Pharmacological Treatment of Early Motor Manifestations of Parkinson Disease (PD).
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ABSTRACT:
SUBMITTER: Sy MAC
PROVIDER: S-EPMC7851218 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parkinson disease (PD) is a progressive neurologic condition that causes motor and nonmotor manifestations. Treatment provides symptomatic benefit but no current treatment has been proven to slow disease progression. Research studies of PD require a means of rating the severity of disease by measurement of motor manifestations, assessment of ability to perform daily functional activities, and symptomatic response to medication. The most common rating scales are the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr staging, and the Schwab and England rating of activities of daily living. Each of these rating scales are described, including detailed instructions on how to implement these ratings. Although these are the most widely applied rating scales of PD, there are still substantial limitations to these scales that must be considered when using them for research. Finally, some common applications of these scales are described.
| S-EPMC2897716 | biostudies-literature
Project description:ImportanceOptimizing assessments of rate of progression in Parkinson disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents.ObjectiveTo examine the value of measures of impairment, disability, and quality of life in assessing progression in early PD.Design, setting, and participantsInception cohort analysis of data from 413 patients with early, untreated PD who were enrolled in 2 multicenter, randomized, double-blind clinical trials.InterventionsParticipants were randomly assigned to 1 of 5 treatments (67 received creatine, 66 received minocycline, 71 received coenzyme Q10, 71 received GPI-1485, and 138 received placebo). We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment.Main outcomes and measuresTime between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression.ResultsAfter adjusting for baseline confounding variables with regard to the Unified Parkinson's Disease Rating Scale (UPDRS) Part II score, the UPDRS Part III score, the modified Rankin Scale score, level of education, and treatment group, we assessed the rate of change for the following measurements: the UPDRS Part II score; the UPDRS Part III score; the Schwab and England Independence Scale score (which measures activities of daily living); the Total Functional Capacity scale; the 39-item Parkinson's Disease Questionnaire, summary index, and activities of daily living subscale; and version 2 of the 12-item Short Form Health Survey Physical Summary and Mental Summary. Variables reaching the statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid change (ie, worsening) in the UPDRS Part II score (hazard ratio, 1.15 [95% CI, 1.08-1.22] for 1 scale unit change per 6 months), the UPDRS Part III score (hazard ratio, 1.09 [95% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 1.12-1.48] for 5 percentage point change per 6 months) was associated with earlier need for symptomatic therapy.ConclusionsAND RELEVANCE In early PD, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson's Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change.Trial registrationclinicaltrials.gov Identifiers: NCT00063193 and NCT00076492.
| S-EPMC4188544 | biostudies-literature
Project description:ObjectiveTo assess effects of caffeine on Parkinson disease (PD).MethodsIn 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.ResultsSixty 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).ConclusionCaffeine 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 identifierNCT01738178.Classification of evidenceThis study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.
| S-EPMC5664303 | biostudies-literature
Project description:ObjectiveTo describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).MethodsSTEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.ResultsThe entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).InterpretationSTEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.
| S-EPMC5454402 | biostudies-literature
Project description:ObjectiveTo assess differences in gray matter (GM) atrophy between 2 Parkinson disease (PD) subtypes: the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype.MethodsPatients were classified as belonging to the predominately PIGD (n = 30) or predominately TD (n = 29) subtype. Voxel-based morphometry was used to compare GM in these 2 subtypes and to evaluate correlations between predefined regions of interest and the degree of symptoms. In the regions where GM atrophy was associated with symptoms, the relationship between GM volumes and functional connectivity was examined.ResultsGM was reduced in the predominately PIGD group, compared with the predominately TD group, in areas that involve motor, cognitive, limbic, and associative functions (p < 0.05, false discovery rate corrected). Lower GM volumes in the pre-supplementary motor area (SMA) and in the primary motor area were associated with increased severity of PIGD symptoms (r = -0.42, p < 0.001; r = -0.38, p < 0.003, respectively). Higher GM volumes within the pre-SMA were associated with stronger functional connectivity between the pre-SMA and the putamen (r = 0.415, p < 0.025) in the patients with predominately PIGD.ConclusionsIn patients with PD, PIGD symptoms are apparently associated with GM atrophy in motor-related regions and decreased functional connectivity. GM degeneration and a related decrease in spontaneous coactivation between cortical and subcortical motor-planning areas may partially account for the unique clinical characteristics of a subset of patients with PD.
| S-EPMC3662357 | biostudies-literature
Project description:Background and objectivesThe genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.MethodsWe performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores.ResultsWe included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode).DiscussionOur study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.
