Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Patient-perceived progression in multiple system atrophy: natural history of quality of life.

BACKGROUND: Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy. METHODS: We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. A four-step strategy (1) determined the subdimensions of Hr-QoL, (2) modelled the subdimension trajectories over time, (3) mapped item impairments with disease stages and (4) identified most informative items. RESULTS: Four dimensions were identified. In addition to the original motor, non-motor and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the non-motor and emotional aspects were already impaired at cohort entry and deteriorated slowly over the disease course. Impairments were associated with sex, diagnosis subtype and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items. CONCLUSION: The multidimensional Hr-QoL deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL over time using the four-step strategy can provide perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective.

Advantages and Challenges of Platform Trials for Disease Modifying Therapies in Parkinson's Disease.

Traditional drug development in Parkinson's disease (PD) faces significant challenges because of its protracted timeline and high costs. In response, innovative master protocols are emerging and designed to address multiple research questions within a single overarching protocol. These trials may offer advantages such as increased efficiency, agility in adding new treatment arms, and potential cost savings. However, they also present organizational, methodological, funding, regulatory, and sponsorship challenges. We review the potential of master protocols, focusing on platform trials, for disease modifying therapies in PD. These trials share a common control group and allow for the termination or addition of treatment arms during a trial with non-predetermined end. Specific issues exist for a platform trial in the PD field considering the heterogeneity of patients in terms of phenotype, genotype and staging, the confounding effects of symptomatic treatments, and the choice of outcome measures with no consensus on a non-clinical biomarker to serve as a surrogate and the slowness of PD progression. We illustrate these aspects using the examples of the main PD platform trials currently in development with each one targeting distinct goals, populations, and outcomes. Overall, platform trials hold promise in expediting the evaluation of potential therapies for PD. However, it remains to be proven whether these theoretical benefits will translate into increased production of high-quality trial data. Success also depends on the willingness of pharmaceutical companies to engage in such trials and whether this approach will ultimately hasten the identification and licensing of effective disease-modifying drugs. © 2024 International Parkinson and Movement Disorder Society.

Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

BACKGROUND: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Recent Advances in Clinical Trials in Multiple System Atrophy.

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.

High frequency of Depressive Disorders and Suicidal Phenomena in Late-Stage Parkinson´s Disease - A Cross-Sectional Study.

BACKGROUND: Depressive disorders (DD) are widely recognized as one of the most frequent neuropsychiatric disorders in Parkinson´s disease. Patients with late-stage Parkinson´s disease (LSPD) continue to be a neglected population, and little is known about DD frequency in LSPD. OBJECTIVES: To determine the frequency of DD in LSPD patients through a clinical diagnostic interview (CDI) and according to diagnostic DSM- 5 criteria. Secondary objectives were to determine the predictive ability of depressive scales to detect DD, to identify potential predictors of DD in LSPD and, to evaluate suicidal phenomena in LSPD. METHODS: A cross-sectional study including LSPD patients (≥7 years from symptom onset and Hoehn and Yahr scale score >3 or a Schwab and England scale score <50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Six depression scales were applied. RESULTS: 92 LSPD patients were included. 59.78% of LSPD patients had a current diagnosis of DD according to CDI, 38.04% patients had a diagnosis of major depressive disorder, and 21.72% non-major depressive disorder. Suicidal ideation was present in 36.96% of patients. All applied scales were able to detect depressive disorders. CONCLUSIONS: More than half of LSPD patients met DD diagnostic criteria and over one-third were diagnosed with major depressive disorder. Overall, the LSPD population seem to have a unique clinical phenotype regarding the frequency and features of DD, whose early identification and treatment could improve the quality of life of patients and caregivers.

Ambulatory blood pressure and drug treatment for orthostatic hypotension as predictors of mortality in patients with multiple system atrophy.

