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Skin conditions in early Parkinson's disease.
Dinesh, D, Lee, JS, Gao, X, Palacios, N
Parkinsonism & related disorders. 2021;:40-46
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OBJECTIVE Skin conditions have been associated with increased risk of Parkinson's disease (PD). Little is known about clinical and biomarker differences according to presence of skin conditions among PD patients. Studying these differences might provide insight into PD pathogenesis. METHODS We examined the association between common skin conditions and risk of PD in a case-control study of 423 early drug-naïve PD cases and 196 healthy controls (HC) in the Parkinson's Progression Markers Initiative (PPMI). Among PD participants, we examined if skin conditions were associated with clinical and PD-relevant biomarkers. RESULTS Skin conditions occurred more frequently among PD participants (41%) relative to HC (32%). In multivariate analyses, we observed an association between any skin condition and PD (OR = 1.49, 95% CI = 1.03-2.16) and basal cell carcinoma and PD (OR = 2.05, 95% CI = 1.02-4.08). PD participants who reported skin conditions were older (OR = 1.68, 95% CI = 1.21-2.35) more educated (OR = 1.70, 95% CI = 0.99-2.91), had higher Semantic Fluency Test (SFT) scores (OR = 1.45, 95% CI = 1.07-1.96) and Hopkins Verbal Learning Test (HVLT) retention scores (OR = 1.55, 95% CI = 1.09-2.22) compared to PD patients without skin conditions. None of the associations remained significant after Bonferroni correction for multiple comparisons. CONCLUSIONS We observed a positive association between any skin condition as well as basal cell carcinoma and PD. PD participants with skin conditions were older, more educated, had higher SFT and HVLT retention scores compared to those without skin conditions. However, all associations were no longer significant after Bonferroni multiple comparisons correction. Observed associations should be confirmed in larger, longitudinal studies.
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Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial.
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Annals of internal medicine. 2020;(9):591-598
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BACKGROUND Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD). OBJECTIVE To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD. DESIGN Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842). SETTING 57 Parkinson Study Group sites in North America. PARTICIPANTS Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment. INTERVENTION 5 mg of immediate-release isradipine twice daily or placebo for 36 months. MEASUREMENTS The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures. RESULTS 336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness. LIMITATION The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects. CONCLUSION Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD. PRIMARY FUNDING SOURCE National Institute of Neurological Disorders and Stroke.
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Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson's disease: A randomized, double-blind, placebo-controlled, phase II/III study.
Hattori, N, Tsuboi, Y, Yamamoto, A, Sasagawa, Y, Nomoto, M, ,
Parkinsonism & related disorders. 2020;:17-23
Abstract
INTRODUCTION Safinamide is a reversible and selective monoamine oxidase-B (MAO-B) and sodium channel inhibitor with demonstrated efficacy in mid-to late-stage Parkinson's disease (PD) as an adjunct to l-DOPA. This study aimed to confirm the efficacy and safety of safinamide in PD patients with wearing-off. METHODS This 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study included Japanese PD patients with wearing-off on l-DOPA treatment. Patients were randomized to receive placebo (P), safinamide 50 mg/day (S50), or safinamide 100 mg/day (S100). The primary endpoint was the change from baseline in mean daily ON-time without troublesome dyskinesias (ON-time). Other measures included the changes in mean daily OFF-time, the unified Parkinson's disease rating scale (UPDRS) score, and the PDQ-39 summary index. RESULTS A total of 406 subjects were randomized, of whom 349 completed the study. Baseline characteristics were balanced. Differences in the change of mean daily ON-time at Week 24 compared with the P group were 1.39 h (p = 0.0002) in the S50 group and 1.66 h (p < 0.0001) in the S100 group. Changes from baseline in mean daily OFF-time, UPDRS Part II total score (OFF phase), UPDRS Part III total score (ON phase), and UPDRS Part I also showed significant improvements. Adverse events occurred in 58.9%, 60.2%, and 61.4% of the P, S50, and S100 groups, respectively. The most common adverse drug reactions were dyskinesias (2.1%, 8.3%, and 10.6%) and visual hallucinations (1.4%, 3.0%, and 4.5%). CONCLUSION As an adjunct to l-DOPA, safinamide safely increased ON-time and improved PD symptoms/signs in PD patients with wearing-off.
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Randomized, double-blind, multicenter trial of hydrogen water for Parkinson's disease.
Yoritaka, A, Ohtsuka, C, Maeda, T, Hirayama, M, Abe, T, Watanabe, H, Saiki, H, Oyama, G, Fukae, J, Shimo, Y, et al
Movement disorders : official journal of the Movement Disorder Society. 2018;(9):1505-1507
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Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial.
Phillips, MCL, Murtagh, DKJ, Gilbertson, LJ, Asztely, FJS, Lynch, CDP
Movement disorders : official journal of the Movement Disorder Society. 2018;(8):1306-1314
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BACKGROUND Preliminary evidence suggests that diet manipulation may influence motor and nonmotor symptoms in PD, but conflict exists regarding the ideal fat to carbohydrate ratio. OBJECTIVES We designed a pilot randomized, controlled trial to compare the plausibility, safety, and efficacy of a low-fat, high-carbohydrate diet versus a ketogenic diet in a hospital clinic of PD patients. METHODS We developed a protocol to support PD patients in a diet study and randomly assigned patients to a low-fat or ketogenic diet. Primary outcomes were within- and between-group changes in MDS-UPDRS Parts 1 to 4 over 8 weeks. RESULTS We randomized 47 patients, of which 44 commenced the diets and 38 completed the study (86% completion rate for patients commencing the diets). The ketogenic diet group maintained physiological ketosis. Both groups significantly decreased their MDS-UPDRS scores, but the ketogenic group decreased more in Part 1 (-4.58 ± 2.17 points, representing a 41% improvement in baseline Part 1 scores) compared to the low-fat group (-0.99 ± 3.63 points, representing an 11% improvement) (P < 0.001), with the largest between-group decreases observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. There were no between-group differences in the magnitude of decrease for Parts 2 to 4. The most common adverse effects were excessive hunger in the low-fat group and intermittent exacerbation of the PD tremor and/or rigidity in the ketogenic group. CONCLUSIONS It is plausible and safe for PD patients to maintain a low-fat or ketogenic diet for 8 weeks. Both diet groups significantly improved in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry.
