Motor Fluctuations Development Is Associated with Non-Motor Symptoms Burden Progression in Parkinson’s Disease Patients: A 2-Year Follow-Up Study

Citation: Santos-García, D.; de Deus Fonticoba, T.; Bartolomé, C.C.; Painceiras, M.J.F.; Castro, E.S.; Canfield, H.; Miró, C.M.; Jesús, S.; Aguilar, M.; Pastor, P.; et al. Motor Fluctuations Development Is Associated with Non-Motor Symptoms Burden Progression in Parkinson’s Disease Patients: A 2-Year Follow-Up Study. Diagnostics 2022,12, 1147. https://doi.org/ 10.3390/diagnostics12051147 Academic Editor: Aldo Quattrone Received: 30 March 2022 Accepted: 29 April 2022 Published: 5 May 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). diagnostics Article Motor Fluctuations Development Is Associated with Non-Motor Symptoms Burden Progression in Parkinson’s Disease Patients: A 2-Year Follow-Up Study Diego Santos-García1,* , Teresa de Deus Fonticoba 2, Carlos Cores Bartolomé1, Maria J. Feal Painceiras 1, Ester Suárez Castro 2, Héctor Canfield 2, Cristina Martínez Miró1, Silvia Jesús3,4, Miquel Aguilar 5, Pau Pastor 5, Lluís Planellas 6, Marina Cosgaya 7, Juan García Caldentey 8, Nuria Caballol 9, Ines Legarda 10, Jorge Hernández-Vara 4,11, Iria Cabo 12, Lydia López Manzanares 13, Isabel González Aramburu 4,14, Maria A. Ávila Rivera 15, Víctor Gómez Mayordomo 16, Víctor Nogueira 17, Víctor Puente 18, Julio Dotor García-Soto 19, Carmen Borrué20, Berta Solano Vila 21, MaríaÁlvarez 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 Gastón31, Jaime Kulisevsky 4,32, Marta Blázquez Estrada 33, Manuel Seijo 12, Javier Rúiz Martínez 34, Caridad Valero 35, Mónica Kurtis 36, Oriol de Fábregues 11, Jessica González Ardura 37, Ruben Alonso Redondo 38, Carlos Ordás39, Luis M. López Díaz 40, Darrian McAfee 41, Pablo Martinez-Martin 4, Pablo Mir 3,4 and COPPADIS Study Group † 1 Department of Neurology, Hospital Universitario de A Coruña (HUAC), Complejo Hospitalario Universitario de A Coruña (CHUAC), C/As Xubias 84, 15006 A Coruña, Spain 2CHUF, Complejo Hospitalario Universitario de Ferrol, 15006 A Coruña, Spain 3Unidad 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 4CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), 28031 Madrid, Spain 5Hospital Universitari Mutua de Terrassa, 08221 Terrassa, Barcelona, Spain 6Clínica del Pilar, 08006 Barcelona, Spain 7Hospital Clínic de Barcelona, 08036 Barcelona, Spain 8Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain 9Consorci Sanitari Integral, Hospital Moisés Broggi, 08970 Sant Joan Despí, Barcelona, Spain 10 Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain 11 Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain 12 Complejo Hospitalario Universitario de Pontevedra (CHOP), 36071 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, Lugo, Spain 18 Hospital del Mar, 08003 Barcelona, Spain 19 Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain 20 Hospital Infanta Sofía, 28703 Madrid, Spain 21 Institut d’Assistència Sanitària (IAS)—Institut Catalàde 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, Tarragona, Spain 25 Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain 26 Hospital Universitario de Canarias, 38320 San Cristóbal de la Laguna, Santa Cruz de Tenerife, 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), 36213 Vigo, Spain 30 Complejo Hospitalario de Toledo, 45004 Toledo, Spain 31 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain 32 Hospital de Sant Pau, 08041 Barcelona, Spain 33 Hospital Universitario Central de Asturias, 33011 Oviedo, Spain 34 Hospital Universitario Donostia, 20014 San Sebastián, Spain 35 Hospital Arnau de Vilanova, 46015 Valencia, Spain 36 Hospital Ruber Internacional, 28034 Madrid, Spain Diagnostics 2022,12, 1147. https://doi.org/10.3390/diagnostics12051147 https://www.mdpi.com/journal/diagnostics Diagnostics 2022,12, 1147 2 of 18 37 Hospital de Cabueñes, 33394 Gijón, Spain 38 Hospital Universitario Lucus Augusti (HULA), 27003 Lugo, Spain 39 Hospital Rey Juan Carlos, 28933 Madrid, Spain 40 Complejo Hospitalario Universitario de Orense (CHUO), 32005 Orense, Spain 41 University of Maryland School of Medicine, Baltimore, MD 21201, USA *Correspondence: [email protected]; Tel.: +34-646173341 † Collaborators/Membership of the COPPADIS Study Group is provided in the Appendix A. Abstract: Objective: The aim of the present study was to analyze the progression of non-motor symptoms (NMS) burden in Parkinson’s disease (PD) patients regarding the development of motor fluctuations (MF). Methods: PD patients without MF at baseline, who were recruited from January 2016 to November 2017 (V0) and evaluated again at a 2-year follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this analysis. MF development at V2 was defined as a score ≥ 1 in the item-39 of the UPDRS-Part IV, whereas NMS burden was defined according to the Non-motor Symptoms Scale (NMSS) total score. Results: Three hundred and thirty PD patients (62.67 ±8.7 years old; 58.8% males) were included. From V0 to V2, 27.6% of the patients developed MF. The mean NMSS total score at baseline was higher in those patients who developed MF after the 2-year follow-up (46.34 ± 36.48 vs. 34.3 ± 29.07; p= 0.001). A greater increase in the NMSS total score from V0 to V2 was observed in patients who developed MF (+16.07 ± 37.37) compared to those who did not develop MF (+6.2 ± 25.8) (p= 0.021). Development of MF after a 2-year follow-up was associated with an increase in the NMSS total score ( β = 0.128; p= 0.046) after adjustment to age, gender, years from symptoms onset, levodopa equivalent daily dose (LEDD) and the NMSS total score at baseline, and the change in LEDD from V0 to V2. Conclusions: In PD patients, the development of MF is associated with a greater increase in the NMS burden after a 2-year follow-up. Keywords: burden; follow-up; non-motor symptoms; motor fluctuations; Parkinson’s disease 1. Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms (NMS) that result in disability, loss of patient autonomy, and diminished quality of life (QoL) [ 1 ]. From a pathophysiological point of view, motor symptoms in PD are attributed to the degeneration of the dopaminergic nigrostriatal system [ 2 ]. Nevertheless, increasing evidence has shown that PD is a multisystem disorder characterized also by the degeneration of the mesocortical dopaminergic system, the noradrenergic system of the locus coeruleus, the serotonergic system of the dorsal raphe nuclei, and the cholinergic system of the nucleus basalis of Meynert, as well as the histaminergic, peptidergic, and olfactory-related systems [ 3 ]. This explains the complexity in management of NMS in PD and why many therapeutic strategies are based on correcting the deficit of neurotransmitters other than dopamine [ 4 ]. However, NMS can be related to dopamine as well. Increasing dopamine activity not only in the striatum but also in other areas of the brain could improve some NMS such as attention, executive functions, apathy, depression, anxiety, restless legs and periodic limb movements, urinary urgency, nocturia, dribbling of saliva, constipation, pain, or fatigue [ 5 – 9 ]. Moreover, NMS can be related to dopamine changes in brain and blood [ 10 ]. Thus, some patients can suffer from non-motor fluctuations (NMF) (i.e., NMS that fluctuate during the day) [ 11 ] or can experience motor fluctuations (MF) with the development of NMS during the OFF episodes (e.g., pain associated with dystonia) [ 12 ]. The close connection of NMF and MF strongly suggests that the strategies used to treat motor complications—namely, continuous dopaminergic stimulation—also apply for the therapy of NMF. Thus, a dopaminergic treatment reducing the daily OFF time can improve some NMS [ 9 , 13 , 14 ] or even the global NMS burden [ 15 , 16 ]. In line with this, we demonstrated recently in a cross-sectional study conducted in Spain that MF are frequent and associated with a greater NMS burden even during the first 5 years of disease duration [ 17 ]. This is of great importance because NMS burden is associated with a Diagnostics 2022,12, 1147 3 of 18 worse QoL and is also an independent predictor of clinically significant QoL impairment in PD [18,19]. In this context, we hypothesized that PD patients who develop MF in the short-term will increase their NMS burden compared with those patients who do not. Understanding this potential association is of interest because, in clinical practice, to detect MF is an essential point for the application of management strategies in PD [ 20 ]. The aim of the present study was to analyze the progression of NMS burden in PD patients from a Spanish cohort regarding the development of MF after a 2-year follow-up. Moreover, the change in health-related quality of life (HR-QoL) and global QoL (GQoL) was analyzed as well. 2. Material and Methods PD patients without MF at baseline, who were recruited from 35 centers of Spain from the COPPADIS cohort [ 21 ] from January 2016 to November 2017 and evaluated again at 2-year follow-up, were included in the study. Methodology about COPPADIS-2015 study can be consulted in https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0548-9 accessed on 25 February 2016 [ 22 ]. This is a multicenter, observational, longitudinalprospective, 5-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 [22]. In PD subjects, information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected at baseline (visit V0) and at 2 years ± 1 month (visit V2). V0 and V2 evaluations included motor assessment (Hoenh & Yahr [H&Y], Unified Parkinson’s Disease Rating Scale [UPDRS] part III and part IV, Freezing of Gait Questionnaire [FOGQ]), NMS (Non-Motor Symptoms Scale [NMSS], Parkinson’s Disease Sleep Scale [PDSS], Visual Analog Scale-Pain [VAS-Pain], Visual Analog Fatigue Scale [VAFS]), cognition (PD-CRS), mood and neuropsychiatric symptoms (Beck Depression Inventory-II [BDI-II], Neuropsychiatric Inventory [NPI], Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale [QUIP-RS]), disability (Schwab & England Activities of Daily Living Scale [ADLS]), and QoL (the 39-item Parkinson’s disease Questionnaire [PDQ-39], the EUROHIS-QOL 8-item index [EUROHIS-QOL8]) [ 22 ]. In all the scales/questionnaires, a higher score indicates a more severe affectation except for PD-CRS, PDSS, ADLS, and EUROHIS-QOL8, where it is opposite. MF were defined according to the Unified Parkinson’s Disease Rating Scale–Part IV (UPDRS-IV) [ 23 ]. Patients with a score = 0 on item-39 of the UPDRS-IV ( UPDRS-IV-39 ) were considered as without MF whereas those with a UPDRS-IV-39 score ≥ 1 were defined as with MF. For this study, patients from the COPPADIS cohort who presented with MF (i.e., UPDRS-IV-39 ≥ 1) at baseline were excluded. In patients with MF, the motor assessment was made during the OFF state (without medication in the last 12 h) and during the ON state. On the other hand, the assessment was only performed without medication in patients without MF. Other data about motor complications were obtained from the UPDRS-IV. The NMS burden was defined according to the NMSS total score [ 24 ]. The NMSS includes 30 items, each with a different non-motor symptom. The symptoms refer to the 4 weeks prior to assessment. The total score for each item is the result of multiplying the frequency (0, never; 1, rarely; 2, often; 3, frequent; 4, very often) × severity (1, mild; 2, moderate ; 3, severe) and will vary from 0 to 12 points. The scale score ranges from 0 to 360 points. The items are grouped into 9 different domains: (1) Cardiovascular (items 1 and 2; score, 0 to 24); (2) Sleep/fatigue (items 3, 4, 5, and 6; score, 0 to 48); (3) Mood/apathy (items 7, 8, 9, 10, 11, and 12; score, 0 to 72); (4) Perceptual problems/hallucinations (items 13, 14, and 15; score, 0 to 36); (5) Attention/memory (items 16, 17, and 18; score, 0 to 36); (6) Gastrointestinal symptoms (items 19, 20, and 21; score 0 to 36); (7) Urinary symptoms (items 22, 23, and 24; score, 0 to 36); (8) Sexual dysfunction (items 25 and 26; score 0 to 24 ); (9) Miscellaneous (items 27, 28, 29, and 30; score, 0 to 48). Regarding the NMS burden, different groups were defined: mild (NMSS 1–20); moderate (NMSS 21–40); severe (NMSS 41–70); very severe (NMSS > 70) [25]. Diagnostics 2022,12, 1147 4 of 18 The PDQ-39 [ 26 ] and EUROHIS-QOL8 [ 27 ] were used to assess the HRQoL and GQoL, respectively. The PDQ-39 includes 39 items grouped into 8 domains: (1) Mobility ( items 1 to 10 ); (2) Activities of daily living (ADL) (items 11 to 16); (3) Emotional wellbeing (items 17 to 22); (4) Stigma (items 23 to 26); (5) Social support (items 27 to 29); (6) Cognition (items 30 to 33); (7) Communication (items 34 to 36); (8) Pain and discomfort (items 37 to 39 ). For each item, the score may range from 0 (never) to 4 (always). The symptoms refer to the 4 weeks prior to assessment. Domain total scores are expressed as a percentage of the corresponding maximum possible score and a Summary Index is obtained as average of the domain scores. The EUROHIS-QOL8 is an 8-item GQoL questionnaire (quality of life, health status, energy, autonomy for ADL, self-esteem, social relationships, economic capacity, and habitat) derived from the WHOQOL-BREF. For each item, the score ranges from 0 (not at all) to 5 (completely). The total score is expressed as the mean of the individual scores. A higher score indicates a better QoL. 3. Data Analysis Data were processed using SPSS 20.0 for Windows. Only PD patients from the COPPADIS cohort with data of the UPDRS-IV and NMSS total score collected at both visits, V0 and V2, were included in the analysis. For comparisons between patients with vs. without MF at V2, the Student’s t-test, Mann–Whitney U test, Chi-square test, or Fisher test were used as appropriate (distribution for variables was verified by one-sample KolmogorovSmirnov test). Spearman’s or Pearson’s correlation coefficient, as appropriate, were used for analyzing the relationship between the change from V0 to V2 in continuous variables (NMSS, PDQ-39SI, EUROHIS-QOL8). Correlations were considered weak for coefficient values ≤ 0.29, moderate for values between 0.30 and 0.59, and strong for values ≥ 0.60. Marginal homogeneity tests were applied for comparing the frequency distribution of groups (NMS burden; from mild to very severe) between V0 and V2. General linear model (GLM) repeated measure was used to test whether the