OBJECTIVES: Multiple system atrophy (MSA) is a rare fatal neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. This study was aimed at investigating possible associations between mortality, 24-h blood pressure (BP) level and variability, and drug treatments for orthostatic hypotension (OH) in MSA patients. METHODS: A total of 129 patients followed at the French Reference Center for MSA who underwent routine 24-h ambulatory BP monitoring were included. Unified MSA Rating Scale (UMSARS) scores, drug treatments and the occurrence and cause of death were recorded. RESULTS: Seventy patients died during follow-up (2.9 ± 1.8 years), mainly from terminal illness, pulmonary or sudden death. Multivariate Cox regression analysis, after adjustment for gender, disease duration and severity (UMSARS I+II score), showed that increased daytime systolic BP variability, OH severity and OH drug treatment were independently correlated with mortality. OH treatment was associated with the risk of cardiac causes and/or sudden death (p = 0.01). In a fully adjusted model, male gender [(female vs. male) hazard ratio (HR) 0.56, 95% CI 0.34-0.94, p = 0.03], UMSARS I+II score (HR 1.04, 95% CI 1.02-1.06, p < 0.01), systolic BP daytime variability (HR 3.66, 95% CI 1.46-9.17, p < 0.01) and OH treatment (HR: 2.13, 95% CI 1.15-3.94, p = 0.02) predicted mortality. CONCLUSIONS: Increased daytime BP variability and OH treatment were predictive of mortality in patients with MSA, independently from disease severity. Further studies are required to assess if these associations are explained by more severe autonomic dysfunction or if OH treatment exposes per se to a specific risk in this population.

Efficacy of safinamide as add-on therapy after subthalamic nucleus deep brain stimulation in Parkinson disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective surgical treatment for advanced Parkinson's disease (PD). However, some patients still experience motor fluctuations or dyskinesia after STN-DBS. Safinamide is approved as add-on treatment to levodopa in fluctuating PD patients. In this study, we evaluated the effect of safinamide as adjunctive therapy in PD patients still experiencing motor fluctuations and dyskinesias after STN-DBS. METHODS: PD patients treated for at least 2 years with bilateral STN-DBST and with troublesome motor fluctuation and/or dyskinesias were examined by means of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the quality of life questionnaire Parkinson's Disease Questionnaire-8 (PDQ-8) and the Non-Motor Symptoms Scale (NMSS) at baseline (T0), after 1 month of treatment with safinamide 50 mg daily (T1) and after another month of treatment with safinamide 100 mg daily (T2). RESULTS: Twenty-nine PD patients were examined. An improvement of the MDS-UPDRS IV score (motor complications) was observed between T0 and T1, T0 and T2, and T1 and T2. The time spent in the OFF state, the functional impact and the complexity of motor fluctuations significantly improved between T0 and T1 and T0 and T2. The mean levodopa equivalent daily dose significantly decreased from T0 to T1 and from T0 to T2. Regarding non-motor symptoms, an improvement on mood and pain was observed. CONCLUSIONS: Safinamide seems to be an effective adjunctive treatment in PD patients treated with bilateral STN-DBS, leading to an improvement of motor complications, mood and pain.

Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial.

BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society.

Gut microbiota and metabolome distinctive features in Parkinson disease: Focus on levodopa and levodopa-carbidopa intrajejunal gel.

BACKGROUND AND PURPOSE: Recent data suggest that imbalances in the composition of the gut microbiota (GM) could exacerbate the progression of Parkinson disease (PD). The effects of levodopa (LD) have been poorly assessed, and those of LD-carbidopa intestinal gel (LCIG) have not been evaluated so far. The aim of this study was to identify the effect of LD and LCIG, in particular, on the GM and metabolome. METHODS: Fecal DNA samples from 107 patients with a clinical diagnosis of PD were analyzed by next-generation sequencing of the V3 and V4 regions of the 16S rRNA gene. PD patients were classified in different groups: patients on LCIG (LCIG group, n = 38) and on LD (LD group, n = 46). We also included a group of patients (n = 23) without antiparkinsonian medicaments (Naïve group). Fecal metabolic extracts were evaluated by gas chromatography mass spectrometry. RESULTS: The multivariate analysis showed a significantly higher abundance in the LCIG group of Enterobacteriaceae, Escherichia, and Serratia compared to the LD group. Compared to the Naïve group, the univariate analysis showed a reduction of Blautia and Lachnospirae in the LD group. Moreover, an increase of Proteobacteria, Enterobacteriaceae, and a reduction of Firmicutes, Lachnospiraceae, and Blautia was found in the LCIG group. No significant difference was found in the multivariate analysis of these comparisons. The LD group and LCIG group were associated with a metabolic profile linked to gut inflammation. CONCLUSIONS: Our results suggest that LD, and mostly LCIG, might significantly influence the microbiota composition and host/bacteria metabolism, acting as stressors in precipitating a specific inflammatory intestinal microenvironment, potentially related to the PD state and progression.

