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Biomedical subjects

Bernard Ravina

Publications and source records attributed to Bernard Ravina.

13 recordsLinked to original sources
PubMed2006

Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease.

OBJECTIVE: Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects. METHODS: Nicotinic acetylcholine receptors were imaged in 10 nondemented Parkinson's disease patients and 15 age-matched healthy subjects using a single-photon emission computed tomography ligand [(123)I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus nondisplaceable), as well as the delivery (K(1)). RESULTS: Parkinson's disease showed a widespread significant decrease (approximately 10%) of V in both cortical and subcortical regions without a significant change in K(1). INTERPRETATION: These results indicate the importance of extending the study to demented patients.

Aged↗
PubMed2006

Provisional diagnostic criteria for depression in Parkinson's disease: report of an NINDS/NIMH Work Group.

Mood disorders are the most common psychiatric problem associated with Parkinson's disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH-sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD-associated depression.

Comorbidity↗
PubMed2005

A responsive outcome for Parkinson's disease neuroprotection futility studies.

Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinson's disease (sensitive to tracking disease progression in the short-term) has not been determined. Data sets from three clinical trials were used to compare Parkinson's disease outcome measures. Total Unified Parkinson's Disease Rating Scale (UPDRS; Mentation + Activities of Daily Living + Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinson's disease are feasible in terms of short duration and small sample size requirements, and this design is being applied in two ongoing Parkinson's disease studies to select agents for future larger and longer term neuroprotection studies.

Clinical Trials as Topic↗
PubMed2005

Non-linearity of Parkinson's disease progression: implications for sample size calculations in clinical trials.

BACKGROUND: Estimation of sample size for long-term studies of neuroprotection in Parkinson's disease requires information on expected clinical decline. Values may be obtained by analyzing existing long-term data sets or by prediction models of clinical decline applied to available data from shorter-term trials. The most commonly used measure to track clinical decline is the Unified Parkinson's Disease Rating Scale (UPDRS) but this measure is also affected by symptomatic therapy. Models can help better understand behavior of the UPDRS after initiation of symptomatic therapy when scores will improve and eventually start deteriorating again. PURPOSE: To understand how UPDRS scores progress after initiation of symptomatic therapy and how this progression impacts sample size calculations. METHODS: We developed a non-linear model of UPDRS after introduction of symptomatic therapy. The model is specified as a non-linear mixed effects model and is applied to three different data sets from clinical trials. The model is then used to produce estimates for the change in UPDRS and its associated variance for a period of up to five years of follow-up. The estimates produced by the model serve as the basis for sample-size calculations for different lengths of follow-up (one through five years) and for different values of clinically meaningful change in UPDRS. RESULTS: Despite differences in the short-term benefit of the dopaminergic drugs, after a period of approximately six months UPDRS scores progress linearly at an estimated rate of approximately three points a year. The sample size that is required for a clinical trial where the baseline coincides with initiation of symptomatic therapy is very large. On the other hand, if baseline is set at six months after initiation of symptomatic therapy then the sample size required decreases with length of follow-up. LIMITATIONS: Model specification and estimation is based on a set of simplifying assumptions regarding the progression of individual level UPDRS scores. CONCLUSIONS: Sample size calculations based on these estimates indicate a substantial reduction in sample size if patients are required to be on symptomatic treatment for a period of time before being randomized to a neuroprotective trial.

Antiparkinson Agents↗
PubMed2004

Exercise-induced dystonia as a preceding symptom of familial Parkinson's disease.

Paroxysmal exercise-induced dystonia can occur with Parkinson's disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise-induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, sequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype-phenotype studies in this and similar families may give clues to pre-symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future.

Aged↗
PubMed2004

Funding evidence: the National Institute of Neurological Disorders and Stroke Clinical Trials Program.