mean differences of the total score and each domain of the NMSS, PDQ-39SI, and EUROHIS-QOL8 between the two visits (V0 and V2) were significant. The Bonferroni method was used as a post-hoc test after ANOVA. Cohen’s d formula was applied for measuring the effect size; it was considered as follows: <0.2—Negligible; 0.2–0.49—Small; 0.50–0.79—Moderate; ≥ 0.80—Large. Age, gender, years from symptoms onset, H&Y stage, levodopa equivalent daily dose (LEDD) and the NMSS total score at baseline, and the change in LEDD from V0 to V2 were included as covariates in the model. The total score of each scale at V0 (NMSS, PDQ-39SI, and EUROHIS-QOL8) was included as covariate for the analysis of their domains. With the aim to investigate if the development of MF from V0 to V2 was an independent factor associated with an increase in the NMS burden and impairment in the QoL, linear regression models with the change from V0 to V2 in the total score of the NMSS, PDQ-39SI, and EUROHIS-QOL8 (these variables as dependent variable in each model) were conducted. In all cases, the analysis was adjusted to age, gender, years from symptoms onset, H&Y stage, LEDD and the NMSS total score at baseline, and the change in LEDD from V0 to V2. The p-value was considered significant when it was <0.05. 4. Standard Protocol Approvals, Registrations, and Patient Consents For this study, we received approval from the Comitéde Ética de la Investigación Clínica de Galicia in Spain (2014/534; 02/DEC/2014). Written informed consent was obtained from all participants in this study. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Postauthorization Prospective Follow-up study with the code COH-PAK-2014-01. 5. Data Availability The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Diagnostics 2022,12, 1147 5 of 18 6. Results Three hundred and thirty PD patients (62.67 ± 8.7 years old; 58.8% males) without MF at baseline were included. From V0 to V2, 27.6% of the patients (91/330) developed MF. In the group of patients with MF at V2, OFF episodes were predictable in 89% of the cases and unpredictable in 15.4%; early morning dystonia was reported by 25.3% of the patients; and the proportion of the waking day during the OFF state was 82.4% from 1 to 25%, 16.5% from 26 to 50%, and only 1 patient with >50%. Thirty-six out of 91 patients who developed MF (39.6%) presented dyskinesia as well, being disabling in 15 patients (15/36; 41.7%). Compared with those patients who did not develop MF from V0 to V2, at V0, patients who presented with MF at V2 were younger (60.75 ± 9.06 vs. 63.41 ± 8.46 years old; p= 0.012 ), had a longer disease duration (5.36 ± 3.51 vs. 3.65 ± 3.09 years from symptoms onset; p< 0.0001); were receiving more dopaminergic medication; and had a worse status in terms of motor symptoms, NMS, QoL, and autonomy for ADL (Table 1). The mean NMSS total score at baseline was higher in those patients who developed MF after the 2-year follow-up than in those who did not develop MF (46.34 ± 36.48 vs. 34.3 ± 29.07; p= 0.001 ) (Table 1and Figure 1). At V0, the frequency of severe and very severe NMS burden was higher in those patients who developed MF at V2 compared with those who did not (27.5% vs. 18% and 18.7% vs. 12.1%, respectively; p= 0.011) (Figure 2). Table 1. Different PD-related variables in PD patients who developed MF at V2 (MF at V2; N = 91) compared with those patients who did not develop MF at V2 (nonMF at V2; N = 239). All Sample (N = 330) nonMF at V2 (N = 239) MF at V2 (N = 91) p Males (%) 58.8 59.8 56 0.308 At V0 Age 62.67 ±8.7 63.41 ±8.46 60.75 ±9.06 0.012 Years from symptoms onset 4.13 ±3.3 3.65 ±3.09 5.36 ±3.51 <0.0001 Time on levodopa therapy (months) 18.99 ±27.99 14.71 ±24.37 29.65 ±33.25 <0.0001 Daily dose of levodopa (mg/day) 231.85 ±257.89 175.74 ±216.46 379.62 ±298.07 <0.0001 DA equivalent daily dose (mg/day) 152.77 ±149.36 143.21 ±148.24 177.96 ±150.18 0.047 LEDD (mg/day) 437.71 ±325.85 372.62 ±283.4 609.1 ±367.38 <0.0001 H&Y stage (OFF) 0.277 Stage from 1 to 3 99.7 100 98.8 Stage from 4 to 5 0.3 0 1.2 UPDRS-III (OFF) 18.9 ±9.54 17.57 ±8.81 22.4 ±10.51 <0.0001 UPDRS-IV 0.71 ±0.87 0.66 ±0.79 0.86 ±1.05 0.241 FOGQ 1.97 ±3.13 1.56 ±2.51 3.06 ±4.19 <0.0001 Tremotic motor phenotype (%) 55.5 59 46.2 0.024 PD-CRS 92.93 ±15.17 92.32 ±15.39 94.51 ±14.55 0.205 NMSS 37.62 ±31.69 34.3 ±29.07 46.34 ±36.48 0.001 BDI-II 7.49 ±6.63 6.98 ±6.33 8.82 ±7.22 0.037 PDSS 119.82 ±23.36 122.41 ±22.02 113.01 ±25.45 <0.0001 QUIP-RS 3.68 ±7.44 2.72 ±5.94 6.42 ±10.15 <0.0001 NPI 4.43 ±6.62 4.22 ±6.41 4.95 ±7.13 0.381 VAS–PAIN 2.31 ±2.8 2.22 ±2.76 2.54 ±2.91 0.363 VASF–physical 2.43 ±2.57 2.27 ±2.54 2.86 ±2.61 0.050 VASF–mental 1.86 ±2.45 1.75 ±2.42 2.17 ±2.51 0.084 PDQ-39SI 13.08 ±10.59 11.44 ±9.16 17.39 ±12.74 <0.0001 EUROHIS-QOL8 3.87 ±0.51 3.92 ±0.5 3.74 ±0.49 0.006 S&E-ADLS 91.12 ±8.04 92.05 ±7.24 88.68 ±9.45 0.001 Change at V2 (V2 vs. V0) Daily dose of levodopa (mg/day) +126.73 ±190.01 +113.37 ±186.82 +161.89 ±208.83 0.021 DA equivalent daily dose (mg/day) +13.35 ±188.95 +6.32 ±117.41 +31.85 ±306.18 0.288 LEDD (mg/day) +190.55 ±278.38 +158.22 ±222.42 +275.65 ±377.62 0.008 Diagnostics 2022,12, 1147 6 of 18 Table 1. Cont. All Sample (N = 330) nonMF at V2 (N = 239) MF at V2 (N = 91) p UPDRS-III (OFF) +3.5 ±9.73 +2.11 ±8.61 +7.01 ±11.46 <0.0001 UPDRS-IV +1.02 ±2.09 +0.09 ±1.03 +3.5 ±2.18 <0.0001 FOGQ +1.37 ±3.63 +0.94 ±3.18 +2.52 ±4.44 0.001 PD-CRS −0.9 ±10.87 −0.79 ±11.49 −1.19 ±9.11 0.873 NMSS +8.91 ±29.77 +6.2 ±25.8 +16.03 ±37.37 0.021 BDI-II +0.46 ±7.16 +0.33 ±7.2 +0.8 ±7.07 0.463 PDSS +0.61 ±23.46 +1.05 ±22.26 −0.55 ±26.42 0.654 QUIP-RS +0.79 ±8.74 +0.93 ±7.45 +0.42 ±11.56 0.564 NPI +0.4 ±8.45 −0.23 ±8.51 +1.89 ±8.15 0.270 VAS–PAIN +0.47 ±3.15 +0.33 ±3.13 +0.86 ±3.17 0.109 VASF–physical +0.57 ±2.84 +0.42 ±2.85 +0.94 ±2.79 0.216 VASF–mental +0.12 ±2.75 −0.07 ±2.61 +0.65 ±3.04 0.062 PDQ-39SI +3.85 ±10.18 +3.01 ±9.15 +6.09 ±12.28 0.005 EUROHIS-QOL8 −0.05 ±0.56 −0.03 ±0.55 −0.12 ±0.58 0.249 S&E-ADLS −3.87 ±9.73 −3.4 ±9.35 −5.11 ±10.62 0.177 Chi-square and Mann–Whitney–Wilcoxon tests were used. The results represent mean ± SD or %. ADLS, Schwab and England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; DA, dopamine agonist; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent daily dose; N, number; NMSS, Non-motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDSS, Parkinson’s Disease Sleep Scale; QUIP-RS, Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease-Rating Scale; TS, total score; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS–Pain, Visual Analog Scale–Pain. Diagnostics 2022, 12, x FOR PEER REVIEW 6 of 23 PDQ-39SI 13.08 ± 10.59 11.44 ± 9.16 17.39 ± 12.74 <0.0001 EUROHIS-QOL8 3.87 ± 0.51 3.92 ± 0.5 3.74 ± 0.49 0.006 S&E-ADLS 91.12 ± 8.04 92.05 ± 7.24 88.68 ± 9.45 0.001 Change at V2 (V2 vs. V0) Daily dose of levodopa (mg/day) +126.73 ± 190.01 +113.37 ± 186.82 +161.89 ± 208.83 0.021 DA equivalent daily dose (mg/day) +13.35 ± 188.95 +6.32 ± 117.41 +31.85 ± 306.18 0.288 LEDD (mg/day) +190.55 ± 278.38 +158.22 ± 222.42 +275.65 ± 377.62 0.008 UPDRS-III (OFF) +3.5 ± 9.73 +2.11 ± 8.61 +7.01 ± 11.46 <0.0001 UPDRS-IV +1.02 ± 2.09 +0.09 ± 1.03 +3.5 ± 2.18 <0.0001 FOGQ +1.37 ± 3.63 +0.94 ± 3.18 +2.52 ± 4.44 0.001 