Safety and efficacy of tolcapone in Parkinson's disease: systematic review.

PURPOSE: Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians' choices in the use of an enlarging PD therapeutic armamentarium. METHODS: We searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson's disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity. RESULTS: Thirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone. Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1-3.2), of levodopa was 108.9 mg (1-251.5), of "On" UPDRS-III was 3.6 points (1.1-6.5). Most studies reported a significant improvement of QoL and non-motor symptoms. CONCLUSION: Literature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.

Effectiveness of a dance-physiotherapy combined intervention in Parkinson's disease: a randomized controlled pilot trial.

BACKGROUND: Physical therapies have been recommended as crucial components in Parkinson's disease (PD) rehabilitation. OBJECTIVE: The study aims to examine the effectiveness of a new dance-physiotherapy combined intervention, called DArT method, in mild PD patients. METHODS: A prospective, randomized, single-blind, controlled pilot trial was conducted on 38 mild PD patients under dopaminergic therapy. The intervention consisted in an add-on protocol: the control group received 1 h of conventional physiotherapy followed by 1 h of conventional physiotherapy each day, 3 times a week, for 5 weeks. The experimental group received 1 h of conventional physiotherapy followed by 1 h of dance class each day, 3 times a week, for 5 weeks. The week before and after the training period, patients were assessed for motor, cognitive, emotional, and sensory components of PD, with MDS-UPDRS-III as primary outcome measure. RESULTS: DArT method was associated with a 2.72-point reduction in the post-treatment MDS-UPDRS-III total score compared to control group (95% CI - 5.28, - 0.16, p = 0.038, d = 0.71), and with a 2.16-point reduction in the post-treatment MDS-UPDRS-III upper body subscore (95% CI - 3.56, - 0.76, p = 0.003, d = 1.02). Conversely, conventional physiotherapy program was associated with a 2.95-point reduction in the post-treatment trait anxiety compared to the experimental group (95% CI 0.19, 5.71, p = 0.037, d = 0.70). Withdrawal and fall rates were equal to 0% in both groups. CONCLUSION: DArT method showed to be safe, well accepted, and more effective than an intensive program of conventional physiotherapy in improving motor impairment in mild PD.

Should We Consider Deep Brain Stimulation Discontinuation in Late-Stage Parkinson's Disease?

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. METHODS: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment. RESULTS: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred. CONCLUSIONS: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society.

Excessive buccal saliva in patients with Parkinson's disease of the French COPARK cohort.

We describe excessive buccal saliva (EBS) prevalence in patients with Parkinson's Disease (PD) and controls of the COPARK study, its changes between "ON" and OFF" conditions and over time, its impact on Health-related Quality of life (HRQoL), and factors associated with this condition. We studied 671 ambulatory PD patients and 177 age/sex-matched controls. We defined "sialorrhea" as UPDRS item #6 (salivation) = 1 or 2; and "drooling" as item #6 = 3 or 4. SCOPA-Aut drooling score (item #2) was also available in a subset (45%) of the cohort. HRQoL was assessed by the PDQ-39 and SF-36 scales. Twenty-four months' follow-up data were available in 401/671 patients. EBS as assessed by UPDRS was present in 38% of PD patients in the "ON" condition ("Sialorrhea": 35%; "drooling": 3%). There were also more PD patients reporting "drooling" than controls according to the SCOPA-Aut (49% vs 19%, p < 0.01). UPDRS salivation score was worse in the "OFF" vs "ON" condition in PD patients with motor fluctuations (0.90 ± 0.94 vs 0.54 ± 0.79, p < 0.01). UPDRS salivation score worsened after ~ 24 months of follow-up (0.47 ± 0.70 vs 0.64 ± 0.81, p < 0.01). Worse PDQ-39 scores were observed in PD patients with EBS in bivariate but not in multivariate analyses. EBS was directly related to PD duration and severity, male gender, dysphagia, hypomimia, and autonomic dysfunction (logistic regression). EBS was more frequent in PD patients than controls, worsened in the "OFF" condition and after ~ 24 months of follow-up, moderately affected HRQoL, and was correlated with indices of bradykinesia, dysphagia, and autonomic dysfunction.

