baseline in PD males vs. females; *, p < 0.05; Quality of life, p = 0.014; Health status, p = 0.020; Energy, p = 0.04.
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Figure 3. Mean and standard deviation at V0, V12M, and V24M in males vs. females in the LEDD (mg/day) and the score on UPDRS-III-OFF, UPDRS-IV, NMSS, and ADLS; *, p < 0.05; **, p < 0.001; ***, p < 0.0001. The symbol above the line represents the significance of the change between one visit and another (in men and women) while the symbol above the point/diamond represents the difference in that visit between men and women. ADLS, Schwab and England Activities of Daily Living Scale; LEDD, levodopa equivalent daily dose; NMSS, Non-Motor Symptoms Scale; UPDRS, Unified Parkinson’s Disease Rating Scale.
Figure 3. Mean and standard deviation at V0, V12M, and V24M in males vs. females in the LEDD (mg/day) and the score on UPDRS-III-OFF, UPDRS-IV, NMSS, and ADLS; *, p < 0.05; **, p < 0.001; ***, p < 0.0001. The symbol above the line represents the significance of the change between one visit and another (in men and women) while the symbol above the point/diamond represents the difference in that visit between men and women. ADLS, Schwab and England Activities of Daily Living Scale; LEDD, levodopa equivalent daily dose; NMSS, Non-Motor Symptoms Scale; UPDRS, Unified Parkinson’s Disease Rating Scale.
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Table
Table 1. Sociodemographic and lifestyle variables and comorbidities in PD patients from the COPPADIS cohort at baseline (V0) regarding sex (n = 681).
Table 1. Sociodemographic and lifestyle variables and comorbidities in PD patients from the COPPADIS cohort at baseline (V0) regarding sex (n = 681).
All Sample (n = 681)Males (n = 410)Females (n = 271)p
Age62.54 ± 8.9362.36 ± 8.7362.8 ± 9.240.297
Education level (%): 0.006
  -Primary42.13848.1
  -Secondary31.531.531.5
  -University26.530.520.4
Civil status (%): <0.0001
  -Married78.483.970
  -Single7.14.411.1
  -Widowed6.83.711.5
  -Divorced6.66.86.3
  -Other1.11.21.1
Living style (%): <0.0001
  -With the partner79.385.170.4
  -Alone10.77.615.6
  -With a son/daughter5.32.79.3
  -Other4.74.64.8
Habitat (%): 0.438
  -Rural (<5.000)11.812.710.4
  -Semiurban (5.000–20.000)18.917.643.8
  -Urban (>20.000)69.469.868.8
Arterial hypertension (%)33.735.5310.229
Diabetes mellitus (%)9.110.37.40.200
Dyslipidemia (%)30.130.130.30.959
Cardiopathy (%)7.9104.80.014
Cardiac arrhythmia (%)5.15.94.10.296
Smoking (%): <0.0001
  -Smoker9.49.59.2
  -Ex-smoker3035.921
  -Non-smoker60.654.569.8
Alcohol consumption (%): <0.0001
  -Excessive drinker0.30.50
  -Non-excessive drinker20.628.48.9
  -Non-drinker79.171.191.1
To be receiving (%):
  -Antidepressant agent24.318.133.3<0.0001
  -Benzodiazepine1611.223.2<0.0001
  -Antipsychotic 2.23.20.70.034
  -Analgesic24.319.8310.002
Number of non-antiparkinsonian drugs2.58 ± 2.462.4 ± 2.362.86 ± 2.60.029
Assistance to a patient association (%)14.11217.40.047
Speech therapy (%)11.311.511.20.925
Physiotherapy (%)2827.628.50.800
Regular exercise (%)69.872.665.60.050
Cognitive stimulation therapy (%)15.815.216.70.598
Chi-square and Mann–Whitney–Wilcoxon test were used. The results represent mean ± SD or %. A p ≤ 0.002 was considered significant (Bonferroni correction).