PD-CRS −0.9 ± 10.87 −0.79 ± 11.49 −1.19 ± 9.11 0.873 NMSS +8.91 ± 29.77 +6.2 ± 25.8 +16.03 ± 37.37 0.021 BDI-II +0.46 ± 7.16 +0.33 ± 7.2 +0.8 ± 7.07 0.463 PDSS +0.61 ± 23.46 +1.05 ± 22.26 −0.55 ± 26.42 0.654 QUIP-RS +0.79 ± 8.74 +0.93 ± 7.45 +0.42 ± 11.56 0.564 NPI +0.4 ± 8.45 −0.23 ± 8.51 +1.89 ± 8.15 0.270 VAS– PAIN +0.47 ± 3.15 +0.33 ± 3.13 +0.86 ± 3.17 0.109 VASF–physical +0.57 ± 2.84 +0.42 ± 2.85 +0.94 ± 2.79 0.216 VASF–mental +0.12 ± 2.75 −0.07 ± 2.61 +0.65 ± 3.04 0.062 PDQ-39SI +3.85 ± 10.18 +3.01 ± 9.15 +6.09 ± 12.28 0.005 EUROHIS-QOL8 −0.05 ± 0.56 −0.03 ± 0.55 −0.12 ± 0.58 0.249 S&E-ADLS −3.87 ± 9.73 −3.4 ± 9.35 −5.11 ± 10.62 0.177 Chi-square and Mann–Whitney–Wilcoxon tests were used. The results represent mean ± SD or %. ADLS, Schwab and England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; DA, dopamine agonist; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent daily dose; N, number; NMSS, Non-motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDSS, Parkinson’s Disease Sleep Scale; QUIP-RS, Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease-Rating Scale; TS, total score; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS–Pain, Visual Analog Scale–Pain. (A) (B) Figure 1. (A) NMSS total score (y-axis) at baseline (V0) and after a 2-year follow-up (V2) in PD patients who developed MF at V2 (MF at V2 (PD-MFV2); N = 91) and those patients who did not develop MF at V2 (nonMF at V2 (PD-nonMFV2); N = 239). NMSS total score at V0, PD-MFV2 vs. PDnonMFV2, p = 0.001; NMSS total score at V2, PD-MFV2 vs. PD-nonMFV2, p < 0.0001; change in the NMSS total score from V0 to V2 in PD-MFV2, p < 0.0001; change in the NMSS total score from V0 to V2 in PD-nonMFV2, p < 0.0001; comparison between the change in the NMSS total score from V0 to Figure 1. ( A ) NMSS total score (y-axis) at baseline (V0) and after a 2-year follow-up (V2) in PD patients who developed MF at V2 (MF at V2 (PD-MF V2 ); N = 91) and those patients who did not develop MF at V2 (nonMF at V2 (PD-nonMF V2 ); N = 239). NMSS total score at V0, PD-MFV2 vs. PD-nonMFV2 , p= 0.001 ; NMSS total score at V2, PD-MF V2 vs. PD-nonMF V2 ,p< 0.0001; change in the NMSS total score from V0 to V2 in PD-MF V2 ,p< 0.0001; change in the NMSS total score from V0 to V2 in PD-nonMF V2 ,p< 0.0001; comparison between the change in the NMSS total score from V0 to V2 in PD-MF V2 vs. PD-nonMF V2 ,p= 0.021. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). ( B ) Mean score on each domain of the NMSS at V0 and at V2 in both groups, PD-MF V2 and PD-nonMF V2 . At V0, the difference was significant between Diagnostics 2022,12, 1147 7 of 18 both groups in NMSS-1 (Cardiovascular) (p= 0.001), NMSS-2 (Sleep/fatigue) (p= 0.001), NMSS-4 (Perceptual symptoms) (p< 0.0001), and NMSS-9 (Miscellaneous) (p= 0.005). At V2, the difference was significant between both groups in all domains (pvalues from 0.024 to <0.0001) except in NMSS-5 (Attention/memory) (p= 0.364). pvalues were computed using the Kolmogorov–Smirnov, Mann–Whitney , and Wilcoxon tests. Mild outliers (O) are data points that are more extreme than Q1 −1.5 * IQR or Q3 + 1.5 * IQR. Diagnostics 2022, 12, x FOR PEER REVIEW 7 of 23 V2 in PD-MFV2 vs. PD-nonMFV2, p = 0.021. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). (B) Mean score on each domain of the NMSS at V0 and at V2 in both groups, PD-MFV2 and PD-nonMFV2. At V0, the difference was significant between both groups in NMSS-1 (Cardiovascular) (p = 0.001), NMSS-2 (Sleep/fatigue) (p = 0.001), NMSS-4 (Perceptual symptoms) (p < 0.0001), and NMSS-9 (Miscellaneous) (p = 0.005). At V2, the difference was significant between both groups in all domains (p values from 0.024 to <0.0001) except in NMSS-5 (Attention/memory) (p = 0.364). p values were computed using the Kolmogorov– Smirnov, Mann–Whitney, and Wilcoxon tests. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 * IQR or Q3 + 1.5 * IQR. Figure 2. Frequency of patients with mild (NMSS 1–20), moderate (NMSS 21–40), severe (NMSS 41– 70), and very severe (NMSS > 70) NMS burden at V0 and at V2 considering two groups: patients who developed MF at V2 (MF at V2 (PD-MFV2); N = 91) and those who did not developed MF at V2 (nonMF at V2 (PD-nonMFV2); N = 239). PD-nonMFV2 vs. PD-MFV2 at V0, p = 0.011; PD-nonMFV2 vs. PD-MFV2 at V2, p < 0.0001; change in PD-nonMFV2 from V0 to V2, p = 0.003; change in PD-MFV2 from V0 to V2, p = 0.001. p values were computed using the Chi-square and marginal homogeneity test. A greater increase in the NMSS total score from V0 to V2 was observed in those patients who developed MF at V2 (+16.07 ± 37.37) compared with those who did not develop MF (+6.2 ± 25.8) (p = 0.021) (Table 1 and Figure 1). Two-hundred and two out of 330 patients (64.2%) presented at V2 a NMSS total score higher than at V0, but no differences between patients who developed MF vs. those who did not develop MF after the 2-year follow-up were observed (68.1% vs. 62.1%; p = 0.218). However, after the 2-year followup, the frequency of severe and very severe NMS burden was significantly higher in the group who developed MF (p < 0.0001) (Figure 2). Applying GLM repeated measure and after adjustment to covariates (age, gender, years from symptoms onset, H&Y stage, LEDD and the NMSS total score at baseline, and the change in LEDD from V0 to V2), a significantly greater increase (34.6% vs. 17.9%; p = 0.005) in the NMSS total score was observed in patients who developed MF at V2 (from 46.34 ± 36.48 to 62.37 ± 44.15; Cohen’s effect size = 0.57; p = 0.003) compared with those who did not develop MF (from 34.3 ± 29.07 vs. 40.5 ± 35.4; Cohen’s effect size = 0.33; p < 0.0001) (Table 2). An increase in the score of different domains from V0 to V2 was significant in both groups, with and without MF at V2, but there were no significant differences between them (Table 2 and Figure 1). Regarding QoL, the increase in the PDQ-39SI and decrease in EUROHIS-QOL8 total score Figure 2. Frequency of patients with mild (NMSS 1–20), moderate (NMSS 21–40), severe (NMSS 41–70) , and very severe (NMSS > 70) NMS burden at V0 and at V2 considering two groups: patients who developed MF at V2 (MF at V2 (PD-MF V2 ); N = 91) and those who did not developed MF at V2 (nonMF at V2 (PD-nonMF V2 ); N = 239). PD-nonMF V2 vs. PD-MF V2 at V0, p= 0.011; PD-nonMFV2 vs. PD-MFV2 at V2, p< 0.0001; change in PD-nonMF V2 from V0 to V2, p= 0.003; change in PD-MF V2 from V0 to V2, p= 0.001. pvalues were computed using the Chi-square and marginal homogeneity test. A greater increase in the NMSS total score from V0 to V2 was observed in those patients who developed MF at V2 (+16.07 ± 37.37) compared with those who did not develop MF (+6.2 ± 25.8) (p= 0.021) (Table 1and Figure 1). Two-hundred and two out of 330 patients (64.2%) presented at V2 a NMSS total score higher than at V0, but no differences between patients who developed MF vs. those who did not develop MF after the 2-year follow-up were observed (68.1% vs. 62.1%; p= 0.218). However, after the 2-year follow-up, the frequency of severe and very severe NMS burden was significantly higher in the group who developed MF (p< 0.0001) (Figure 2). Applying GLM repeated measure and after adjustment to