Video analysis of long-term effects of levodopa-carbidopa intestinal gel on gait and posture in advanced Parkinson's disease.

Gait and posture parameters of ten advanced Parkinson's disease (PD) patients were assessed before and after starting levodopa-carbidopa intestinal gel (LCIG) treatment by means of both objective video analysis and clinical assessment. After 3 years of treatment, gait and posture remained stable. A slower gait velocity at baseline significantly correlates with a higher axial and motor severity at follow-up. This pilot study suggests that validated video analysis software may support the clinical assessment of axial signs in PD patients who are candidates for device-aided therapies.

Long-term effect of levodopa-carbidopa intestinal gel on axial signs in Parkinson's disease.

BACKGROUND: Few studies have suggested that levodopa-carbidopa intestinal gel (LCIG) may have a benefit on Parkinson's disease (PD) axial signs. AIMS OF THE STUDY: To investigate the long-term effect of LCIG on axial signs and the related prognostic factors. METHODS: A retrospective study on 49 PD patients treated with LCIG. Axial signs as per the Unified Parkinson Disease Rating Scale axial score (AS), Hoehn and Yahr (H&Y) scale, and levodopa equivalent daily dose (LEDD) were assessed at baseline (before starting LCIG treatment) and at the last follow-up (FU). RESULTS: After 47.6 ± 30 months of treatment, total AS deteriorated while motor complications still improved, in spite of a significant LEDD/Kg increment. When adjusted for LCIG treatment duration, a higher AS and freezing of gait severity at FU were predicted by a baseline lower response to l-dopa and higher H&Y (P < 0.01) and they were related to a lower independency in activity of daily life at FU (P < 0.001). Single axial items remain stable up to one year and postural instability up to four years. CONCLUSION: Baseline disease severity and the magnitude of l-dopa response predict axial signs' severity after around four years of LCIG treatment, with consequent implication on patients' functional independence.

Validation of the Italian version of the PSP Quality of Life questionnaire.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP. METHODS AND RESULTS: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach's alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts. CONCLUSION: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.

Validation of the Italian version of carers' quality-of-life questionnaire for parkinsonism (PQoL Carer) in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. Caring for a partner or relative who suffers from PSP entails a strenuous and demanding task, usually lasting for years that affects carers' everyday life routines and emotional and social well-being. The 26-item Parkinsonism Carers QoL (PQoL Carer) is a self-administered, concise instrument evaluating the quality of life of caregivers of patients with atypical parkinsonism (both PSP and multiple system atrophy). Here, the PQoL Carer was translated into Italian and validated in 162 carers of PSP patients (54.3% women; mean age (standard deviation), 62.4 (15.4)) diagnosed according to the Movement Disorder Society criteria and recruited in 16 third-level movement disorders centers participating in the Neurecanet project. The mean PQoL total score was 40.66 ± 19.46. The internal consistency was excellent (Cronbach's alpha = 0.941); corrected item-total correlation was > 0.40 for all the items. A correlation with other health-related quality of life measures as well as with behavioral assessments was shown suggesting adequate convergent validity of the scale. PQoL also correlated with patients' severity of disease. The discriminant validity of the scale was evidenced by its capacity to differentiate between carers with varying levels of self-reported health (p < 0.001). In conclusion, the Italian version of the PQoL Carer is an easy, consistent, and valid tool for the assessment of the quality of life in carers of PSP patients.