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 (R = 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

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

Malaltia de Parkinson; Fenotip; TremolorEnfermedad de Parkinson; Fenotipo; TemblorParkinson’s disease; Phenotype; TremorBackground 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.Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bia

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

COPPADIS Study Group.[Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia.[Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models.[Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02).[Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.This work was supported by the Alzheimer Forschung Initiative e.V. (AFI International Training Grant to MJG), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576, PI20/00613], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], the Fundación Alicia Koplowitz and the Fundación “Curemos el Parkinson” (https://www.curemoselparkinson.org). MJG is supported by the “Miguel Servet” program [CP19/00031], MALE by the University of Seville [USE-20046-J], JFM by the “Sara Borrell” program [CD13/00229] and VI-PPIT-US from the University of Seville [USE-18817-A], SJ by the “Acción B-Clínicos-Investigadores” program [B-0007-2019], and DMG by the “Río Hortega” program [CM18/00142].Peer reviewe

5-2-1 Criteria: A Simple Screening Tool for Identifying Advanced PD Patients Who Need an Optimization of Parkinson’s Treatment

Objective. 5- (5 times oral levodopa tablet taken/day) 2- (2 hours of OFF time/day) 1- (1 hour/day of troublesome dyskinesia) criteria have been proposed by a Delphi expert consensus panel for diagnosing advanced Parkinson’s disease (PD). The aim of the present study is to compare quality of life (QoL) in PD patients with “5-2-1 positive criteria” vs QoL in PD patients without “5-2-1 positive criteria” (defined as meeting ≥1 of the criteria). Methods. This is a cross-sectional, observational, monocenter study. Three different instruments were used to assess QoL: the 39-Item Parkinson’s Disease Quality of Life Questionnaire Summary Index Score (PDQ-39SI); a subjective rating of perceived QoL (PQ-10); and the EUROHIS-QOL 8-Item Index (EUROHIS-QOL8). Results. From a cohort of 102 PD patients (65.4 ± 8.2 years old, 53.9% males; disease duration 4.7 ± 4.5 years), 20 (19.6%) presented positive 5-2-1 criteria: 6.9% for 5, 17.6% for 2, and 4.9% for 1. 37.5% (12/32) and 25% (5/20) of patients with motor complications and dyskinesia, respectively, presented 5-2-1 negative criteria. Both health-related (PDQ-39SI, 25.6 ± 14 vs 12.1 ± 9.2; p<0.0001) and global QoL (PQ-10, 6.1 ± 2 vs 7.1 ± 1.3; p=0.007; EUROHIS-QOL8, 3.5 ± 0.5 vs 3.7 ± 0.4; p=0.034) were worse in patients with 5-2-1 positive criteria. Moreover, nonmotor symptoms burden (Non-Motor Symptoms Scale total score, 64.8 ± 44.8 vs 39.4 ± 35.1; p<0.0001) and autonomy for activities of daily living (ADLS scale, 73.5 ± 13.1 vs 89.2 ± 9.3; p<0.0001) were worse in patients with 5-2-1 positive criteria. Patient’s principal caregiver’s strain (Caregiver Stain Index, 4.3 ± 3 vs 1.5 ± 1.6; p<0.0001), burden (Zarit Caregiver Burden Inventory, 28.4 ± 12.5 vs 10.9 ± 9.8; p<0.0001), and mood (Beck Depression Inventory II, 12.2 ± 7.2 vs 6.2 ± 6.1; p<0.0001) were worse in patients with 5-2-1 positive criteria as well. Conclusions. QoL is worse in patients meeting ≥1 of the 5-2-1 criteria. This group of patients and their caregivers are more affected as a whole. These criteria could be useful for identifying patients in which it is necessary to optimize Parkinson’s treatment

Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson’s disease

COPPADIS Study Group.[Background and purpose] The objective of this study was to analyze the relationship between motor complications and non‐motor symptom (NMS) burden in a population of patients with Parkinson’s disease (PD) and also in a subgroup of patients with early PD.[Methods] Patients with PD from the COPPADIS cohort were included in this cross‐sectional study. NMS burden was defined according to the Non‐Motor Symptoms Scale (NMSS) total score. Unified Parkinson’s Disease Rating Scale (UPDRS) part IV was used to establish motor complication types and their severity. Patients with ≤5 years of symptoms from onset were included as patients with early PD.[Results] Of 690 patients with PD (62.6 ± 8.9 years old, 60.1% males), 33.9% and 18.1% presented motor fluctuations and dyskinesia, respectively. The NMS total score was higher in patients with motor fluctuations (59.2 ± 43.1 vs. 38.3 ± 33.1; P 40, severe or very severe) (odds ratio, 1.31; 95% confidence intervals, 1.17–1.47; P < 0.0001). In the subgroup of patients with early PD (n = 396; mean disease duration 2.7 ± 1.5 years), motor fluctuations were frequent (18.1%) and similar results were obtained.[Conclusions] Motor complications were frequent and were associated with a greater NMS burden in patients with PD even during the first 5 years of disease duration

Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease

[Background] Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive.[Objective] To characterize the cortical structural correlates of homocysteine levels in PD.[Methods] From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample.[Results] A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = −2.2, p = 0.03), correlating in turn with cognitive performance (r = −0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected).[Conclusions] Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.This work was partially supported by funds from CERCA, CIBERNED, la Marató de TV3 (grants #2014/U/477 and #20142910), Fondo de Investigaciones Sanitarias (grants #PI15/00962 and #PI18/01717FIS), Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER). MJG receives support from the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] from the ISCIII-FEDER. MALE receives support from the VI-PPIT-US project at the University of Seville [USE-20046-J].Peer reviewe

Non-motor symptoms burden, mood, and gait problems are the most significant factors contributing to a poor quality of life in non-demented Parkinson's disease patients: Results from the COPPADIS Study Cohort

[Objective] To identify factors related to a poor health-related and global quality of life (QoL) in a cohort of non-demented Parkinson's disease (PD) patients and compare to a control group.[Methods] The data correspond to the baseline evaluation of the COPPADIS-2015 Study, an observational, 5-year follow-up, multicenter, evaluation study. Three instruments were used to assess QoL: (1) the 39-item Parkinson's disease Questionnaire (PDQ-39), (2) a subjective rating of global QoL (PQ-10), and (3) the EUROHIS-QOL 8-item index (EUROHIS-QOL8). Multiple linear regression methods were used to evaluate the direct impact of different variables on these QoL measures.[Results] QoL was worse in PD patients (n = 692; 62.6 ± 8.9 years old, 60.3% males) than controls (n = 206; 61 ± 8.3 years old, 49.5% males): PDQ-39, 17.1 ± 13.5 vs 4.4 ± 6.3 (p < 0.0001); PQ-10, 7.3 ± 1.6 vs 8.1 ± 1.2 (p < 0.0001); EUROHIS-QOL8, 3.8 ± 0.6 vs 4.2 ± 0.5 (p < 0.0001). A high correlation was observed between PDQ-39 and Non-Motor Symptoms Scale (NMSS) (r = 0.72; p < 0.0001), and PDQ-39 and Beck Depression Inventory-II (BDI-II) (r = 0.65; p < 0.0001). For health-related QoL (PDQ-39), non-motor symptoms burden (NMSS), mood (BDI-II), and gait problems (Freezing Of Gait Questionnaire [FOGQ]) provided the highest contribution to the model (β = 0.32, 0.28, and 0.27, respectively; p < 0.0001); whereas mood and gait problems contributed the most to global QoL (PQ-10, β = -0.46 and −0.21, respectively; EUROHIS-QOL8, β = -0.44 and −0.23, respectively).[Conclusions] QoL is worse in PD patients than in controls. Mood, non-motor symptoms burden, and gait problems seem to be the most relevant factors affecting health-related and global perceived QoL in non-demented PD patients.Peer reviewe

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; R = 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