covariates (age, gender, years from symptoms onset, H&Y stage, LEDD and the NMSS total score at baseline, and the change in LEDD from V0 to V2), a significantly greater increase (34.6% vs. 17.9%; p= 0.005) in the NMSS total score was observed in patients who developed MF at V2 (from 46.34 ± 36.48 to 62.37 ± 44.15; Cohen’s effect size = 0.57; p= 0.003) compared with those who did not develop MF (from 34.3 ± 29.07 vs. 40.5 ± 35.4; Cohen’s effect size = 0.33; p< 0.0001) (Table 2). An increase in the score of different domains from V0 to V2 was significant in both groups, with and without MF at V2, but there were no significant differences between them (Table 2and Figure 1). Regarding QoL, the increase in the PDQ-39SI and decrease in EUROHIS-QOL8 total score indicating a QoL impairment between both visits, V0 and V2, was significantly Diagnostics 2022,12, 1147 8 of 18 greater in the group of patients who developed MF (PDQ-39SI, +35% vs. +26.5% (p= 0.002); EUROHIS-QOL8, − 29.9% vs. − 0.7% (p= 0.030)) (Table 2). By domain and after adjustment to covariates including the PSQ-39SI score at V0, the increase on the score of “pain and discomfort” domain in the group who developed MF at V2 (from 28.55 ± 20.01 to 32.87 ±24.33 ; Cohen’s effect size = 0.30; p= 0.015) was significantly higher (p= 0.039) compared with patients who did not develop MF (from 20.65 ± 18.82 to 23.97 ± 22.12; Cohen’s d effect size = 0.16; p= 0.071) (Table 2). The mean score on all domains of the PDQ-39SI was the highest in patients who developed MF after the 2-year follow-up at V2 and the lowest in patients who did not develop MF, at V0 (Figure 3). A moderate correlation was observed between the change from V0 to V2 in the NMSS total score and the change in the PDQ-39SI in the whole cohort (N = 320; r = 0.402; p< 0.0001) and in both groups, patients with (N = 91; r = 0.328; p= 0.002) and without MF (N = 239; r = 0.433; <0.0001) at V2. However, the correlation between the change in the total score of the NMSS and the EUROHIS-QOL8 was only significant in patients who developed MF at V2 ( N = 91; r = −0.277 ;p= 0.009) but not in patients who did not develop MF at V2 (N = 239; r = − 0.111; p= 0.088). Table 2. Changes in non-motor symptoms and quality of life in PD patients who developed MF at V2 (MF at V2; N = 91) compared with those patients who did not develop MF at V2 (nonMF at V2; N = 239). nonMF at V2 V0 nonMF at V2 V2 Cohen’s Test paMF at V2 V0 MF at V2 V2 Cohen’s Test pbpcpd NMSS 34.3 ±29.07 40.5 ±35.4 0.33 <0.0001 46.34 ±36.48 62.37 ±44.15 0.57 0.003 0.387 0.005 Cardiovascular 3.63 ±7.35 8.66 ±12.36 0.61 <0.0001 6.63 ±10.22 12.36 ±13.78 0.54 0.002 0.973 0.240 Sleep/fatigue 11.52 ±13.03 13.91 ±15.09 0.24 0.024 18.09 ±16.8 23.53 ±18.47 0.39 0.027 0.069 0.104 Mood/apathy 8.86 ±13.56 9.68 ±15.51 0.09 0.101 10.51 ±16 15.82 ±18.13 0.46 0.012 0.090 0.261 Perceptual symptoms 0.87 ±3.48 2.41 ±8.09 0.31 0.002 4.17 ±8.84 7.11 ±16 0.31 0.080 0.672 0.105 Attention/memory 8.05 ±12.6 10.75 ±16.24 0.27 0.002 8.93 ±11.51 12.36 ±15.78 0.32 0.062 0.736 0.175 Gastrointestinal symptoms 7.41 ±10.67 9.61 ±11.95 0.32 <0.0001 10.42 ±14.81 13.64 ±15.02 0.31 0.168 0.852 0.580 Urinary symptoms 17.45 ±19.77 20.09 ±21.92 0.21 0.035 19.63 ±20.42 26 ±23.95 0.43 0.042 0.923 0.532 Sexual dysfunction 16.58 ±25.16 19.4 ±26.65 0.14 0.119 21.55 ±28.26 27.1 ±27.55 0.24 0.128 0.980 0.082 Miscellaneous 10.96 ±13.06 11.68 ±12.83 0.07 0.945 15.84 ±16.16 19.84 ±16 0.34 <0.0001 0.058 0.060 PDQ-39SI 11.4 ±9.16 14.41 ±12.63 0.46 <0.0001 17.39 ±12.74 23.48 ±16.62 0.65 <0.0001 0.397 0.002 Mobility 8.84 ±12.67 12.76 ±15.86 0.42 <0.0001 16.2 ±18.23 25.11 ±22.48 0.69 <0.0001 0.034 N. A. Activities of daily living 11.35 ±13.19 14.98 ±26.2 0.32 0.006 19.35 ±19.34 26.2 ±21.37 0.46 0.002 0.224 0.271 Emotional well-being 16.91 ±17.25 18.41 ±21.8 0.15 0.167 22.36 ±20.74 27.38 ±24.33 0.35 0.089 0.852 0.576 Stigmatization 10.03 ±16.81 10.5 ±18.63 0.05 0.477 10.7 ±14.64 17.5 ±22.91 0.46 0.002 0.032 N. A. Social support 3.76 ±10.59 5.3 ±12.77 0.17 0.074 10.06 ±17.04 12.59 ±21.46 0.16 0.396 0.861 0.224 Cognition 14.94 ±15.84 20.4 ±18.11 0.49 <0.0001 18.05 ±16.82 24.3 ±22.43 0.42 0.027 0.833 0.424 Communication 5.01 ±9.05 8.19 ±14.68 0.33 <0.0001 11.34 ±17.09 15.64 ±19.42 0.26 0.056 0.574 0.387 Pain and discomfort 20.65 ±18.82 23.97 ±22.12 0.16 0.071 28.55 ±20.01 32.87 ±24.33 0.30 0.015 0.432 0.039 EUROHIS-QOL8 3.92 ±0.5 3.89 ±0.57 −0.07 0.699 3.74 ±0.49 2.62 ±0.54 −0.21 0.120 0.109 0.030 Quality of life 3.96 ±0.67 3.82 ±0.77 −0.17 0.047 3.82 ±0.61 3.57 ±0.75 −0.44 0.005 0.148 0.281 Health status 3.4 ±0.82 3.46 ±0.87 +0.22 0.116 3.13 ±0.81 3.11 ±0.88 −0.12 0.903 0.071 0.266 Energy 3.99 ±0.73 3.9 ±0.84 −0.14 0.322 3.64 ±0.81 3.49 ±3.83 −0.19 0.318 0.249 0.002 Autonomy for ADL 3.82 ±0.81 3.82 ±0.85 0.00 0.967 3.57 ±0.81 3.44 ±0.79 −0.25 0.372 0.136 0.058 Self-esteem 3.9 ±0.71 3.95 ±0.76 +0.04 0.449 3.8 ±0.73 3.69 ±0.77 −0.10 0.078 0.003 N. A. Social relationships 4.12 ±0.61 4.03 ±3.72 −0.15 0.046 3.97 ±0.67 3.82 ±0.75 −0.24 0.052 0.115 0.069 Economic capacity 3.93 ±0.81 3.89 ±0.78 −0.06 0.795 3.81 ±0.74 3.64 ±0.83 −0.28 0.080 0.115 0.821 Habitat 4.29 ±0.61 4.27 ±0.64 −0.04 0.485 4.21 ±0.72 4.24 ±0.64 +0.07 0.759 0.466 0.359 pvalues were computed using general linear models (GLM) repeated measures. The results represent mean ±SD; p a , change over time (V2 vs. V0) in nonMF at V2; p b , change over time (V2 vs. V0) in MF at V2; p c , group visit interaction; p d , MF at V2 vs. nonMF at V2. Age, gender, disease duration, Hoehn&Yahr stage and LEDD at V0, and the change in LEDD from V0 to V2 were included as covariates in the model; the total score of each scale at V0 (NMSS, PDQ-39SI, and EUROHIS-QOL8) was included as covariate for the analysis of the domains. MF at V2 vs. nonMF at V2 is not applicable if test of interaction is significant (a significant test of interaction means the rates of changes over time are different between the two groups). ADL, activities of daily living; EUROHIS-QOL8, EUROHIS-QOL 8-item index; LEDD, levodopa equivalent daily dose; PDQ-39SI, Parkinson’s Disease Quality of Life Questionnaire Summary Index. To develop MF after a 2-year follow-up was associated with an increase in the NMSS total score without controlling for other factors ( β = 0.148; 95% CI, 2.69–16.98; p= 0.007) but also after adjustment to age, gender, years from symptoms onset, LEDD and the NMSS total score at baseline, and the change in LEDD from V0 to V2 as well ( β = 0.128; 95% CI, 0.17–16.86; p= 0.046). However, when time on levodopa and the H&Y stage were included in the model as covariates, it was not significant (with time on levodopa therapy, p= 0.062; with H&Y, p= 0.167; both variables, p= 0.212). Development of MF was associated with an increase in the PDQ39SI from V0 to V2 ( β = 0.135; 95% CI, 0.61–5.55; p= 0.015) but not with the change in the EUROHIS-QOL8 total score (p= 0.207). However, it was not significant Diagnostics 2022,12, 1147 9 of 18 after controlling for other covariates (age, gender, years from symptoms onset, LEDD and the PDQ-39SI at baseline, and the change in LEDD from V0 to V2) (p= 0.094). Diagnostics 2022, 12, x FOR PEER REVIEW 8 of 23 indicating a QoL impairment between