Benefit For Parkinson's Disease Patients Research Articles

Morbidity Milestones Demonstrate Long Disability-Free Survival in Parkinson's Disease Patients with Deep Brain Stimulation of the Subthalamic Nucleus.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD). The long-term benefit in PD patients with STN-DBS in comparison to medical treatment (MT) alone has not yet been demonstrated conclusively. To judge the long-term outcome of patients with STN-DBS. To assess the evolution of PD symptoms and health-related quality of life (HRQoL) after deep brain stimulation (DBS) surgery, we conducted a cross-sectional analysis of 115 patients with STN-DBS with rater-based scales and self-reported questionnaires. In addition, we screened records of all our STN-DBS patients (2001-2019, n=162 patients) for the onset of the morbidity milestones (falls, hallucinations, dementia, and nursing home placement) to assess disability-free life expectancy. In the first year of STN-DBS, levodopa equivalent dose was reduced and motor function improved. Nonmotor symptoms and cognition remained stable. These effects were similar to previous studies. Morbidity milestones occurred 13 ± 7 years after diagnosis. Motor function, cognition, and HRQoL significantly worsened after the occurrence of any milestone, confirming the clinical relevance of these milestones. After onset of the first milestone, mean survival time was limited to 5 ± 0.8 years, which is comparable with patients with PD but without STN-DBS. On average, PD patients with STN-DBS live with their disease for a longer time, and morbidity milestones occur later in the disease course than in PD patients with MT. As judged by morbidity milestones, morbidity remains compressed into the final 5 years of life in PD patients with STN-DBS.

Direct switch from levodopa/benserazide or levodopa/carbidopa to levodopa/carbidopa/entacapone in Parkinson’s disease patients with wearing-off: efficacy, safety and feasibility—an open-label, 6-week study

The study objective was to assess the efficacy, safety and feasibility of switching from levodopa/benserazide (LB) or levodopa/carbidopa (LC) to levodopa/carbidopa/entacapone (LCE) in Parkinson's disease (PD) patients with wearing-off. This was a multicenter, open-label, 6-week study; the primary outcome was success rate based on the patient-assessed Clinical Global Impression of Change (P-CGI-C). Secondary outcomes included investigator-assessed CGI-C (I-CGI-C), change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS), motor/non-motor wearing-off symptoms and quality of life-visual analog scale (QoL-VAS). After switching to LCE, 77% of patients reported an 'improvement' (p < 0.0001 vs. patients reporting 'no change or worsening'). Significant improvements were seen in I-CGI-C, UPDRS and QoL-VAS, regardless of prior therapy. Oral levodopa dosing was increased in 28% of patients; the primary outcome remained significant when these patients were excluded. The data suggest that switching from LB/LC to LCE provided a significant benefit in PD patients with wearing-off.

Localized striatal delivery of GDNF as a treatment for Parkinson disease.

Te n years ago, a glial cell line‐derived neurotrophic factor (GDNF) that has prominent actions on nigral dopaminergic neurons, both in vitro and in animal models of Parkinson disease (PD), was discovered. A recently published open-label clinical trial now reports that long-term intracerebral delivery of GDNF may also markedly improve symptoms in patients with PD. Here we review the experimental data underlying the current clinical trial and discuss the types of structural and functional changes induced by GDNF that may provide symptomatic benefit in PD patients. Data obtained in rodent and primate models of PD highlight the importance of how and where the factor is administered, supporting the view that GDNF has to be delivered locally in the brain parenchyma, at the receptive target site, to provide therapeutic benefit in PD patients. The cardinal symptoms of PD, including a difficulty in initiating movement, slowness of movement and stiffness and shaking at rest, are to a large extent caused by the progressive degeneration of the dopamine-producing neurons in the substantia nigra. Nigral cell loss proceeds over many years, during the early symptomatic stage, during manifest PD and during severe, end-stage disease. At the onset of disease, about 50% of dopaminergic neurons have been lost, and there is on average a further loss of 45% within the first decade, accompanied by a profound striatal dopaminergic denervation. It is this slow and protracted degenerative process that creates opportunities for disease intervention, such as blocking nigral cell loss and promoting recovery by improved function—and possibly by inducing regeneration and sprouting—of the surviving nigral dopaminergic neurons. Results obtained in animal models of PD indicate that GDNF may possess the desired properties to be used as a disease-modifying therapeutic factor for PD. Neurotrophic factors, by virtue of their neuroprotective properties, have attracted considerable interest as potential therapeutic agents in neurodegenerative diseases. Attempts to apply these factors clinically, however, have so far been disappointing because of their poor efficacy and induction of troublesome side effects. In these clinical trials, the recombinant protein was delivered either systemically or into the cerebrospinal fluid (intraventricularly or intrathecally) in patients suffering from amyotrophic lateral sclerosis, peripheral neuropathy, PD or Alzheimer disease 1,2 .R esults from these studies indicate that the neurotrophic factors, whose receptors are widely distributed, are prone to inducing pronounced side effects when delivered by these routes. The poor penetration across the blood‐brain barrier, as well as the limited passage of proteins from the cerebrospinal fluid into the brain tissue, has made it necessary to administer the factors at doses that are likely to induce side effects. These effects may not be so evident in small-sized experimental animals. For this reason, they may have gone unnoticed in the preclinical studies and may have become apparent in some cases only at the phase II/III stage of the clinical trails when larger numbers of patients were included. The therapeutic value of neurotrophic-factor delivery, therefore, may not be possible to achieve unless the factors are delivered locally at the receptive target sites within the central nervous system. Steven Gill and collaborators 3 have, for the first time, tested this mode of delivery in patients with advanced PD using continuous intracerebral infusion of GDNF. Although quite promising, the results of this initial open-label trial should be interpreted cautiously because the study was based on a small number of patients who were monitored over a relatively short follow-up period. Nevertheless, the data reported indicate that pronounced clinical benefit, in the absence of any serious side effects, may be possible to obtain by GDNF using intrastriatal delivery. Neuroprotective effects of GDNF in animal models of PD