Off-medication Scores Research Articles

Efficacy of short pulse and conventional deep brain stimulation in Parkinson's disease: a systematic review and meta-analysis.

Deep brain stimulation (DBS) is a common treatment for Parkinson's disease. However, the clinical efficacy of short pulse width DBS (spDBS) compared with conventional DBS (cDBS) is still unknown. This meta-analysis investigated the effectiveness of spDBS versus cDBS in patients with PD. Four databases (PubMed, Cochrane, Web of Science, and Embase) were independently searched until October 2021 by two reviewers. We utilized the following scales and items: therapeutic windows (TW), efficacy threshold, side effect threshold, Movement Disorder Society-Sponsored Revision Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off-medication score, Speech Intelligence Test (SIT), and Freezing of Gait Questionnaire (FOG-Q). The analysis included seven studies with a total of 87 patients. The results indicated that spDBS significantly widened the therapeutic windows (0.99, 95% CI = 0.61 to 1.38) while increasing the threshold amplitudes of side effects (2.25, 95% CI = 1.69 to 2.81) and threshold amplitudes of effects (1.60, 95% CI = 0.84 to 2.36). There was no statistically significant difference in UPDRS part III, SIT, and FOG-Q scores between spDBS and cDBS groups, suggesting that treatment with both cDBS and spDBS may result in similar effects of improved dysarthria and gait disorders. Compared with cDBS, spDBS is effective in expanding TW. Both types of deep brain stimulation resulted in improved gait disorders and speech intelligibility.

Predictors of Long-Term Outcome of Subthalamic Stimulation in Parkinson Disease.

This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses. In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome. Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597.

Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease

Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti-L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P < .001) and phosphorylated mechanistic target of rapamycin (mTOR) (0.22 AU; 95% CI, 0.04-0.40 AU; P = .02). Improvements in Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 off-medication scores were associated with levels of total mTOR (F4,50 = 5.343, P = .001) and phosphorylated mTOR (F4,50 = 4.384, P = .04). The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.

Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial

Summary Background Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. Methods In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Findings Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Interpretation Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. Funding Michael J Fox Foundation for Parkinson's Research.

The long-term efficacy of STN vs GPi deep brain stimulation for Parkinson disease: A meta-analysis.

Objective:This meta-analysis assessed the long-term efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) for Parkinson disease (PD).Methods:PubMed, Cochrane Library, and Clinical Trials databases were searched. Outcomes were unified Parkinson disease rating scale section (UPDRS) III off-medication score, Parkinson's disease questionnaire: 39 activities of daily living (PDQ-39 ADL) score, and levodopa-equivalent dosage after DBS.Results:During the off-medication state, pooled weighted mean difference (WMD) of UPDRS III score was .69 (95% confidence interval [CI] = −1.77 to 3.16, P = .58). In subgroup analysis, WMD of UPDRS III off-medication scores from baseline to 2 years and 3 years post-DBS were −.61 (95% CI = −2.97 to 1.75, P = .61) and 2.59 (95% CI = −2.30 to 7.47, P = .30). Pooled WMD of changes in tremor, rigidity, and gait scores were 1.12 (95% CI = −0.05 to 2.28, P = .06), 1.22 (95% CI = −0.51 to 2.94, P = .17) and .37 (95% CI = −0.13 to 0.87, P = .15), respectively. After DBS, pooled WMD of PDQ-39 ADL and LED were −3.36 (95% CI = −6.36 to −0.36, P = .03) and 194.89 (95% CI = 113.16 to 276.63, P < .001).Conclusions:STN-DBS and GPi-DBS improve motor function and activities of daily living for PD. Differences in the long-term efficacy for PD on motor symptoms were not observed.

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. Michael J Fox Foundation for Parkinson's Research.

Predictive factors of speech intelligibility following subthalamic nucleus stimulation in consecutive patients with Parkinson's disease

Speech changes after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) can be variable, with the majority of patients experiencing speech deterioration over time. The aim of this study was to describe the perceptual characteristics of speech following chronic STN-DBS and to analyze clinical and surgical factors that could predict speech change. Fifty-four consecutive patients (34 men; mean age ± standard deviation (SD), 58.8 ± 6.3 years; mean ± SD disease duration, 12.5 ± 4.7 years; mean ± SD levodopa equivalent, 1556 ± 671 mg/day; mean ± SD Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) off-medication score, 48.1 ± 17.9 [range, 20-89]; and mean ± SD UPDRS-III on-medication score, 12.4 ± 7.8 [range, 2-31]) participated in this study. They were assessed before and at 1 year after surgery using the Assessment of Intelligibility for the Dysarthric Speech, the perceptual scale from Darley et al., and the UPDRS-III. Speech intelligibility deteriorated on average by 14.4% (P = 0.0006) after 1 year of STN-DBS when off-medication and by 12.3% (P = 0.001) when on-medication. The effect on speech was not linked to age at surgery, unlike the effect on motor outcome. The most significant predictive factors for deterioration of speech intelligibility when patients were off-medication/on-stimulation were lower preoperative speech intelligibility on-medication, longer disease duration, and medially placed left hemisphere active electrode contact. Speech change after STN-DBS is variable and multifactorial. Consistent preoperative speech evaluation would help inform patients about the possible effects of surgery. Appropriate consideration of speech deficits might assist surgical targeting, particularly of the left electrode.

