Levodopa-Induced Dyskinesias are Frequent and Impact Quality of Life in Parkinson's Disease: A 5-Year Follow-Up Study.

BACKGROUND: Levodopa-induced dyskinesias (LID) are frequent in Parkinson's disease (PD). OBJECTIVE: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients' quality of life (QoL). PATIENTS AND METHODS: PD patients from the 5-year follow-up COPPADIS cohort were included. LID were defined as a non-zero score in the item "Time spent with dyskinesia" of the Unified Parkinson's Disease Rating Scale-part IV (UPDRS-IV). The UPDRS-IV was applied at baseline (V0) and annually for 5 years. The 39-item Parkinson's disease Questionnaire Summary Index (PQ-39SI) was used to asses QoL. RESULTS: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5-year follow-up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (ß = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (ß = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ-39SI. CONCLUSION: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

Efectividad y seguridad de la safinamida en la Unidad de Trastornos de Movimiento de Toledo / Effectiveness and safety of safinamide in the Toledo Movement Disorders Unit

Introducción El manejo de las fluctuaciones motoras en la enfermedad de Parkinson (EP) puede suponer un reto, que cuenta entre las diversas opciones terapéuticas actuales con el uso de inhibidores de la monoaminooxidasa B (IMAO-B), entre otros. El objetivo de este estudio fue evaluar la efectividad y seguridad de la safinamida en la práctica clínica de la Unidad de Trastornos de Movimiento de Toledo. Pacientes y métodos Es un estudio retrospectivo en el que se registraron datos en una visita inicial y a los seis meses de pacientes con EP en los que se inició tratamiento con safinamida como terapia adicional con una dosis estable de levodopa según la práctica clínica habitual. Se realizó un análisis por subgrupos: pacientes que recibieron safinamida en dosis bajas y pacientes que recibieron previamente rasagilina. Resultados Completaron los seis meses de seguimiento 90 pacientes (47 recibieron previamente rasagilina). Tanto en los pacientes que recibieron rasagilina previa como en los tratados con dosis bajas de safinamida se observó una disminución estadísticamente significativa de la acinesia matutina, la acinesia nocturna, el wearing off, el fenómeno off impredecible y la Unified Parkinson’s Disease Rating Scale-III. No hubo variación en las discinesias. Los acontecimientos adversos descritos fueron leves, y se describieron sensación de debilidad generalizada, mareo, náuseas, cefalea y alopecia. Conclusiones La safinamida ha demostrado ser eficaz y segura en la mejoría de fluctuaciones motoras, los síntomas motores y la percepción subjetiva de la gravedad de la enfermedad tanto en pacientes con EP que recibieron previamente rasagilina como en los que recibieron safinamida en dosis bajas, todo ello acompañado de un buen perfil de seguridad. (AU)

Introduction. The management of motor fluctuations in Parkinson's disease (PD) can be challenging, and current therapeutic options include the use of monoamine oxidase B inhibitors (MAO-B inhibitors), among others. The aim of this study was to evaluate the effectiveness and safety of safinamide in the clinical practice carried out in the Toledo Movement Disorders Unit. Patients and methods. This is a retrospective study in which data were collected at baseline and at six months from PD patients who were started on safinamide as an add-on therapy with a stable dose of levodopa in line with standard clinical practice. An analysis was performed by subgroups: patients who were given low-dose safinamide and patients who previously received rasagiline. Results. Ninety patients (47 previously received rasagiline) completed the six-month follow-up. A statistically significant decrease in morning akinesia, nocturnal akinesia, wearing off, unpredictable off phenomenon and Unified Parkinson's Disease Rating Scale-III was observed both in those who previously received rasagiline and in those treated with low doses of safinamide. No variation was found in the dyskinesias. The adverse events described were mild, with generalised weakness, dizziness, nausea, headache and alopecia. Conclusions. Safinamide has been shown to be effective and safe in improving motor fluctuations, motor symptoms and the subjective perception of disease severity in PD patients previously receiving rasagiline and in those receiving low-dose safinamide, all of which is accompanied by a good safety profile. (AU)

Staging Parkinson's disease according to the MNCD classification correlates with caregiver burden.