both visits, V0 and V2, was significantly greater in the group of patients who developed MF (PDQ-39SI, +35% vs. +26.5% (p = 0.002); EUROHIS-QOL8, −29.9% vs. −0.7% (p = 0.030)) (Table 2). By domain and after adjustment to covariates including the PSQ-39SI score at V0, the increase on the score of “pain and discomfort” domain in the group who developed MF at V2 (from 28.55 ± 20.01 to 32.87 ± 24.33; Cohen’s effect size = 0.30; p = 0.015) was significantly higher (p = 0.039) compared with patients who did not develop MF (from 20.65 ± 18.82 to 23.97 ± 22.12; Cohen’s d effect size = 0.16; p = 0.071) (Table 2). The mean score on all domains of the PDQ-39SI was the highest in patients who developed MF after the 2-year follow-up at V2 and the lowest in patients who did not develop MF, at V0 (Figure 3). A moderate correlation was observed between the change from V0 to V2 in the NMSS total score and the change in the PDQ39SI in the whole cohort (N = 320; r = 0.402; p < 0.0001) and in both groups, patients with (N = 91; r = 0.328; p = 0.002) and without MF (N = 239; r = 0.433; <0.0001) at V2. However, the correlation between the change in the total score of the NMSS and the EUROHISQOL8 was only significant in patients who developed MF at V2 (N = 91; r = −0.277; p = 0.009) but not in patients who did not develop MF at V2 (N = 239; r = −0.111; p = 0.088). (A) (B) Figure 3. (A) QoL (PDQ-39SI) (y-axis) at baseline (V0) and after a 2-year follow-up (V2) (x-axis) in PD patients who developed MF at V2 (MF at V2 (PD-MFV2); N = 91) and those patients who did not developed MF at V2 (nonMF at V2 (PD-nonMFV2); N = 239). PDQ-39SI at V0, PD-MFV2 vs. PDnonMFV2, p < 0.0001; PDQ-39SI at V2, PD-MFV2 vs. PD-nonMFV2, p < 0.0001; change in the PDQ-39SI from V0 to V2 in PD-MFV2, p < 0.0001; change in the PDQ-39SI from V0 to V2 in PD-nonMFV2, p < 0.0001; comparison between the change in the PDQ-39SI from V0 to V2 in PD-MFV2 vs. PD-nonMFV2, p = 0.005. (B) Mean score on each domain of the PDQ-39SI at V0 and at V2 in both groups, PD-MFV2 and PD-nonMFV2. At V0, the difference was significant between both groups in all domains (p values from 0.023 to <0.0001) except in PDQ-39SI-4 (Stigmatization) (p = 0.169) and PDQ-39SI-6 (Cognition) (p = 0.097). At V2, the difference was significant between both groups in all domains (p values from 0.005 to <0.0001) except in PDQ-39SI-6 (Cognition) (p = 0.319). PDQ-39 is expressed as a Summary Index (PDQ-39SI). Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). p values were computed using the Kolmogorov–Smirnov, Mann– Whitney, and Wilcoxon tests. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 * IQR or Q3 + 1.5 * IQR. Figure 3. ( A ) QoL (PDQ-39SI) (y-axis) at baseline (V0) and after a 2-year follow-up (V2) (x-axis) in PD patients who developed MF at V2 (MF at V2 (PD-MFV2); N = 91) and those patients who did not developed MF at V2 (nonMF at V2 (PD-nonMFV2); N = 239). PDQ-39SI at V0, PD-MFV2 vs. PD-nonMFV2 , p< 0.0001; PDQ-39SI at V2, PD-MF V2 vs. PD-nonMF V2 ,p< 0.0001; change in the PDQ-39SI from V0 to V2 in PD-MF V2 ,p< 0.0001; change in the PDQ-39SI from V0 to V2 in PD-nonMF V2 ,p< 0.0001; comparison between the change in the PDQ-39SI from V0 to V2 in PD-MF V2 vs. PD-nonMF V2 , p= 0.005 . ( B ) Mean score on each domain of the PDQ-39SI at V0 and at V2 in both groups, PD-MF V2 and PD-nonMF V2 . At V0, the difference was significant between both groups in all domains (pvalues from 0.023 to <0.0001) except in PDQ-39SI-4 (Stigmatization) (p= 0.169) and PDQ-39SI-6 (Cognition) (p= 0.097). At V2, the difference was significant between both groups in all domains (pvalues from 0.005 to <0.0001) except in PDQ-39SI-6 (Cognition) (p= 0.319). PDQ-39 is expressed as a Summary Index (PDQ-39SI). Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). pvalues were computed using the Kolmogorov–Smirnov, Mann–Whitney, and Wilcoxon tests. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 * IQR or Q3 + 1.5 * IQR. 7. Discussion The present study observes that MF are frequent in PD, appearing in a cohort of 330 patients with a mean of 4 years from symptoms onset in one of every 4 subjects after a 2-year follow-up, and also that they are related to NMS. Specifically, NMS burden was greater at baseline in PD patients who 2 years later developed MF, and the increase in the NMS burden after the 2-year follow-up was double in this group as well. Moreover, similar results were obtained in terms of QoL. Importantly, all patients at baseline were without MF and this is the first time that NMS burden progression is specifically analyzed regarding the development of MF in a PD cohort. MF are frequent in PD [ 28 – 31 ]. In the COPPADIS cohort, of 690 patients with a mean disease duration of 5.5 years (DS 4.37), 33.9% had MF [ 17 ]. This percentage was 18.1% in the subgroup of patients with ≤ 5 years of disease duration (N = 396), with a mean disease duration of 2.7 years (DS 1.5) from symptoms onset [ 17 ]. The frequency will depend in part on the methods used—from an interview to wearable tools—and how sensitive we can be Diagnostics 2022,12, 1147 16 of 18 Name (Last Name, First Name) Location Role Contribution Miranda Santiago, Javier Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Morales Casado, Maria Isabel Complejo Hospitalario de Toledo, Toledo, Spain. Site investigator Evaluation of participants and/or data management Moreno Diéguez, Antonio Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Nogueira, Víctor Hospital Da Costa de Burela, Lugo, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Novo Amado, Alba Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Novo Ponte, Sabela Hospital Universitario Puerta de Hierro, Madrid, Spain. Site investigator Evaluation of participants and/or data management Ordás, Carlos Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain. Site investigator Evaluation of participants and/or data management Pagonabarraga, Javier Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Pareés, Isabel Hospital Ruber Internacional, Madrid, Spain Site investigator Evaluation of participants and/or data management Pascual-Sedano, Berta Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Pastor, Pau Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Pérez Fuertes, Aída Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Blood analysis Pérez Noguera, Rafael Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator Evaluation of participants and/or data management Planas-Ballvé, Ana Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain Site investigator Evaluation of participants and/or data management Planellas, Lluís Hospital Clínic de Barcelona, Barcelona, Spain Site investigator (until DEC/19) Evaluation of participants and/or data management Prats, Marian Ángeles Institut d’Assistència Sanitària (IAS)-InstituíCátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management Prieto Jurczynska, Cristina Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Puente, Víctor Hospital del Mar, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Pueyo Morlans, Mercedes Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management Puig Daví, Arnau Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Redondo, Nuria