Antonini, A, Poewe, W, Chaudhuri, KR, Jech, R, Pickut, B, Pirtošek, Z, Szasz, J, Valldeoriola, F, Winkler, C, Bergmann, L, et al
Parkinsonism & related disorders. 2017;:13-20
Abstract
INTRODUCTION This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. METHODS Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of "On" and "Off" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. RESULTS Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in "Off" time (hours/day) (mean ± SD = -4.1 ± 3.5, P < 0.001), "On" time with dyskinesia (hours/day) (-1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (-16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (-7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). CONCLUSIONS LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.
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Which patients discontinue? Issues on Levodopa/carbidopa intestinal gel treatment: Italian multicentre survey of 905 patients with long-term follow-up.
Sensi, M, Cossu, G, Mancini, F, Pilleri, M, Zibetti, M, Modugno, N, Quatrale, R, Tamma, F, Antonini, A, ,
Parkinsonism & related disorders. 2017;:90-92
Abstract
OBJECTIVES To report the results of a national survey aimed at quantifying the current level of diffusion of Levodopa/carbidopa intestinal gel (LCIG) in Italy. METHODS Sixty Parkinson's Disease (PD) specialists in Italy were invited to complete a survey covering issues on clinical and practical aspects of LCIG therapy. RESULTS Clinical features of 905 patients were collected retrospectively. The majority of centres reported the use of a multidisciplinary team, biochemistry testing, neurophysiological and neuropsychological tests before and after treatment, in addition to caregivers' training and patient's follow as outpatients. Most centres (60%) used internal guidelines for patient selection. The overall rate of adverse events was 55.1%. Weight loss, chronic polyneuropathy and stoma infection were the most frequently reported. 40% of centres used replacement therapy with Vitamin B12 and Folic acid from the start of LCIG and continued this for the duration of treatment. The rate of discontinuation was of 25.7% overall, with 9.5% of cases occurring in the first year. The main causes of withdrawal were device-related complications, disease progression (comorbidity, severe dementia) and caregiver and/or patient dissatisfaction. CONCLUSIONS In Italy LCIG infusion is managed in a uniform manner at a clinical, practical and organizational level even though the selection criteria are not standardized through the country. The high percentage of patients remaining on treatment in the short- and long-term follow-up confirms effectiveness of treatment, careful follow-up, and appropriate patient and caregivers training.
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Long-Term Effects of Safinamide on Mood Fluctuations in Parkinson's Disease.
Cattaneo, C, Müller, T, Bonizzoni, E, Lazzeri, G, Kottakis, I, Keywood, C
Journal of Parkinson's disease. 2017;(4):629-634
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BACKGROUND Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. OBJECTIVE To investigate the effects of safinamide on mood over two-year treatment in PD patients with motor fluctuations. METHODS This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. RESULTS Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). CONCLUSION The favorable effect of safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.
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Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial.
Postuma, RB, Anang, J, Pelletier, A, Joseph, L, Moscovich, M, Grimes, D, Furtado, S, Munhoz, RP, Appel-Cresswell, S, Moro, A, et al
Neurology. 2017;(17):1795-1803
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OBJECTIVE To assess effects of caffeine on Parkinson disease (PD). METHODS In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. RESULTS Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). CONCLUSION Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects. CLINICALTRIALSGOV IDENTIFIER NCT01738178. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.
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Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson's disease patients.
Kumar, R, Hauser, RA, Mostillo, J, Dronamraju, N, Graf, A, Merschhemke, M, Kenney, C
The International journal of neuroscience. 2016;(1):20-4
Abstract
Long-term use of levodopa (L-dopa) in patients with Parkinson's disease is associated with development of dyskinesia. This study explored whether Parkinson's disease patients with L-dopa-induced dyskinesia experience improved OFF-time from higher L-dopa doses without worsening of dyskinesias when receiving adjunctive mavoglurant. Patients with moderate-to-severe L-dopa-induced dyskinesia were randomized to receive mavoglurant or placebo. Mavoglurant (AFQ056) was up-titrated over two weeks from 25 mg twice daily (bid) to 100 mg bid (L-dopa kept stable), followed by three weeks during which the daily L-dopa dosage was increased by up to 300 mg/day. A sample size of 30 was initially planned; however, the study was terminated prematurely due to enrollment challenges. OFF-time showed greater improvements in the mavoglurant group (n = 7) compared with the placebo group (n = 7); difference at week 5 was -2.77 h (90% confidence interval -5.44, -0.09 h; p = 0.09). ON-time without troublesome dyskinesia increased more from baseline to week 5 in the mavoglurant group (4.38 h) versus the placebo group (0.63 h). Clinician-rated measures were conflicting. The Modified Abnormal Involuntary Movement Scale scores showed a slight improvement with mavoglurant compared with placebo, while the Unified Dyskinesia Rating Scale parts III and IV worsened slightly with mavoglurant compared with placebo. Due to the low patient numbers and conflicting clinician-rated outcomes data, our findings are not conclusive. However, our results suggest that mavoglurant combined with higher doses of L-dopa may be effective in treating patients with Parkinson's disease experiencing L-dopa-related motor fluctuations and dyskinesias.