The goal of the National Institute of Neurological Disorders and Stroke (NINDS) Clinical Trials Program is to foster clinical trials that will provide the evidence needed to inform clinical care. The NINDS currently supports clinical research in over 150 neurological disorders. The rapid pace of preclinical discovery and the diversity of neurological diseases, however, present challenges for clinical trials. There is a growing number of potential interventions to be tested in clinical trials. The NINDS Clinical Trials program is therefore exploring ways of making drug selection for clinical trials more evidence-based. Additionally, NINDS supports pilot clinical trials that focus on the timely and efficient testing of agents to determine if resource-intensive comparative efficacy trials are warranted. In concert with the National Institutes of Health Roadmap, NINDS is planning to expand clinical trials infrastructure. This infrastructure is intended to enable the conduct of clinical trials for rare diseases and diseases without previous trials experience and facilitate the recruitment of a broad range of participants. Rigorous programs to select agents, and design and monitor clinical trials will encourage the efficient use of this clinical trials infrastructure and will ensure that NINDS-funded studies meet the highest scientific and ethical standards.

Academies and Institutes↗
PubMed2003

Early-onset Parkinson's disease caused by a compound heterozygous DJ-1 mutation.

Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD.

Adult↗
PubMed2003

Mutation at the SCA17 locus is not a common cause of parkinsonism.

Spinocerebellar ataxia (SCA) 17 is a dominant, progressive, neurodegenerative disorder. The disease is caused by a triplet repeat expansion mutation within TATA-binding protein (TBP). Ataxia, dementia, parkinsonism and dystonia are common features. We have previously shown in several pedigrees that SCA-2 and SCA-3 can cause both parkinsonism and typical Parkinson's disease in the absence of prominent ataxia; a finding which has been confirmed by others. Given these previous findings and the description of parkinsonism as a common feature of SCA-17 we examined this locus in a series of probands from families with 2 or more members affected with parkinsonism (n=51) and a group of sporadic parkinsonism patients (n=59). We did not find any repeat sizes in the pathogenic range. The repeats we observed ranged from 29 to 41 (mean 36.8; median 37). We conclude that SCA-17 repeat expansion mutations are not a common cause of familial parkinsonism.

Adolescent↗
PubMed2003

Brain banking for neurodegenerative diseases.

PURPOSE OF REVIEW: Brain banking remains a necessity for the study of neurodegenerative diseases. While the characterization of pathology observed at autopsy confirms clinical diagnosis, the structure and contents of pathological hallmarks are the starting point from which disease pathogenesis may be elucidated. Traditional neuropathology has served to define, characterize, and diagnose neurodegenerative diseases, accompanied by clinical presentation. The pathological substrates are then studied for their role in how they cause dysfunction in disease, or how their accumulation is presumably damaging. RECENT FINDINGS: New genetic findings have revolutionized these studies and have prompted a reexamination of traditional pathological definitions of disease. Many familial genetic mutations have been found, encoding proteins such as synuclein, parkin, tau, and others, creating genetic ways to define neurodegenerative diseases. Many of these proteins are components of aggregates, thus the ability to label these proteins has revealed new pathological characteristics that must be standardized. More complicating is that many proteins genetically linked to clinically distinct diseases are involved in overlapping neuropathology of what now appears to be a spectrum of diseases: 'synucleinopathies', 'tauopathies', and so on. Moreover, as genetic discoveries fuel molecular experiments on brain tissue, banking methods must now accommodate these techniques. Lastly, DNA screening involves ethical issues beyond those which were previously considered with postmortem tissue banking. SUMMARY: As more proteins are linked to disease, more is revealed about the underlying causative mechanisms, exposing points for interventions. To achieve this end, characterization for neurodegenerative disease in the post genomic era must include genotype, phenotype and clinical characterization, and postmortem brain banking data which includes these.

Brain↗
PubMed2002

Preference-based quality-of-life in patients with Parkinson's disease.