BACKGROUND AND OBJECTIVE: Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients' quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status. PATIENTS AND METHODS: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4-5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers. CONCLUSION: Staging PD according to the MNCD classification is correlated with caregivers' strain and burden.

Response to levodopa in Parkinson's disease over time. A 4-year follow-up study.

BACKGROUND AND OBJECTIVE: A good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD with motor fluctuations followed for 4 years. PATIENTS AND METHODS: PwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale - part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS-III-OFF, UPDRS-III-ON, and ΔUPDRS-III (UPDRS-III-OFF - UPDRS-III-ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate. RESULTS: Sixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS-III-OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS-III-ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III. CONCLUSION: In this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.

Cognitive impairment and dementia in young onset Parkinson's disease.

BACKGROUND AND OBJECTIVE: Patients with young-onset Parkinson's disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls. PATIENTS AND METHODS: Patients with Parkinson's disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson's Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1 month (V2y), and 4-year ± 3 months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50 years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65-80 mild cognitive impairment (MCI). RESULTS: One-hundred and twenty-four YOPD (50.7 ± 7.9 years; 66.1% males), 234 non-YOPD (67.8 ± 7.8 years; 59.3% males) patients, and 205 controls (61 ± 8.3 years; 49.5% males) were included. The score on the PD-CRS and its subscore domains was higher at all visits in YOPD compared to non-YOPD patients and to controls (p < 0.0001 in all analysis), but no differences were detected between YOPD patients and controls. Only non-YOPD patients had significant impairment in their cognitive function from V0 to V4y (p < 0.0001). At V4y, the frequency of dementia and MCI was 5% and 10% in YOPD compared to 25.2% and 22.3% in non-YOPD patients (p < 0.0001). A lower score on the Parkinson's Disease Sleep Scale at baseline was a predictor of CI at V4y in YOPD patients (Adjusted R2 = 0.61; OR = 0.965; p = 0.029). CONCLUSION: Cognitive dysfunction progressed more slowly in YOPD than in non-YOPD patients.

Suicidal ideation among people with Parkinson's disease and comparison with a control group.

BACKGROUND: Detection of suicidal ideation (SI) is key for trying to prevent suicide. The aim of this study was to analyze the frequency of SI and related factors in Spanish people with Parkinson's Disease (PwPD) and to compare them with a control group. METHODS: PD patients and controls recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. Two visits were conducted: V0 (baseline); V2 (2-year ± 1 month follow-up). SI was defined as a score ≥1 on item nine of the Beck Depression Inventory-II (BDI-II). Regression analyses were conducted to identify factors related to SI. RESULTS: At baseline, 693 PwPD (60.2% males; 62.59 ± 8.91 years old) and 207 controls (49.8% males; 60.99 ± 8.32 years old) were included. No differences between PwPD and controls were detected in SI frequency at either V0 (5.1% [35/693] vs. 4.3% [9/207]; p = 0.421) or at V2 (5.1% [26/508] vs. 4.8% [6/125]; p = 0.549). Major depression (MD) and a worse quality of life were associated with SI at both visits in PwPD: V0 (MD, OR = 5.63; p = 0.003; PDQ-39, OR = 1.06; p = 0.021); V2 (MD, OR = 4.75; p = 0.027; EUROHIS-QOL8, OR = 0.22; p = 0.006). A greater increase in the BDI-II total score from V0 to V2 was the only factor predicting SI at V2 (OR = 1.21; p = 0.002) along with an increase in the total number of non-antiparkinsonian drugs (OR = 1.39; p = 0.041). CONCLUSION: The frequency of SI (5%) in PwPD was similar to in controls. Depression, a worse quality of life, and a greater comorbidity were related to SI.

Prevalence and Factors Associated with Drooling in Parkinson's Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group.

