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Dopamine-Related Genotypes and Physical Activity Change During an Intervention: The Lifestyle Interventions and Independence for Elders Study.
Rosso, AL, Metti, AL, Glynn, NW, Boudreau, RM, Rejeski, WJ, Bohnen, N, Chen, H, Johannsen, NM, King, AC, Manini, TM, et al
Journal of the American Geriatrics Society. 2018;(6):1172-1179
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Abstract
OBJECTIVES To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. DESIGN Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). SETTING Multicenter study, 8 U.S. PARTICIPANTS Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). INTERVENTIONS Structured PA versus health education (HE) for an average of 2.6 years. MEASUREMENTS Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. RESULTS White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. CONCLUSION Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01072500.
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Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study.
Whone, AL, Watts, RL, Stoessl, AJ, Davis, M, Reske, S, Nahmias, C, Lang, AE, Rascol, O, Ribeiro, MJ, Remy, P, et al
Annals of neurology. 2003;(1):93-101
Abstract
Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.
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Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group.
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JAMA. 2000;(15):1931-8
Abstract
CONTEXT Pramipexole and levodopa both ameliorate the motor symptoms of early Parkinson disease (PD), but no controlled studies have compared long-term outcomes after initiating dopaminergic therapy with pramipexole vs levodopa. OBJECTIVE To compare the development of dopaminergic motor complications after initial treatment of early PD with pramipexole vs levodopa. DESIGN Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS Three hundred one patients with early PD who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997. INTERVENTIONS Subjects were randomly assigned to receive pramipexole, 0.5 mg 3 times per day, with levodopa placebo (n = 151); or carbidopa/levodopa, 25/100 mg 3 times per day, with pramipexole placebo (n = 150). For patients with residual disability, the dosage was escalated during the first 10 weeks. From week 11 to month 23.5, investigators were permitted to add open-label levodopa to treat continuing or emerging disability. MAIN OUTCOME MEASURES Time to the first occurrence of any of 3 dopaminergic complications: wearing off, dyskinesias, or on-off motor fluctuations; changes in scores on the Unified Parkinson's Disease Rating Scale (UPDRS), assessed at baseline and follow-up evaluations; and, in a subgroup of 82 subjects evaluated at baseline and 23.5 months, ratio of specific to nondisplaceable striatal iodine 123 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane (beta-CIT) uptake on single photon emission computed tomography imaging of the dopamine transporter. RESULTS Initial pramipexole treatment resulted in significantly less development of wearing off, dyskinesias, or on-off motor fluctuations (28%) compared with levodopa (51%) (hazard ratio, 0.45; 95% confidence interval [CI], 0. 30-0.66; P<.001). The mean improvement in total UPDRS score from baseline to 23.5 months was greater in the levodopa group than in the pramipexole group (9.2 vs 4.5 points; P<.001). Somnolence was more common in pramipexole-treated patients than in levodopa-treated patients (32.4% vs 17.3%; P =.003), and the difference was seen during the escalation phase of treatment. In the subgroup study, patients treated initially with pramipexole (n = 39) showed a mean (SD) decline of 20.0% (14.2%) in striatal beta-CIT uptake compared with a 24.8% (14.4%) decline in subjects treated initially with levodopa (n = 39; P =.15). CONCLUSIONS Fewer patients receiving initial treatment for PD with pramipexole developed dopaminergic motor complications than with levodopa therapy. Despite supplementation with open-label levodopa in both groups, the levodopa-treated group had a greater improvement in total UPDRS compared with the pramipexole group. JAMA. 2000;284:1931-1938.