Table
Table 2. Different PD-related variables in PD patients from the COPPADIS cohort at baseline (V0) regarding sex (n = 681).
Table 2. Different PD-related variables in PD patients from the COPPADIS cohort at baseline (V0) regarding sex (n = 681).
All Sample (n = 681)Males (n = 410)Females (n = 271)p
Disease Treatments
  Years from symptoms onset5.48 ± 4.385.66 ± 4.655.21 ± 4.110.259
  To be receiving (%):
    -Levodopa72.273.570.10.337
    -DA68.872.163.80.024
    -MAO-B inhibitor73.577.267.90.007
    -COMT inhibitor18.620.3160.160
    -Amantadine7.87.190.382
  Number of antiparkinsonian drugs2.43 ± 1.112.32 ± 1.092.51 ± 1.110.011
  Daily dose of levodopa (mg/day)346.13 ± 309.64365.95 ± 319.73316.44 ± 291.960.047
  DA equivalent daily dose (mg/day)167.49 ± 155.08181.06 ± 159.41147.17 ± 146.320.005
  LEDD (mg/day)566.13 ± 515.75607.79 ± 432.61503.71 ± 381.490.002
  Weight (kgs) 75.77 ± 13.7780.89 ± 11.8468.04 ± 12.31<0.0001
  LEDD/Kgs7.64 ± 5.87.61 ± 5.56.69 ± 7.170.676
Motor Symptoms
  HY stage (OFF)2 [2,2]2 [2,2]2 [1.5,2]0.810
    -Stage from 3 to 5 (%)9.58.910.40.521
  UPDRS-III (OFF)22.8 ± 11.2123.24 ± 11.2822.15 ± 11.10.265
  UPDRS-IV2.01 ± 2.411.94 ± 2.822.11 ± 2.580.994
    -Motor fluctuations (%)32.832.533.30.825
    -Dyskinesia (%)18.717.919.80.552
  FOGQ3.79 ± 4.593.79 ± 4.563.79 ± 4.580.994
    -FOG (%)34.535.133.60.680
    -Falls (%)13.110.616.70.022
  Tremoric motor phenotype (%)54.957.750.60.067
Non-Motor Symptoms
  PD-CRS91.27 ± 15.8391.24 ± 15.5991.32 ± 16.210.974
    -Cognitive impairment (%)25.425.525.30.950
  NMSS45.26 ± 37.9943.49 ± 36.8947.94 ± 39.520.208
    -Very severe NMS burden (%)19.518.221.50.289
  BDI-II8.75 ± 7.347.95 ± 6.849.95 ± 7.890.001
    -Major depression (%)16.31222.9<0.0001
  PDSS114.84 ± 26.99115.27 ± 26.95115.27 ± 26.950.408
  QUIP-RS4.33 ± 8.294.67 ± 8.563.83 ± 7.850.049
    -ICD and/or CB (%)1717.416.30.703
  NPI6.06 ± 8.885.54 ± 7.236.86 ± 8.880.362
  VAS-PAIN2.62 ± 2.922.13 ± 2.623.37 ± 3.17<0.0001
    -Pain (%)5751.764.90.001
  VAFS–physical2.95 ± 2.752.55 ± 2.583.57 ± 2.88<0.0001
  VAFS–mental2.16 ± 2.551.91 ± 2.342.54 ± 2.80.012
Autonomy and QOL
  PDQ-39SI17.18 ± 13.5616.05 ± 13.3318.88 ± 13.760.002
  EUROHIS-QOL83.78 ± 0.553.82 ± 0.533.71 ± 0.560.009
  ADLS88.56 ± 10.4588.76 ± 10.0988.26 ± 10.980.835
    -Dependency for ADL (%)97.611.10.113
Chi-square and Mann–Whitney–Wilcoxon test were used. The results represent mean ± SD, median [p25, p75] or %. The value was not available on all variables, with the smallest n being 574 for the NPI. A p ≤ 0.002 was considered significant (Bonferroni correction). It is shown in bold. ADL, activities of daily living; ADLS, Schwab and England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; DA, dopamine agonist; MAO-B, monoamine oxidase-B; COMT, catechol-O-methyltransferase; FOG, freezing of gait; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent daily dose; HY, Hoenh and Yahr; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDSS, Parkinson’s Disease Sleep Scale; VAS-Pain, Visual Analog Scale-Pain; VAFS; Visual Analog Fatigue Scale; QOL, quality of life; PDQ, Parkinson’s disease Questionnaire; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; ICD, impulse control disorder; CB, compulsive behavior; UPDRS, Unified Parkinson’s Disease Rating Scale.