Introduction: Drooling in Parkinson's disease (PD) is frequent but often goes underrecognized. Our aim was to examine the prevalence of drooling in a PD cohort and compare it with a control group. Specifically, we identified factors associated with drooling and conducted subanalyses in a subgroup of very early PD patients. Patients and Methods. PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort were included in this longitudinal prospective study. Subjects were classified as with or without drooling according to item 19 of the NMSS (Nonmotor Symptoms Scale) at V0, V1 (1-year ± 15 days), and V2 for patients and at V0 and V2 for controls. Results: The frequency of drooling in PD patients was 40.1% (277/691) at V0 (2.4% (5/201) in controls; p < 0.0001), 43.7% (264/604) at V1, and 48.2% (242/502) at V2 (3.2% (4/124) in controls; p < 0.0001), with a period prevalence of 63.6% (306/481). Being older (OR = 1.032; p = 0.012), being male (OR = 2.333; p < 0.0001), having greater nonmotor symptom (NMS) burden at the baseline (NMSS total score at V0; OR = 1.020; p < 0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR = 1.012; p < 0.0001) were identified as independent predictors of drooling after the 2-year follow-up. Similar results were observed in the group of patients with ≤2 years since symptom onset, with a cumulative prevalence of 64.6% and a higher score on the UPDRS-III at V0 (OR = 1.121; p = 0.007) as a predictor of drooling at V2. Conclusion: Drooling is frequent in PD patients even at the initial onset of the disease and is associated with a greater motor severity and NMS burden.

Staging Parkinson's Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life.

BACKGROUND: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). OBJECTIVE: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. METHODS: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. CONCLUSION: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.

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

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.

Risk of Cognitive Impairment in Patients With Parkinson's Disease With Visual Hallucinations and Subjective Cognitive Complaints.

BACKGROUND AND PURPOSE: Visual hallucinations (VH) and subjective cognitive complaints (SCC) are associated with cognitive impairment (CI) in Parkinson's disease. Our aims were to determine the association between VH and SCC and the risk of CI development in a cohort of patients with Parkinson's disease and normal cognition (PD-NC). METHODS: Patients with PD-NC (total score of >80 on the Parkinson's Disease Cognitive Rating Scale [PD-CRS]) recruited from the Spanish COPPADIS cohort from January 2016 to November 2017 were followed up after 2 years. Subjects with a score of ≥1 on domain 5 and item 13 of the Non-Motor Symptoms Scale at baseline (V0) were considered as "with SCC" and "with VH," respectively. CI at the 2-year follow-up (plus or minus 1 month) (V2) was defined as a PD-CRS total score of <81. RESULTS: At V0 (n=376, 58.2% males, age 61.14±8.73 years [mean±SD]), the frequencies of VH and SCC were 13.6% and 62.2%, respectively. VH were more frequent in patients with SCC than in those without: 18.8% (44/234) vs 4.9% (7/142), p<0.0001. At V2, 15.2% (57/376) of the patients had developed CI. VH presenting at V0 was associated with a higher risk of CI at V2 (odds ratio [OR]=2.68, 95% confidence interval=1.05-6.83, p=0.0.039) after controlling for the effects of age, disease duration, education, medication, motor and nonmotor status, mood, and PD-CRS total score at V0. Although SCC were not associated with CI at V2, presenting both VH and SCC at V0 increased the probability of having CI at V2 (OR=3.71, 95% confidence interval=1.36-10.17, p=0.011). CONCLUSIONS: VH were associated with the development of SCC and CI at the 2-year follow-up in patients with PD-NC.

Falls Predict Acute Hospitalization in Parkinson's Disease.

BACKGROUND: There is a need for identifying risk factors for hospitalization in Parkinson's disease (PD) and also interventions to reduce acute hospital admission. OBJECTIVE: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. METHODS: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit. RESULTS: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065-5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319-6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757-8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124-4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080-8.322; p = 0.035) was an independent predictor of AH. CONCLUSION: Falls is an independent predictor of AH in PD patients.

Validation of the OPTIMIPARK Questionnaire: A Tool to Optimize Treatment in Parkinson's Disease.