Gender differences in quality of life following subthalamic stimulation for Parkinson's disease

Surveys of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD) have shown that this procedure is roughly twice more common in men than in women. Here, we investigate possible differences between women and men undergoing STN DBS, with respect to health-related quality of life. Forty-nine consecutive patients (18 women) received STN DBS. The impact of PD and its surgical treatment was compared between women and men, before and at mean of 19 ± 11 months after surgery, using the Unified Parkinson Disease Rating Scale (UPDRS) and the Parkinson's Disease Questionnaire-39 (PDQ-39). Duration of disease at surgery and off-medication scores of the motor part of the UPDRS were similar in women and men. At baseline, women had lower doses of dopaminergic medication than men, experienced more disability due to dyskinesias, had more sensory symptoms and perceived more difficulties in mobility. Following DBS, both men and women showed equal and significant (P < 0.001) improvement in off-medication scores on the UPDRS III. On the PDQ-39, women expressed improvement in ADL to a greater extent than men. Moreover, women but not men showed a positive effect on mobility, stigma and cognition as well as on the summary score of PDQ-39. Although STN DBS results in equal degree of motor improvement between women and men, health-related quality of life seems to improve to a greater extent in women.

A two‐year randomized controlled trial of progressive resistance exercise for Parkinson's disease

The effects of progressive resistance exercise (PRE) on the motor signs of Parkinson's disease have not been studied in controlled trials. The objective of the current trial was to compare 6-, 12-, 18-, and 24-month outcomes of patients with Parkinson's disease who received PRE with a stretching, balance, and strengthening exercise program. The authors conducted a randomized controlled trial between September 2007 and July 2011. Pairs of patients matched by sex and off-medication scores on the Unified Parkinson's Disease Rating Scale, motor subscale (UPDRS-III), were randomly assigned to the interventions with a 1:1 allocation ratio. The PRE group performed a weight-lifting program. The modified fitness counts (mFC) group performed a stretching, balance, and strengthening exercise program. Patients exercised 2 days per week for 24 months at a gym. A personal trainer directed both weekly sessions for the first 6 months and 1 weekly session after 6 months. The primary outcome was the off-medication UPDRS-III score. Patients were followed for 24 months at 6-month intervals. Of 51 patients, 20 in the PRE group and 18 in the mFC group completed the trial. At 24 months, the mean off-medication UPDRS-III score decreased more with PRE than with mFC (mean difference, -7.3 points; 95% confidence interval, -11.3 to -3.6; P<0.001). The PRE group had 10 adverse events, and the mFC group had 7 adverse events. PRE demonstrated a statistically and clinically significant reduction in UPDRS-III scores compared with mFC and is recommended as a useful adjunct therapy to improve Parkinsonian motor signs. © 2013 Movement Disorder Society.

Side‐effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson's disease

We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS) in 20 patients with Parkinson's disease (PD) by means of clinical assessments and patient diaries 12 months after surgery. STN-DBS reduced the UPDRS part III off-medication score by 33%, and successively improved complete daily on-time without dyskinesia at 12 months significantly. In conclusion, our study demonstrates the efficacy of chronic STN-DBS on motor features in a selected population of advanced PD patients. In addition to clinical assessments, patients' diaries serve as an essential tool to evaluate the functional motor status after STN-DBS.

Bilateral Subthalamic Nucleus Stimulation for Parkinson's Disease: A Systematic Review of the Clinical Literature

To evaluate the benefits and adverse effects of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease (PD) by systematically reviewing the published literature. A search of the PubMed database using the key words subthalamic, nucleus, and stimulation yielded 624 articles published between 1966 and December 2003. Only articles that included original, nonduplicated descriptions of patients with PD treated with bilateral subthalamic nucleus stimulation were selected for further analysis. A total of 38 studies from 34 neurosurgical centers in 13 countries were identified for critical review. The outcomes for 471 patients with PD treated with bilateral subthalamic nucleus stimulation were assessed according to the Unified Parkinson's Disease Rating Scale in both on-medication and off-medication conditions. With stimulation, Unified Parkinson's Disease Rating Scale motor scores in the off-medication condition improved by 50% after 6 months, 56% after 12 months, 51% after 2 years, and 49% after 5 years compared with preoperative off-medication scores. At 12 months of subthalamic nucleus stimulation, the mean improvement in tremor was 81%, in rigidity was 63%, in bradykinesia was 52%, in gait was 64%, and in postural instability was 69% when compared with preoperative off-medication subscores. On-medication dyskinesias were reduced by 94%, as assessed 12 months after stimulation using the Unified Parkinson's Disease Rating Scale IV complications of therapy score. There was an overall 52% reduction in the l-dopa-equivalent dose intake after 12 months of stimulation. Most adverse effects were mild to moderate. There was a 1 to 2% incidence of severe adverse effects (death or permanent neurological deficits related to intracerebral hemorrhages). Nineteen percent of the patients had adverse effects related to stimulation that could be reversed by changing stimulation parameters. There was a 9% incidence of adverse effects related to the hardware (infections, lead and pulse generator problems). Bilateral subthalamic nucleus stimulation is effective in the treatment of PD. Further refinements in patient selection and surgical technique may lessen the incidence of complications associated with this procedure.