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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.

In this randomized trial comparing neurostimulation of the subthalamic nucleus with medical management alone in 156 patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. In patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. Parkinson's disease is one of the most disabling chronic neurologic diseases and leads to a significant loss of quality of life. 1 , 2 Several drugs are available that can effectively treat the symptoms of the disease, but long-term medical management is often complicated by the appearance of levodopa-induced motor complications, leading to rapid changes between periods of severe akinesia and periods of mobility that may be accompanied by troublesome hyperkinesias. 3 Dopamine agonists, amantadine, catechol O -methyltransferase (COMT) inhibitors, 3 and other drugs can effectively improve mobility and reduce dyskinesias initially but typically fail after several years. 4 The administration of high-frequency continuous electrical . . .

Background Parkinson’s disease is associated with a dysbiotic, proinflammatory gut microbiome, disruptions to intestinal barrier functions, and immunological imbalance. Microbiota-produced short-chain fatty acids, such as propionic and butyric acid promote gut barrier integrity and immune regulation, but their impact on Parkinson’s disease pathology remains mostly unknown. Methods In a randomized double-blind prospective study, 72 people with Parkinson’s disease received propionic and butyric acid and/or the prebiotic fiber 2′-fucosyllactose supplementation over 6 months in combination with existing Parkinson’s disease-specific therapy. Patients underwent complete neurological assessment and provided blood and stool samples before as well as 3 and 6 months after supplementation. Results We observed a robust improvement in motor symptoms, with all intervention groups achieving clinically meaningful reductions. These motor benefits were paralleled by clinically relevant reductions in levodopa medication. In contrast, effects on nonmotor symptoms were more heterogeneous. Notably, the interventions also modulated peripheral immune responses and enhanced mitochondrial respiration in immunocytes. Postintervention microbiota remodeled inflammatory and barrier-related gene sets in gut organ cultures and improved in vitro barrier functions. Treatment response was associated with microbiome composition, distinct patterns of colonic transcription and permeability ex vivo. Multiobjective analysis revealed immune parameters associated with an optimal response to supplementation. Conclusion Short-chain fatty acids ameliorate clinical symptoms in Parkinson’s disease patients and modulate intestinal and peripheral immunity. Registration: This clinical trial was retrospectively registered with the German Clinical Trials Register (DRKS), registration number DRKS00027061 on 11/19/2021.

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.

The heterogeneity of Parkinson’s disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α -synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut–brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.