Table
Table 3. Differences in motor aspects, cognition, impulsive-compulsive behaviors, and QoL between men and women with PD from the COPPADIS cohort at baseline (V0) (n = 681).
Table 3. Differences in motor aspects, cognition, impulsive-compulsive behaviors, and QoL between men and women with PD from the COPPADIS cohort at baseline (V0) (n = 681).
All Sample (n = 681)Males (n = 410)Females (n = 271)p
Motor Symptoms
  UPDRS-III-Off22.8 ± 11.2123.24 ± 11.2822.15 ± 11.10.265
      Hypomimia1.16 ± 0.75 1.29 ± 0.760.96 ± 0.69<0.0001
      Speech0.64 ± 0.680.78 ± 0.710.43 ± 0.64<0.0001
      Tremor 3.29 ± 3.153.2 ± 3.193.43 ± 3.090.226
      Rigidity 5.5 ± 3.265.87 ± 3.34.95 ± 3.12<0.0001
      Bradykinesia 6.11 ± 3.785.96 ± 3.76.32 ± 3.90.324
      Axial symptoms 1.77 ± 1.861.67 ± 1.741.93 ± 2.040.613
      Global bradykinesia 1.35 ± 0.91.36 ± 0.881.33 ± 0.920.777
Non-Motor Symptoms
  PD-CRS total score91.27 ± 15.8391.24 ± 15.5991.32 ± 16.210.974
  PD-CRS FS sub-score63.67 ± 14.4963.5 ± 14.5263.93 ± 14.470.794
      Immediate verbal memory8.07 ± 2.17.91 ± 2.138.32 ± 2.030.007
      Sustained attention8.47 ± 1.898.56 ± 1.818.33 ± 20.160
      Working memory6.85 ± 2.47.07 ± 2.386.51 ± 2.380.003
      Clock drawing8.94 ± 1.698.96 ± 1.778.92 ± 1.570.499
      Delayed verbal memory5.54 ± 2.725.36 ± 2.645.81 ± 2.820.049
      Alternating verbal fluency11.25 ± 4.7411.26 ± 4.411.25 ± 4.580.723
      Action verbal fluency14.59 ± 5.6914.44 ± 5.8514.8 ± 5.430.266
  PD-CRS PC sub-score27.6 ± 3.3727.74 ± 3.3127.39 ± 3.460.083
      Confrontation naming18.05 ± 3.0618.23 ± 2.9617.79 ± 3.190.012
      Clock copy9.55 ± 1.219.51 ± 1.299.6 ± 1.050.712
  NMSS45.26 ± 37.9943.49 ± 36.8947.94 ± 39.520.208
      Cardiovascular5.85 ± 10.215.41 ± 10.16.52 ± 10.360.137
      Sleep/fatigue16.42 ± 16.1215.35 ± 15.6318.03 ± 16.720.041
      Mood/apathy11.38 ± 16.459.79 ± 15.1913.78 ± 17.960.003
      Perceptual symptoms 3.13 ± 8.712.86 ± 7.983.52 ± 9.710.529
      Attention/memory 9.97 ± 14.0510 ± 14.139.92 ± 13.960.912
      Gastrointestinal symptoms 9.69 ± 13.1310.51 ± 13.98.46 ± 11.790.057
      Urinary symptoms21.61 ± 22.4822.48 ± 22.2220.29 ± 22.840.047
      Sexual dysfunction18.79 ± 25.6919.1 ± 25.3118.32 ± 26.30.201
      Miscellaneous14.92 ± 15.4913.56 ± 14.4916.98 ± 16.710.010
  QUIP-RS
      Any ICD and/or CB (%)1717.416.30.703