Background: Dopamine replacement therapy reduces most motor and nonmotor features of Parkinson's disease. However, with disease progression, adjustments of dopaminergics and the application of advanced therapies must be considered. Objectives: To validate the OPTIMIPARK questionnaire as a tool to help clinicians make therapeutic decisions on patients treated with levodopa. Methods: We tested a questionnaire including 9 items encompassing motor and nonmotor signs, complications, and disability in a multicenter, observational, cross-sectional study. A neurologist (neurologist 1 [N1]) assessed patients according to regular clinical practice and blinded to the OPTIMIPARK questionnaire score. Therapeutic decisions were classified as "no changes," "adjustment of conventional treatment," and "advanced therapy indicated." External neurologists (neurologist 3 [N3] and neurologist 4 [N4]), who only knew the patient age, years of disease, and current treatment, made their therapeutic decisions based on the OPTIMIPARK score. Concordance between the criterion of the N1 versus the OPTIMIPARK-based N3-N4 consensus was analyzed applying weighted κ. The area under Receiving Operating Characteristic (ROC) curves was calculated for OPTIMIPARK scores. Results: A total of 113 patients with Parkinson's disease were included. The OPTIMIPARK-based decision led to a higher proportion of patients requiring therapeutic modification than N1 assessment (74% vs. 60%; P = 0.002). Concordance between the N1 and N3-N4 decisions was moderate, whereas interobserver agreement among N3 and N4 was high. Area Under the Curve(AUC) values of 0.83 and 0.82 were found for "no changes" and "advanced therapy indicated" decisions by the N1 neurologist. Conclusions: OPTIMIPARK might be more sensitive than regular clinical practice in suggesting the need for a therapeutic change. Furthermore, the low and high scores identify with high accuracy well-adjusted patients and candidates for advanced therapy, respectively.

Comparison of the Results of a Parkinson's Holter Monitor With Patient Diaries, in Real Conditions of Use: A Sub-analysis of the MoMoPa-EC Clinical Trial.

Background: For specialists in charge of Parkinson's disease (PD), one of the most time-consuming tasks of the consultations is the assessment of symptoms and motor fluctuations. This task is complex and is usually based on the information provided by the patients themselves, which in most cases is complex and biased. In recent times, different tools have appeared on the market that allow automatic ambulatory monitoring. The MoMoPa-EC clinical trial (NCT04176302) investigates the effect of one of these tools-Sense4Care's STAT-ON-can have on routine clinical practice. In this sub-analysis the agreement between the Hauser diaries and the STAT-ON sensor is analyzed. Methods: Eighty four patients from MoMoPa-EC cohort were included in this sub-analysis. The intraclass correlation coefficient was calculated between the patient diary entries and the sensor data. Results: The intraclass correlation coefficient of both methods was 0.57 (95% CI: 0.3-0.73) for the OFF time (%), 0.48 (95% CI: 0.17-0.68) for the time in ON (%), and 0.65 (95% CI%: 0.44-0.78) for the time with dyskinesias (%). Furthermore, the Spearman correlations with the UPDRS scale have been analyzed for different parameters of the two methods. The maximum correlation found was -0.63 (p < 0.001) between Mean Fluidity (one of the variables offered by the STAT-dON) and factor 1 of the UPDRS. Conclusion: This sub-analysis shows a moderate concordance between the two tools, it is clearly appreciated that the correlation between the different UPDRS indices is better with the STAT-ON than with the Hauser diary. Trial Registration: https://clinicaltrials.gov/show/NCT04176302 (NCT04176302).

Constipation Predicts Cognitive Decline in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-up and Comparison with a Control Group.

