Levodopa therapy for Parkinson disease: A look backward and forward

Although levodopa is widely recognized as the most effective therapy for Parkinson disease (PD), its introduction 5 decades ago was preceded by several years of uncertainty and equivocal clinical results. The translation of basic neuroscience research by Arvid Carlsson and Oleh Hornykiewicz provided a logical pathway for treating PD with levodopa. Yet the pioneering clinicians who transformed PD therapeutics with this drug--among them Walther Birkmayer, Isamu Sano, Patrick McGeer, George Cotzias, Melvin Yahr, and others--faced many challenges in determining whether the concept and the method for replenishing deficient striatal dopamine was correct. This article reviews highlights in the early development of levodopa therapy. In addition, it provides an overview of emerging drug delivery strategies that show promise for improving levodopa\u27s pharmacologic limitations

Video Review of Baseline Performance on Global Ratings in a Double‐Blind Placebo Surgery Trial

BACKGROUND A randomized double‐blind sham surgery‐controlled trial was conducted to determine the effectiveness of implantation of human embryonic dopamine neurons into the putamen of patients with advanced Parkinson\u27s disease (PD). The present analyses determined whether patients viewing a video of themselves performing motor activities off medications at baseline would affect self‐ratings 12 months later on the Global Rating Scale (GRS). OBJECTIVES To examine changes in GRS scores pre‐/post‐video review for the total sample; to examine differences in scores between actual implant and sham groups, as well as perceived groups pre‐ and post‐video review; to examine differences among four subgroups of patients based on actual and perceived treatment (i.e., actual implant/perceived implant). METHODS Forty participants were recruited and randomly assigned to receive either neural implantation or sham surgery. The primary outcome variable was a one‐item GRS ranging from ‐3 (much worse since surgery) to +3 (much improved since surgery). At 12 months (before the blind was lifted) patients rated themselves on the GRS before and after viewing the baseline video. RESULTS Total sample GRS scores improved after the video (P = .001). There were no differences between the actual implant and sham groups before or after the video, but there were differences between perceived groups at both times (P \u3c .001). Among subgroups, improvement after the video was found only in the group receiving the implant but who thought sham (P = .011). CONCLUSION When self‐ratings are an outcome variable, review of baseline videos is recommended before making comparative ratings

An Estimate of the Prevalence of Dementia in Idiopathic Parkinson's Disease

A review of the records for evidence of dementia using criteria adapted from the third edition of the Diagnostic and Statistical Manual of Mental Disorders in every patient (hospitalized and outpatient) with parkinsonism at a major medical center during an 18-month period revealed an overall prevalence of 10.9% in 339 patients with idiopathic Parkinson's disease. Demented patients were older, had a later age at onset of motor manifestations, and a more rapid progression of physical disability than nondemented patients. Duration of illness and levodopa use and the presence of tremor or depression were similar in demented and nondemented patients. Demented patients more often responded poorly or developed adverse effects to levodopa than nondemented patients. When Parkinson's disease began after age 70 years, dementia was noted over three times more frequently than when the disease began at an earlier age. The age-specific prevalence rate of dementia for patients older than 70 years was more than twice that for younger patients. Moreover, the number of records with evidence for dementia with idiopathic Parkinson's disease was 3.75 times greater than expected in comparison with data from a study of the prevalence of dementia in the elderly

Effects of Perceived Treatment on Quality of Life and Medical Outcomesin a Double-blind Placebo Surgery Trial

Context This study was part of a large double-blind sham surgery–controlled trial designed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the brains of persons with advanced Parkinson\u27s disease. This portion of the study investigated the quality of life (QOL) of participants during the 1 year of double-blind follow-up. Objectives To determine whether QOL improved more in the transplant group than in the sham surgery group and to investigate outcomes at 1 year based on perceived treatment (the type of surgery patients thought they received). Design Participants were randomly assigned to receive either the transplant or sham surgery. Reported results are from the 1-year double-blind period. Setting Participants were recruited from across the United States and Canada. Assessment and surgery were conducted at 2 separate university medical centers. Participants A volunteer sample of 40 persons with idiopathic Parkinson\u27s disease participated in the transplant ( parent ) study, and 30 agreed to participate in the related QOL study: 12 received the transplant and 18 received sham surgery. Interventions Interventions in the parent study were transplantation and sham brain surgery. Assessments of QOL were made at baseline and 4, 8, and 12 months after surgery. Main Outcome Measures Comparison of the actual transplant and sham surgery groups and the perceived treatment groups on QOL and medical outcomes. We also investigated change over time. Results There were 2 differences or changes over time in the transplant and sham surgery groups. Based on perceived treatment, or treatment patients thought they received, there were numerous differences and changes over time. In all cases, those who thought they received the transplant reported better scores. Blind ratings by medical staff showed similar results. Conclusions The placebo effect was very strong in this study, demonstrating the value of placebo-controlled surgical trials

Ageing, masculinity and Parkinson's disease: Embodied perspectives

Parkinson’s Disease (PD) presents as an illness which predominantly affects older men. However older men’s lived experiences of PD, including how they are influenced by age and gender relations has seen little empirical study. Drawing on Watson’s (2000) male body schema, this paper explores PD’s effects on men’s bodies, alongside how men engage with masculinities and ageing in order to make meaning from these experiences. Data is presented from 30 narrative and semi structured interviews with 15 men of various ages who were living with PD. Findings suggest that PD threatens a pragmatic embodiment expressed through men’s everyday occupations; a visceral embodiment located in difficulties with the body’s basic movements and intimate functions and an experiential embodiment concerned with emotions and sensations within and about the body. In addition, each dimension of men’s embodiment also intersected with the ageing process, a process also shaped in turn by broader social and cultural concerns regarding the positions and possibilities of men’s lives as they move through the life course. This paper concludes by discussing the implications of gender and ageing in understanding men’s experiences of PD

Emerging topics in FXTAS

This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis

Case-control study of the parkin gene in early-onset Parkinson disease

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD

How do people live life successfully with Parkinson's disease?

The aim of this paper is to explore how people live life successfully with Parkinson's disease and what contributed to the level of success