      Any ICD (%)12.212.511.80.782
        Compulsive gambling (%)1.51.90.80.268
        Hypersexuality (%)4.77.60.4<0.0001
        Compulsive shopping (%)2.41.63.70.112
        Compulsive eating (%)6.75.28.90.067
      Any CB (%)9.39.39.30.972
        Hobbyism–punding (%)6.96.86.90.962
        Compulsive medication (%)3.83.83.70.921
Quality of Life
  PDQ-39SI17.18 ± 13.5616.05 ± 13.3318.88 ± 13.760.002
      Mobility16.69 ± 19.3114.59 ± 17.8819.87 ± 20.920.001
      Activities of daily living18.1 ± 18.7119.41 ± 19.6916.11 ± 16.980.034
      Emotional well-being21.4 ± 19.9318.6 ± 18.7225.64 ± 20.97<0.0001
      Stigmatization13.62 ± 19.5713.1 ± 18.9514.4 ± 20.490.665
      Social support8.21 ± 16.557.57 ± 16.889.18 ± 16.020.046
      Cognition19.22 ± 17.8119.14 ± 17.5119.33 ± 18.30.939
      Communication10.3 ± 15.3411.99 ± 16.247.74 ± 13.52<0.0001
      Pain and discomfort26.36 ± 22.7221.46 ± 20.233.76 ± 24.31<0.0001
  EUROHIS-QOL83.78 ± 0.553.82 ± 0.533.71 ± 0.560.009
      Quality of life3.8 ± 0.713.86 ± 0.73.73 ± 0.720.014
      Health status3.16 ± 0.883.23 ± 0.873.07 ± 0.870.020
      Energy3.76 ± 0.823.84 ± 0.773.65 ± 0.880.004
      Autonomy for ADL3.62 ± 0.863.66 ± 0.843.55 ± 0.890.062
      Self-esteem3.81 ± 0.813.87 ± 0.793.73 ± 0.840.054
      Social relationships4.04 ± 0.714.04 ± 0.724.03 ± 0.70.798
      Economic capacity3.86 ± 0.773.9 ± 0.783.81 ± 0.760.095
      Habitat4.23 ± 0.684.25 ± 0.684.21 ± 0.690.383
Chi-square and Mann–Whitney–Wilcoxon test were used. The results represent mean ± SD, median [p25, p75] or %. The value was not available on all variables, with the smallest n being 622 for the UPDRS-III. A p ≤ 0.002 was considered significant (Bonferroni correction). CB, compulsive behavior; ICD, impulse control disorder; NMSS, Non-Motor Symptoms Scale; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; FS; fronto-subcortical; PC, posterior-cortical; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale.
Table
Table 4. Changes from the baseline visit (V0) to the two-year follow-up visit (V24M) in different PD-related variables in PD patients from the COPPADIS cohort regarding sex (n = 496).
Table 4. Changes from the baseline visit (V0) to the two-year follow-up visit (V24M) in different PD-related variables in PD patients from the COPPADIS cohort regarding sex (n = 496).