BACKGROUND: Constipation has been linked to cognitive impairment development in Parkinson's disease (PD). OBJECTIVE: Our aim was to analyze cognitive changes observed in PD patients and controls from a Spanish cohort with regards to the presence or not of constipation. METHODS: PD patients and controls recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were followed-up during 2 years. The change in cognitive status from baseline (V0) to 2-year follow-up was assessed with the PD-CRS (Parkinson's Disease Cognitive Rating Scale). Subjects with a score ≥1 on item 21 of the NMSS (Non-Motor Symptoms Scale) at baseline (V0) were considered as "with constipation". Regression analyses were applied for determining the contribution of constipation in cognitive changes. RESULTS: At V0, 39.7% (198/499) of PD patients presented constipation compared to 11.4% of controls (14/123) (p < 0.0001). No change was observed in cognitive status (PD-CRS total score) neither in controls without constipation (from 100.24±13.72 to 100.27±13.68; p = 0.971) and with constipation (from 94.71±10.96 to 93.93±13.03; p = 0.615). The PD-CRS total score decreased significantly in PD patients with constipation (from 89.14±15.36 to 85.97±18.09; p < 0.0001; Coehn's effect = -0.35) compared to patients without constipation (from 93.92±15.58 to 93.14±17.52; p = 0.250) (p = 0.018). In PD patients, to suffer from constipation at V0 was associated with a decrease in the PD-CRS total score from V0 to V2 (ß= -0.1; 95% CI, -4.36 - -0.27; p = 0.026) and having cognitive impairment at V2 (OR = 1.79; 95% CI, 1.01 - 3.17; p = 0.045). CONCLUSION: Constipation is associated with cognitive decline in PD patients but not in controls.

Parkinson's Disease Motor Subtypes Change with the Progression of the Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

BACKGROUND: Motor phenotype (MP) can be associated with a different prognosis in Parkinson's disease (PD), but it is not fixed and can change over time. OBJECTIVE: Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort. METHODS: PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers. RESULTS: Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR  =  0.937) at V0 and a greater increase in the globalNMS burden (OR  =  1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up. CONCLUSION: The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly.

Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

BACKGROUND AND OBJECTIVE: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. PATIENTS AND METHODS: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. RESULTS: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). CONCLUSIONS: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.

Predictors of clinically significant quality of life impairment in Parkinson's disease.

Quality of life (QOL) plays an important role in independent living in Parkinson's disease (PD) patients, being crucial to know what factors impact QoL throughout the course of the disease. Here we identified predictors of QoL impairment in PD patients from a Spanish cohort. PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016, to November 2017, were followed up during 2 years. Health-related QoL (HRQoL) and global QoL (GQoL) were assessed with the 39-item Parkinson's disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8), respectively, at baseline (V0) and at 24 months ± 1 month (V2). Clinically significant QoL impairment was defined as presenting an increase (PDQ-39SI) or decrement (EUROHIS-QOL8) at V2 ≥ 10% of the score at baseline (V0). A comparison with a control group was conducted for GQoL. GQoL did not change significantly in PD patients (N = 507; p = 0.686) or in the control group (N = 119; p = 0.192). The mean PDQ-39SI was significantly increased in PD patients (62.7 ± 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.7 ± 13 to 20.3 ± 16.4; p < 0.0001) at V2. Ninety-three patients (18.6%) presented a clinically significant HRQoL impairment at V2. To be younger (OR = 0.896; 95% CI 0.829-0.968; p = 0.006), to be a female (OR = 4.181; 95% CI 1.422-12.290; p = 0.009), and to have a greater increase in BDI-II (Beck Depression Inventory-II) (OR = 1.139; 95% CI 1.053-1.231; p = 0.001) and NMSS (Non-Motor Symptoms Scale) (OR = 1.052; 95% CI 1.027-1.113; p < 0.0001) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer-Lemeshow test, p = 0.665; R2 = 0.655). An increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting clinically significant HRQoL impairment by 5 (OR = 5.453; 95% CI 1.663-17.876; p = 0.005) and 8 (OR = 8.217; 95% CI, 2.975-22.696; p = 0.002), respectively. In conclusion, age, gender, mood, and non-motor impairment were associated with clinically significant HRQoL impairment after the 2-year follow-up in PD patients.

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease.

BACKGROUND: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. METHODS: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. RESULTS: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). CONCLUSIONS: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.

Predictors of Loss of Functional Independence in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group.

BACKGROUND AND OBJECTIVE: The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson's disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD). PATIENTS AND METHODS: PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%. RESULTS: In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen's effect size = -0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2. CONCLUSIONS: In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.