Hospital La Princesa, Madrid, Spain Site investigator Evaluation of participants and/or data management Rodríguez Méndez, Luisa Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Blood analysis Rodríguez Pérez, Amparo Belén Hospital General Universitario de Elche, Elche, Spain Site investigator Evaluation of participants and/or data management Roldán, Florinda Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Neuroimaging studies Ruíz de Arcos, María Hospital Universitario Virgen Macarena, Sevilla, Spain. Site investigator Evaluation of participants and/or data management Ruíz Martínez, Javier Hospital Universitario Donostia, San Sebastián, Spain Site investigator Evaluation of participants and/or data management Sánchez Alonso, Pilar Hospital Universitario Puerta de Hierro, Madrid, Spain Site investigator Evaluation of participants and/or data management Sánchez-Carpintero, Macarena Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Sánchez Díez, Gema Hospital Universitario Ramón y Cajal, Madrid, Spain Site investigator Evaluation of participants and/or data management Sánchez Rodríguez, Antonio Hospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Santacruz, Pilar Hospital Clínic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Santos García, Diego CHUAC, Complejo Hospitalario Universitario de A Coruña Coordinator of the Project Coordination of the COPPADIS-2015 Segundo Rodríguez, José Clemente Complejo Hospitalario de Toledo, Toledo, Spain Site investigator Evaluation of participants and/or data management Seijo, Manuel Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Sierra, MaríaHospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Solano, Berta Institut d’Assistència Sanitària (IAS)-InstituíCátala de la Salud. Girona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Suárez Castro, Ester Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Evaluation of participants and/or data management Tartari, Juan Pablo Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Valero, Caridad Hospital Arnau de Vilanova, Valencia, Spain Site investigator Evaluation of participants and/or data management Vargas, Laura Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Vela, Lydia Fundación Hospital de Alcorcón, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Villanueva, Clara Hospital Universitario Clínico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management Vives, Bárbara Hospital Universitario Son Espases, Palma de Mallorca, Spain Site investigator Evaluation of participants and/or data management Diagnostics 2022,12, 1147 17 of 18 References 1. Bloem, B.R.; Okun, M.S.; Klein, C. Parkinson’s disease. Lancet 2021,397, 2284–2303. [CrossRef] 2. Armstrong, M.J.; Okun, M.S. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA 2020,323, 548–560. [CrossRef] 3. Schapira, A.; Chaudhuri, K.; Jenner, P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 2017 ,18, 435–450. [CrossRef] 4. Seppi, K.; Ray Chaudhuri, K.; Coelho, M.; Fox, S.H.; Katzenschlager, R.; Lloret, S.P.; Weintraub, D.; Sampaio, C.; the Collaborators of the Parkinson’s Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society EvidenceBased Medicine Committee. Update on treatments for non-motor symptoms of Parkinson’s disease—An evidence-based medicine review. Mov. Disord. 2019,34, 180–198. [CrossRef] 5. Chaudhuri, K.R.; Schapira, A.H. Non-motor symptoms of Parkinson’s disease: Dopaminergic pathophysiology and treatment. Lancet Neurol. 2009,8, 464–474. [CrossRef] 6. Mattay, V.; Tessitore, A.; Callicott, J.; Bertolino, A.; Goldberg, T.E.; Chase, T.N.; Hyde, T.M.; Weinberger, D.R. Dopaminergic modulation of cortical function in patients with Parkinson’s disease. Ann. Neurol. 2002,51, 156–164. [CrossRef] 7. Barone, P.; Scarzella, L.; Marconi, R.; Antonini, A.; Morgante, L.; Bracco, F.; Zappia, M.; Musch, B.; the Depression/Parkinson Italian Study Group. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease. A national multicenter parallel group randomized study. J. Neurol. 2006,253, 601–607. [CrossRef] 8. Fernández-Pajarín, G.; Sesar, Á.; Jiménez Martín, I.; Ares, B.; Castro, A. Continuous subcutaneous apomorphine infusion in the early phase of advanced Parkinson’s disease: A prospective study of 22 patients. Clin. Park. Relat. Disord. 2021 ,6, 100129. [CrossRef] 9. Trenkwalder, C.; Kies, B.; Rudzinska, M.; Fine, J.; Nikl, J.; Honczarenko, K.; Dioszeghy, P.; Hill, D.; Anderson, T.; Myllyla, V.; et al. Recover Study Group. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: A double-blind, randomized, placebo-controlled study (RECOVER). Mov. Disord. 2011,26, 90–99. [CrossRef] 10. Martinez-Castrillo, J.C.; Vela, L.; del Val, J.; Alonso-Canovas, A. Non-motor disorders and their correlation with dopamine: Can they be treated by currently available methods? Neurologist 2011,17 (Suppl. 1), S9–S17. [CrossRef] 11. Martínez-Fernández, R.; Schmitt, E.; Martinez-Martin, P.; Krack, P. The hidden sister of motor fluctuations in Parkinson’s disease: A review on non-motor fluctuations. Mov. Disord. 2016,31, 1080–1094. [CrossRef] 12. Witjas, T.; Kaphan, E.; Azulay, J.P.; Blin, O.; Ceccaldi, M.; Pouget, J.; Poncet, M.; Chérif, A.A. Non-motor fluctuations in Parkinson’s disease: Frequent and disabling. Neurology 2002,59, 408–413. [CrossRef] 13. Honig, H.; Antonini, A.; Martinez-Martin, P.; Forgacs, I.; Faye, G.C.; Fox, T.; Fox, K.; Mancini, F.; Canesi, M.; Odin, P.; et al. Intrajejunal levodopa infusion in Parkinson’s disease: A pilot multicenter study of effects on non-motor symptoms and quality of life. Mov. Disord. 2009,24, 1468–1474. [CrossRef] 14. Martinez-Martin, P.; Reddy, P.; Katzenschlager, R.; Antonini, A.; Todorova, A.; Odin, P.; Henriksen, T.; Martin, A.; Calandrella, D.; Rizos, A.; et al. EuroInf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov. Disord. 2015,30, 510–516. [CrossRef] 15. Santos García, D.; Labandeira Guerra, C.; Yáñez Baña, R.; Cimas Hernando, M.I.; Cabo López, I.; Paz Gonález, J.M.; Alonso Losada, M.G.; González Palmás, M.J.; Martínez Miró, C. Safinamide Improves Non-Motor Symptoms Burden in Parkinson’s Disease: An Open-Label Prospective Study. Brain Sci. 2021,11, 316. [CrossRef] 16. Santos García, D.; Fernández-Pajarín, G.; Oropesa Ruíz, J.M.; Escamilla Sevilla, F.; Rahim López, R.R.A.; Muñoz Enríquez, J.G. Opicapone Improves Global Non-Motor Symptoms Burden in Parkinson ´ s Disease: An Open-label Prospective Study. Brain Sci. 2022,12, 383. [CrossRef] 17. Santos-García, D.; de Deus Fonticoba, T.; Suárez Castro, E.; Díaz, A.A.; McAfee, D.; Catalán, M.J.; Alonso-Frech, F.; Villanueva, C.; Jesús, S.; Mir, P.; et al. Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson’s disease. Eur. J. Neurol. 2020,27, 1210–1223. [CrossRef] 18. Santos García, D.; De Deus Fonticoba, T.; Paz González, J.M.; Bartolomé, C.C.; Aymerich, L.V.; Enríquez, J.G.M.; Suárez, E.; Jesús, S.; Aguilar, M.; Pastor, P.; et al. Staging Parkinson’s Disease Combining Motor and Non-motor Symptoms Correlates with Disability and Quality of Life. Parkinsons Dis. 2021,2021, 8871549. 