Males V0 Males V24MCohen’s p aFemales V0 Females V24MCohen’s pbpcpd
n = 294n = 294Testn = 202n = 202Test
Dose therapy
  LEDD (mg/day)625.25 ± 428.6803.88 ± 4550.73<0.0001509.48 ± 381.37719.22 ± 462.010.96<0.00010.2490.007
  LEDD/weight7.61 ± 5.54 10.82 ± 6.070.870.1317.69 ± 6.1710.53 ± 7.510.710.0050.8590.706
Motor Symptoms
  UPDRS-III (OFF)22.84 ± 10.5626.3 ± 12.010.56<0.000120.74 ± 10.3823.76 ± 12.420.41<0.00010.6860.554
  Hypomimia1.24 ± 0.721.35 ± 0.710.220.0140.93 ± 0.660.99 ± 0.730.150.2540.539<0.0001
  Speech0.72 ± 0.720.81 ± 0.750.130.0320.4 ± 0.58 0.46 ± 0.640.040.0840.808<0.0001
  Tremor 3.3 ± 3.182.36 ± 2.62−0.47<0.00013.26 ± 0.212.41 ± 0.19−0.34<0.00010.8890.763
  Rigidity 5.83 ± 3.216.1 ± 3.620.170.1314.76 ± 2.995.22 ± 3.190.180.0300.5140.018
  Bradykinesia5.86 ± 3.67.3 ± 4.190.55<0.00016.16 ± 3.767.02 ± 4.370.290.0010.2530.226
  Axial symptoms1.67 ± 1.763.03 ± 2.190.72<0.00012 ± 2.013.16 ± 2.310.41<0.00010.4620.237
  Global bradykinesia1.37 ± 0.891.6 ± 0.930.39<0.00011.32 ± 0.921.46 ± 1.050.190.0340.4240.898
  UPDRS-IV1.91 ± 2.252.46 ± 2.640.31<0.00012.08 ± 2.62.94 ± 2.890.47<0.00010.1640.105
FOGQ3.65 ± 4.614.83 ± 5.170.43<0.00013.95 ± 4.854.97 ± 5.160.340.0010.3760.014
Non-Motor Symptoms
  PD-CRS91.61 ± 15.5589.89 ± 17.22−0.210.01192.4 ± 15.990.92 ± 19.35−0.150.0680.8860.615
  PD-CRS FS sub-score63.84 ± 14.2961.99 ± 15.88−0.220.00364.75 ± 14.4463.2 ± 17.24−0.120.0290.8640.237
  PD-CRS PC sub-score27.98 ± 3.1427.97 ± 2.9−0.030.95027.55 ± 3.35 27.25 ± 3.5−0.110.2000.4490.021
  NMSS 42.44 ± 35.8152.25 ± 41.450.43<0.000148.99 ± 40.0855.59 ± 43.880.250.0130.4690.012
    -Cardiovascular4.65 ± 8.8211.73 ± 14.860.71<0.00016.58 ± 11.112.06 ± 13.260.57<0.00010.3000.207
    -Sleep/fatigue14.71 ± 14.9818.8 ± 17.840.33<0.000118.29 ± 16.6519.83 ± 17.230.110.2120.0860.028
    -Mood/apathy9.2 ± 14.311.2 ± 16.770.330.01514.2 ± 17.9716 ± 19.490.10.1590.934<0.0001
    -Perceptual symptoms 2.98 ± 8.965.55 ± 13.290.37<0.00013.94 ± 10.395.43 ± 11.720.170.0820.2750.466
    -Attention/memory 10.1 ± 14.8412.59 ± 16.810.270.00410.15 ± 14.6512.68 ± 17.720.220.0390.9710.723
    -Gastrointestinal10.11 ± 13.7611.82 ± 13.990.240.0189.02 ± 12.5112.67 ± 14.880.38<0.00010.1230.984
    -Urinary symptoms22.35 ± 21.7922.63 ± 22.440.020.10921.02 ± 23.7121.94 ± 23.360.110.5170.2370.493
    -Sexual dysfunction18.64 ± 24.9624.77 ± 28.50.31<0.000119.04 ± 26.9819.25 ± 26.270.020.8210.1010.219
    -Miscellaneous13.01 ± 14.0614.39 ± 14.110.190.08317.45 ± 17.1218.77 ± 16.780.110.3050.921<0.0001
  BDI-II7.34 ± 6.478.23 ± 7.230.160.0439.52 ± 8.489.02 ± 7.92−0.080.4170.0620.003
  PDSS117.78 ± 24.3117.71 ± 25.86−0.040.962115.89 ± 25.13117.97 ± 24.090.110.2600.5530.160
  QUIP-RS4.98 ± 9.215.12 ± 9.590.030.8153.57 ± 6.983.63 ± 8.290.020.9120.9540.187
  NPI5.39 ± 7.525.51± 9.010.020.8396.67 ± 8.647.27 ± 10.120.070.4060.4920.014
  VAS-PAIN2.11 ± 2.682.32 ± 2.590.120.2403.31 ± 3.153.78 ± 2.990.150.0790.398<0.0001
  VAFS–physical2.51 ± 2.542.77 ± 2.650.150.1373.29 ± 2.823.68 ± 2.940.130.0880.551<0.0001
VAFS–mental1.86 ± 2.292.01 ± 2.450.110.3532.39 ± 2.76 2.37 ± 2.7900.9370.005N. A.
