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In this 2-year trial involving patients with Parkinson's disease and early motor complications, subthalamic stimulation plus medical therapy resulted in better quality of life and motor function than medical therapy alone. Parkinson's disease is a progressive neurodegenerative disease that affects dopaminergic neurotransmission, resulting in bradykinesia, rigidity, and rest tremor. After an initial honeymoon period, during which there is a sustained response to dopaminergic treatment, beneficial effects are hampered by levodopa-induced motor complications, 1 progressively compromising quality of life. 2 – 4 Because levodopa-responsive parkinsonian symptoms are improved by high-frequency stimulation of the subthalamic nucleus, 5 , 6 neurostimulation has become an established treatment for advanced Parkinson's disease with medically intractable fluctuations and dyskinesia 7 – 10 and has shown long-term efficacy. 11 – 13 It is typically used after the disease has been present for 11 to 13 years, 7 – . . .

\"We decided to write this book to provide a useful guide to two groups of people. Firstly, for those diagnosed with Parkinson's who are looking for a safe form of exercise that could work for them. ... a number of clients ... tell us how their increased flexibility and strength as well as their improved balance and walking have helped them to remain independent. Secondly, we hope this book will also be enjoyed by Pilates instructors who are wondering how they can best help a client who comes in with a diagnosis of Parkinson's.\" -- Introduction [ix].

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov: NCT04075318 . A first-in-patient trial of UB-312, an active immunotherapeutic for Parkinson’s disease, was well tolerated and elicited antibodies that engage misfolded α-synuclein.

Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment. At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted. UK Medical Research Council, Parkinson's UK, and UK Department of Health.

Repetitive transcranial magnetic stimulation (rTMS) has been used in the clinical treatment of Parkinson's disease (PD). Most of rTMS studies on PD used high‐frequency stimulation; however, excessive nonvoluntary movement may represent abnormally cortical excitability, which is likely to be suppressed by low‐frequency rTMS. Decreased neural activity in the basal ganglia on functional magnetic resonance imaging (fMRI) is a characteristic of PD. In the present study, we found that low‐frequency (1 Hz) rTMS targeting individual finger‐tapping activation elevated the amplitude of local neural activity (percentage amplitude fluctuation, PerAF) in the putamen as well as the functional connectivity (FC) of the stimulation target and basal ganglia in healthy participants. These results provide evidence for our hypothesis that low‐frequency rTMS over the individual task activation site can modulate deep brain functions, and that FC might serve as a bridge transmitting the impact of rTMS to the deep brain regions. It suggested that a precisely localized individual task activation site can act as a target for low‐frequency rTMS when it is used as a therapeutic tool for PD. A “Steady‐state” paradigm of finger‐tapping task detected that self‐initiated finger‐tapping was more intensively associated with the motor‐related brain area than visual‐guided. Low‐frequency rTMS targeting individual task peak activation could precisely elevated the local neural activity in the putamen. The basal ganglia neural activity may be sensitive to low‐frequency rTMS and the excessive nonvoluntary movement of PD is likely to be suppressed by low‐frequency rTMS rather than high frequency.

The serotonin-receptor modulator pimavanserin reduces psychosis in patients with Parkinson’s disease. In a randomized discontinuation trial involving patients with psychosis related to several types of dementia, the frequency of relapse over a period of 26 weeks was 13% with pimavanserin and 28% with placebo.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is recognized as a safe and effective treatment in mid- and advanced-staged Parkinson’s disease (PD) that decreases the need for PD medications and their associated costs. This study reports medication costs from the only clinical trial to evaluate DBS in patients with early-stage PD and projects costs through advanced-stage disease. The DBS in early-stage PD pilot was a prospective, single-blind clinical trial that randomized 30 patients with early-stage PD 1:1 to receive bilateral STN-DBS plus optimal drug therapy (ODT) or ODT alone. Subjects who completed the trial participated in an observational follow-up study and were evaluated annually for five years after randomization. PD medication data collected at each study visit were used to calculate and project medication costs (n = 28). Five-year cumulative medication cost reduction with early DBS+ODT was $28,246. Mean annual medication cost for early DBS+ODT subjects was 2.4 times lower than early ODT subjects (β = 2.4, 95%CI:1.5–3.7, p = 0.0004). Early DBS+ODT is projected to reduce cumulative medication costs by $104,958 over 15 years of disease duration. DBS in early-stage PD may provide long-term medication cost reduction compared to standard care. •Deep brain stimulation (DBS) in early Parkinson’s disease reduces PD medication use.•Early DBS provides long-term PD medication cost savings versus standard care.•Medication cost savings do not outweigh, but may partly offset, DBS-associated costs.

Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for disabling motor symptoms of Parkinson’s disease (PD) that persist despite optimal pharmacological treatment. Currently, DBS is not performed if there is concomitant significant cognitive impairment based on concerns of cognitive deterioration, higher complication rate and less functional improvement. However, this has not been investigated so far. Methods A single center, prospective, randomized, open-label, blinded end-point (PROBE design) pilot clinical trial is being performed. Patients are eligible for the trial if they have PD dementia (PDD), are able to provide informed consent, and experience disabling motor response fluctuations, bradykinesia, dyskinesia, or painful dystonia, despite optimal pharmacological treatment. In total 44 patients will be randomized to either STN-DBS accompanied by best medical treatment (DBS group) or to best medical treatment alone (BMT group). The primary outcome measure is the change from baseline to 30 weeks on the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale part III score in a standardized off-drug phase. The main secondary outcome measures consist of scales assessing cognitive aspects of daily living, neuropsychiatric symptoms and impulsive compulsive disorders. Additional secondary outcome measures include motor signs during on-drug phase, dyskinesia, motor fluctuations, cognitive performance, (severe) adverse events, treatment satisfaction, and caregiver burden. Patients will be followed during 52 weeks after randomization. Discussion The Deep Brain Stimulation for MOtor symptoms in patients with Parkinson’s disease DEmentia (DBS-MODE) trial directly compares the effectiveness and safety of DBS with BMT in patients with PDD. Trial registration The DBS-MODE trial has been registered in the International Clinical Trial Registry Platform (NL9361) on the 24 th of March 2021 ( https://trialsearch.who.int/Trial2.aspx?TrialID=NL9361 ).

Objective: To quantify postural sway in subjects with Parkinson's disease and elderly controls, and determine the effects of Parkinson's disease, deep brain stimulation, levodopa, and their interactions on postural control during quiet stance. Methods: Centre of foot pressure (CoP) displacement under each foot was measured during three 60 s trials of quiet stance with eyes open in 11 controls and six patients with Parkinson's disease. Subjects with Parkinson's disease were tested in four treatment conditions: off both deep brain stimulation and levodopa (off condition); on deep brain stimulation; on levodopa; and on both deep brain stimulation and levodopa. The variables extracted from CoP included: root mean square distance (rms), mean velocity, 95% power frequency (f95%), area of the 95% confidence ellipse (ellipse area), direction of its major axis (mdir), and postural asymmetry between the feet. Results: rms and area of postural sway were larger than normal in subjects with Parkinson's disease in the off condition, increased further with levodopa, and significantly decreased with deep brain stimulation. Mean velocity and f95% were also larger than normal but were restored to normal by all treatments, especially by deep brain stimulation. The combined effect of deep brain stimulation and levodopa resulted in a postural sway that was an average of the effect of each treatment individually. Levodopa increased sway more in the mediolateral than in the anterior-posterior direction. Subjects with Parkinson's disease had asymmetrical mean velocity and f95% between the feet, and this asymmetry increased with levodopa but decreased with deep brain stimulation. The f95% of the CoP correlated with tremor, posture, and gait subcomponents of the unified Parkinson's disease rating scale. Conclusions: Subjects with Parkinson's disease have abnormal postural sway in stance. Treatment with levodopa increases postural sway abnormalities, whereas treatment with deep brain stimulation improves postural sway. Quantitative evaluation of static posturography may be a useful adjunct to clinical measures in patients with Parkinson's disease.