19. Santos García, D.; de Deus Fonticoba, T.; Cores, C.; Muñoz, G.; Paz González, J.M.; Martínez Miró, C.; Suárez, E.; Jesús, S.; Aguilar, M. ; Pastor, P.; et al. Predictors of clinically significant quality of life impairment in Parkinson’s disease. NPJ Parkinsons Dis. 2021,7, 118. [CrossRef] 20. Malaty, I.A.; Martinez-Martin, P.; Chaudhuri, K.R.; Odin, P.; Skorvanek, M.; Jimenez-Shahed, J.; Soileau, M.J.; Lindvall, S.; Domingos, J.; Jones, S.; et al. Does the 5-2-1 criteria identify patients with advanced Parkinson’s disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries. BMC Neurol. 2022,22, 35. [CrossRef] 21. Santos García, D.; Jesús, S.; Aguilar, M.; Planellas, L.L.; Caldentey, J.G.; Caballol, N.; Legarda, I.; Hernández Vara, J.; Cabo, I. ; Manzanares, L.L.; et al. COPPADIS-2015 (COhort of Patients with Parkinson’s DIsease in Spain, 2015): An ongoing global Parkinson’s disease project about disease progression with more than 1000 subjects included. Results from the baseline evaluation. Eur. J. Neurol. 2019,26, 1399–1407. [CrossRef] 22. Santos-García, D.; Mir, P.; Cubo, E.; Vela, L.; Rodríguez-Oroz, M.C.; Martí, M.J.; Arbelo, J.M.; Infante, J.; Kulisevsky, J.; Martínez-Martín, P.; et al . COPPADIS-2015 (COhort of Patients with Parkinson’s DIsease in Spain, 2015), a global–clinical evaluations, serum biomarkers, genetic studies and neuroimaging–prospective, multicenter, non-interventional, long-term study on Parkinson’s disease progression. BMC Neurol. 2016,16, 26. Diagnostics 2022,12, 1147 18 of 18 23. Fahn, S.; Elton, R.L.; Members of the UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In Recent Developments in Parkinson’s Disease; Fahn, S., Marsden, C.D., Calne, D.B., Goldstein, M., Eds.; Macmillan Health Care Information: Florham Park, NJ, USA, 1987; Volume 2, pp. 153–164. 24. Chaudhuri, K.R.; Martinez-Martin, P.; Brown, R.G.; Sethi, K.; Stocchi, F.; Odin, P.; Ondo, W.; Abe, K.; MacPhee, G.; MacMahon, D.; et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov. Disord. 2007,22, 1901–1911. [CrossRef] 25. Martinez-Martin, P.; Rodriguez-Blazquez, C.; Kurtis, M.M.; Chaudhuri, K.R.; NMSS Validation Group. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov. Disord. 2011,26, 399–406. [CrossRef] 26. Jenkinson, C.; Fitzpatrick, R.; Peto, V.; Greenhall, R.; Hyman, N. The Parkinson ´ s Disease Questionnaire (PDQ-39): Development and validation of a Parkinson´s disease summary index score. Age Ageing 1997,26, 353–357. [CrossRef] 27. Da Rocha, N.S.; Power, M.J.; Bushnell, D.M.; Fleck, M.P. The EUROHIS-QOL 8-item index: Comparative psychometric properties to its parent WHOQOL-BREF. Value Health 2012,15, 449–457. [CrossRef] 28. Barone, P.; Antonini, A.; Colosimo, C.; Marconi, R.; Morgante, L.; Avarello, T.P.; Bottacchi, E.; Cannas, A.; Ceravolo, G.; Ceravolo, R.; et al. The PRIAMO study: A multicenter assessment of non-motor symptoms and their impact on quality of life in Parkinson’s disease. Mov. Disord. 2009,24, 1641–1649. [CrossRef] 29. Martinez-Martin, P.; Rodriguez-Blazquez, C.; Abe, K.; Bhattacharyya, K.B.; Bloem, B.R.; Carod-Artal, F.J.; Prakash, R.; Esselink, R.A.J.; Falup-Pecurariu, C.; Gallardo, M.; et al . International study on the psychometric attributes of the non-motor symptoms scale in Parkinson disease. Neurology 2009,73, 1584–1591. [CrossRef] 30. Hauser, R.A.; McDermott, M.P.; Messing, S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch. Neurol. 2006,63, 1756–1760. [CrossRef] 31. Ahlskog, J.E.; Muenter, M.D. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov. Disord. 2001,16, 448–458. [CrossRef] 32. Barrachina-Fernández, M.; Maitín, A.M.; Sánchez-Ávila, C.; Romero, J.P. Wearable Technology to Detect Motor Fluctuations in Parkinson’s Disease Patients: Current State and Challenges. Sensors 2021,21, 4188. [CrossRef] 33. Stocchi, F.; Antonini, A.; Barone, P.; Tinazzi, M.; Zappia, M.; Onofrj, M.; Ruggieri, S.; Morgante, L.; Bonuccelli, U.; Lopiano, L.; et al. Early DEtection of wEaring off in Parkinson disease: The DEEP study. Parkinsonism Relat. Disord. 2014,20, 204–211. [CrossRef] 34. Fox, S.H.; Katzenschlager, R.; Lim, S.Y.; Barton, B.; De Bie, R.M.A.; Seppi, K.; Coelho, M.; Sampaio, C.; Movement Disorder Society Evidence-Based Medicine Committee. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease. Mov. Disord. 2018,33, 1248–1266. [CrossRef] 35. Antonini, A.; Barone, P.; Marconi, R.; Morgante, L.; Zappulla, S.; Pontieri, F.E.; Ramat, S.; Ceravolo, M.G.; Meco, G.; Cicarelli, G.; et al. The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability and quality of life. J. Neurol. 2012,259, 2621–2631. [CrossRef] 36. Todorova, A.; Jenner, P.; Ray Chaudhuri, K. Non-motor parkinson’s: Integral to motor parkinson’s, yet often neglected. Pract. Neurol. 2014,14, 310–322. [CrossRef] 37. Fernandes, M.; Pierantozzi, M.; Stefani, A.; Cattaneo, C.; Bonizzoni, E.A.; Cerroni, R.; Mercuri, N.B.; Liguori, C. Frequency of Non-motor Symptoms in Parkinson’s Patients With Motor Fluctuations. Front. Neurol. 2021,12, 678373. [CrossRef] 38. Watanabe, H.; Saiki, H.; Chiu, S.W.; Yamaguchi, T.; Kashihara, K.; Tsuboi, Y.; Nomoto, M.; Hattori, N.; Maeda, T.; Shimo, Y.; et al. Real-World Non-motor Changes I Patients with Parkinson’s Disease and Motor Fluctuations: J-FIRST. Mov. Disord. Clin. Pract. 2020,7, 431–439. [CrossRef] 39. Santos-García, D.; de Deus, T.; Cores, C.; Canfield, H.; Paz González, J.M.; Martínez Miró, C.; Valdés Aymerich, L.; Suárez, E.; Jesús, S.; Aguilar, M.; et al. Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up. J. Pers. Med. 2021,11, 626. [CrossRef] 40. Chaudhuri, K.R.; Schrag, A.; Weintraub, D.; Rizos, A.; Rodriguez-Blazquez, C.; Mamikonyan, E.; Martinez-Martin, P. The movement disorder society non-motor rating scale: Initial validation study. Mov. Disord. 2020,35, 116–133. [CrossRef] 41. Chen, Y.C.; Chen, R.S.; Weng, Y.H.; Huang, Y.-Z.; Chen, C.C.; Hung, J.; Lin, Y.-Y. The severity progression of non-motor symptoms in Parkinson’s disease: A 6-year longitudinal study in Taiwanese patients. Sci. Rep. 2021,11, 14781. [CrossRef] 42. Ou, R.; Yang, J.; Cao, B.; Wei, Q.; Chen, K.; Chen, X.; Zhao, B.; Wu, Y.; Song, W.; Shang, H. Progression of non-motor symptoms in Parkinson’s disease among different age populations: A two-year follow-up study. J. Neurol. Sci. 2016,360, 72–77. [CrossRef] 43. Cilia, R.; Akpalu, A.; Sarfo, F.S.; Cham, M.; Amboni, M.; Cereda, E.; Fabbri, M.; Adjei, P.; Akassi, J.; Bonetti, A.; et al. The modern pre-levodopa era of Parkinson’s disease: Insights into motor complications from sub-Saharan Africa. Brain 2014 ,137 Pt 10, 2731–2742. [CrossRef] 44. Simuni, T.; Caspell-Garcia, C.; Coffey, C.S.; Weintraub, D.; Mollenhauer, B.; Lasch, S.; Tanner, C.M.; Jennings, D.; Kieburtz, K.; Chahine, L.M.; et al. Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson’s disease: The PPMI cohort. J. Neurol. Neurosurg. Psychiatry 2018,89, 78–88. [CrossRef] 45. Bugalho, P.; Ladeira, F.; Barbosa, R.; Marto, J.P.; Borbinha, C.; Da Conceição, L.; Salavisa, M.; Saraiva, M.; Meira, B.; Fernandes, M. Progression in Parkinson’s Disease: Variation in Motor and Non-motor Symptoms Severity and Predictors of Decline in Cognition, Motor Function, Disability, and Health-Related Quality of Life as Assessed by Two Different Methods. Mov. Disord. Clin. Pract. 2021,8, 885–895. [CrossRef]