Autonomy and QOL
  PDQ-39SI15.37 ± 12.7517.96 ± 15.450.32<0.000118.49 ± 13.4523.27 ± 17.240.53<0.00010.027N. A.
  EUROHIS-QOL83.82 ± 0.493.76 ± 0.56−0.130.0633.69 ± 0.573.72 ± 0.610.070.0460.040N. A.
  ADLS89.12 ± 9.0885.23 ± 12.580.49<0.000187.91 ± 11.4282.76 ± 14.690.57<0.00010.1760.001
p values were computed using general linear models (GLM) repeated measures. The results represent mean ± SD. The value was not available on all variables, with the smallest n being 387 for the UPDRS-III; p a, change over time (V24M vs. V0) in males; p b, change over time (V24M vs. V0) in females. Age at V0, and LEDD (levodopa equivalent daily dose) (except for assessing changes in this variable) at V0 and at V24M were included as covariates; p c, group visit interaction; p d, males vs. females. Males vs. females is not applicable if test of interaction was significant (a significant test of interaction means the rates of changes over time are different between the two groups). All patients with the data at V0 and V24M were included for each comparative analysis. A p < 0.002 (in bold) was considered significant (Bonferroni correction). ADLS, Schwab and England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent daily dose; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; FS, fronto-subcortical; PC, posterior-cortical; PDSS, Parkinson’s Disease Sleep Scale; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; QoL, quality of life; PDQ.39, the 39-item Parkinson’s disease Questionnaire; VAS-Pain, Visual Analog Scale-Pain.
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MDPI and ACS Style

Santos-García, D.; Laguna, A.; Hernández-Vara, J.; de Deus Fonticoba, T.; Cores Bartolomé, C.; Feal Painceiras, M.J.; Íñiguez-Alvarado, M.C.; García Díaz, I.; Jesús, S.; Boungiorno, M.T.; et al. Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson’s Disease. J. Clin. Med. 2023, 12, 1329. https://doi.org/10.3390/jcm12041329

AMA Style

Santos-García D, Laguna A, Hernández-Vara J, de Deus Fonticoba T, Cores Bartolomé C, Feal Painceiras MJ, Íñiguez-Alvarado MC, García Díaz I, Jesús S, Boungiorno MT, et al. Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson’s Disease. Journal of Clinical Medicine. 2023; 12(4):1329. https://doi.org/10.3390/jcm12041329

Chicago/Turabian Style

Santos-García, Diego, Ariadna Laguna, Jorge Hernández-Vara, Teresa de Deus Fonticoba, Carlos Cores Bartolomé, Maria J. Feal Painceiras, Maria Cristina Íñiguez-Alvarado, Iago García Díaz, Silvia Jesús, Maria Teresa Boungiorno, and et al. 2023. "Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson’s Disease" Journal of Clinical Medicine 12, no. 4: 1329. https://doi.org/10.3390/jcm12041329

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