| S-EPMC10409573 | biostudies-literature
Project description:STUDY OBJECTIVES:Parkinson disease (PD) non-motor symptoms are associated with sleep disorders and impair quality of life. Our objective was to assess the effect of obstructive sleep apnea (OSA) treatment using continuous positive airway pressure (CPAP) on PD non-motor symptoms. METHODS:In this prospective observational study, 67 patients with idiopathic PD underwent polysomnography. Those with moderate-severe OSA were offered CPAP therapy. Subjects were divided into those without OSA (OSA-), and those with OSA (OSA+). Analyses were conducted for 6 and 12 months' follow-up data. At 6 months, those who had used CPAP at home for at least 1 month were considered CPAP users (OSA+CPAP+), whereas those who did not try it, or declined further treatment following a short trial were considered non-users (OSA+CPAP-). For the 12-month analysis, only those still actively using CPAP at 12 months were included in the OSA+CPAP+ group. Non-motor symptom measurements were: Epworth Sleepiness Scale, Montreal Cognitive Assessment (MoCA), Unified Parkinson's Disease Rating Scale part 1 (UPDRS1), Parkinson's Disease Sleep Scale (PDSS), Fatigue Severity Scale, Apathy Scale, Beck Depression Inventory, and Hospital Anxiety and Depression Scale (HADS). RESULTS:Sixty-five participants were re-assessed at least once. At 6 months, 30 participants were categorized as OSA+CPAP+, 11 OSA+CPAP-, and 18 OSA-. At 12 months, 21 were categorized as OSA+CPAP+, 21 OSA+CPAP-, and 17 OSA-. The UPDRS1 and PDSS improved from baseline in OSA+CPAP+ at 6 months (-2.7, standard deviation [SD] 4.0, P = .001, and 7.9, SD 19.0, P = .03, respectively) and 12 months (-4.1, SD 5.4, P = .002, and 11.4, SD 24.4, P = .04, respectively), but not in other groups. The MoCA and HADS-A improved in OSA+CPAP+ at 12 months (1.7, SD 3.5, P = .04, and -2.1, SD 3.8, P = .02, respectively). The MoCA improved in those with low baseline MoCA and those with REM sleep behavior disorder. Mean CPAP use in users at 12 months was 3 hours 36 minutes per night. CONCLUSIONS:CPAP treatment of OSA in PD is associated with improved overall non-motor symptoms, sleep quality, anxiety, and global cognitive function over a 12-month period.
| S-EPMC5940433 | biostudies-literature
Project description:Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson disease (PD). Results from a multicenter study of patients with PD systematically sampled by age at onset have not been reported to date.To determine risk factors associated with carrying parkin mutations.Cross-sectional observational study.Thirteen movement disorders centers.A total of 956 patients with early-onset PD, defined as age at onset younger than 51 years.Presence of heterozygous, homozygous, or compound heterozygous parkin mutations.Using a previously validated interview, 14.7% of patients reported a family history of PD in a first-degree relative. Sixty-four patients (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygous, and 2.2% compound heterozygous). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous). Deletions in exons 3 and 4 and 255delA were common among Hispanics (specifically Puerto Ricans). Younger age at onset (<40 years) (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.8-8.8; P = .001), Hispanic race/ethnicity (OR compared with white non-Hispanic race/ethnicity, 2.7; 95% CI, 1.3-5.7; P = .009), and family history of PD in a first-degree relative (OR compared with noncarriers, 2.8; 95% CI, 1.5-5.3; P = .002) were associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous). Hispanic race/ethnicity was associated with carrying a heterozygous mutation (OR compared with white non-Hispanic race/ethnicity, 2.8; 95% CI, 1.1-7.2; P = .03) after adjustment for covariates.Age at onset, Hispanic race/ethnicity, and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation among Hispanics warrants further study.
| S-EPMC3329757 | biostudies-literature
Project description:Background: Asymmetry of motor signs is a cardinal feature of Parkinson disease which may impact phenotypic expression. Objective: To investigate the relationship between lateralization of motor signs and symptom progression and severity during longitudinal observation for up to 4 years in a naturalistic study. Methods: We analyzed data prospectively collected during the NINDS Parkinson Disease Biomarker Project (PDBP). We defined the Movement Disorder Society Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II as the primary measure of symptom progression. Left side predominant subjects were those whose lateralized motor scores on the MDS-UPDRS part III were ≥2 points higher on the left side than on the right side of the body. Multiple regression models (controlled for age, gender, education years, ethnicity, levodopa equivalent daily dose (LEDD) at baseline, and years with PD) were used to estimate the rate of symptom progression comparing left predominant (LPD) with non-left predominant (NLPD) subjects. A sensitivity analysis was performed using the same multiple regression models in the subgroups of low (0-26) or high (>27) MDS-UPDRS II score at baseline to determine if PD severity influenced the results. Results: We included 390 participants, 177 LPD and 213 NLPD. We found that MDS-UPDRS part II progression from baseline to 48 months was faster in LPD compared to NLPD (0.6 points per year faster in LPD, p = 0.05). Additionally, the LPD group was statistically significantly worse at baseline and at 48 months in several subparts of the MDS-UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) mobility score. Significantly slower progression (difference of -0.8, p = 0.01) and lower score at 48 months (difference of -3.8, p = 0.003) was seen for NLPD vs. LPD in the group with lower baseline MDS-UPDRS part II score. Conclusion: Left side lateralization was associated with faster symptom progression and worse outcomes in multiple clinical domains in our cohort. Clinicians should consider using motor predominance in their counseling regarding prognosis.
| S-EPMC8353110 | biostudies-literature
Project description:ObjectiveTo identify the changes in motor cortical facilitatory and inhibitory circuits in Parkinson disease (PD) by detailed studies of their time courses and interactions.MethodsShort-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) were measured with a paired-pulse paradigm using transcranial magnetic stimulation. Twelve patients with PD in both ON and OFF medication states and 12 age-matched healthy controls were tested. The first experiment tested the time course of SICF in PD and controls. The second experiment tested SICI at different times corresponding to SICF peaks and troughs to investigate whether SICI was affected by SICF.ResultsSICF was increased in PD OFF state and was reduced by dopaminergic medications. The reduction in SICF from the OFF to ON state correlated with the improvement in PD motor signs. SICI was reduced in PD OFF state and was only partially normalized by dopaminergic medications. At SICF peaks, improvement in SICI with medication correlated with improvement in PD motor sign. Principal component analysis showed that variations of SICF and SICI were explained by the same principal component only in the PD OFF group, suggesting that decreased SICI in the OFF state is related to increased SICF.ConclusionsMotor cortical facilitation is increased and inhibition is decreased in PD. Increased cortical facilitation partly accounts for the decreased inhibition, but there is also impairment in synaptic inhibition in PD. Increased cortical facilitation may be a compensatory mechanism in PD.
| S-EPMC3719423 | biostudies-literature