BACKGROUND: Preference-based instruments are a specific type of health-related quality-of-life scale designed to measure the relative value of health. Because of this property, they are the appropriate measures of quality of life for cost-effectiveness analysis. Although preference-based scales are widely used, their validity has rarely been tested in specific patient groups. OBJECTIVES: To assess quality of life using preference-based scales in a group of patients with PD and to compare these scores with measures of clinical severity and traditional quality of life. METHODS: Each patient was rated using the Disability and Distress Index (DDI), the Euroqol System (EQ-5D), and the Health Utilities Index Mark II (HUI). Clinical severity was measured using the Unified PD Rating Scale (UPDRS) and PD Questionnaire-39 (PDQ-39) quality-of-life instrument. Results from preference-based instruments were compared with each other and with clinical measures of disease severity. RESULTS: One hundred subjects participated in the study, and 97 completed all preference-based instruments. Scores from all three instruments correlated well with the UPDRS and most domains of the PDQ-39. The mean scores for the DDI, HUI, and EQ-5D were 0.92 (range 0 to 1), 0.74 (range 0.19 to 1), and 0.58 (range -0.429 to 1). Differences between mean scores for the instruments were significant. CONCLUSIONS: In the sample of patients with PD, the Disability and Distress Index, Euroqol System, and the Health Utilities Index Mark II correlate well with measures of disease severity and quality of life. However, they give strikingly different values. When applied in cost-effectiveness analysis, these discrepancies could result in substantially different cost-effectiveness ratios for PD-related interventions.

Aged↗
PubMed2002

Randomized, placebo-controlled, parallel group versus crossover study designs for the study of dementia in Parkinson's disease.

In studies of dementia, crossover designs are controversial, reflecting concerns about temporal stability of disease, confounding of treatment effects with period by treatment interactions and/or carryover effects. Carryover effects are differences in the lingering effect of treatments (placebo) into subsequent periods. In the context of a trial to study the effect of donepezil on dementia in patients with Parkinson's disease, we examine two-sequence crossover studies with two or four periods, and a four-sequence design with two periods. We quantify bias in estimated treatment effects due to carryover effects and explore the use of biased estimators in hypothesis testing. For hypothesis testing, type I error rates are valid if (1) repeated administration of treatment alters the outcome only for effective treatments and (2) carryover effects due to placebo following treatment periods are nonzero only for effective treatments. For crossover and parallel group designs, sample sizes are adjusted for reduced statistical power due to carryover effects and temporal changes in variance. For the proposed clinical study, we estimate that a single-period parallel group design with baselines would require 104 patients and take about 23 months to complete. A two-sequence, four-period parallel group design with baselines would require about 80 patients and about 20 months to complete. We conservatively assume a carryover effect of 50% of the treatment effect for a two-sequence four-period crossover design. The estimated treatment effect for this model may underestimate the true treatment effect by up to 13%. The sample size/study length requirements are 28 patients or 12.4 months, respectively, a substantial saving over either parallel group design. The cost of allowing for carryover in the sample size calculation is about 1.2 months of study time.

Bias↗
PubMed2002

Bilateral stimulation of the subthalamic nucleus in patients with Parkinson disease: a study of efficacy and safety.

OBJECT: Palliative neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson disease (PD) that is complicated by severe motor fluctuations. Despite great enthusiasm for long-term deep brain stimulation (DBS) of the subthalamic nucleus (STN), existing reports on this treatment are limited. The present study was designed to investigate the safety and efficacy of bilateral stimulation of the STN for the treatment of PD. METHODS: In 12 patients with severe PD, electrodes were stereotactically implanted into the STN with the assistance of electrophysiological conformation of the target location. All patients were evaluated preoperatively during both medication-off and -on conditions, as well as postoperatively at 3, 6, and 12 months during medication-on and -off states and stimulation-on and -off conditions. Tests included assessments based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests. The stimulation effect was significant in patients who were in the medication-off state, resulting in a 47% improvement in the UPDRS Part III (Motor Examination) score at 12 months, compared with preoperative status. The benefit was stable for the duration of the follow-up period. Stimulation produced no additional benefit during the medication-on state, however, when compared with patient preoperative status. Significant improvements were made in reducing dyskinesias, fluctuations, and duration of off periods. CONCLUSIONS: This study demonstrates that DBS of the STN is an effective treatment for patients with advanced, medication-refractory PD. Deep brain stimulation of the STN produced robust improvements in motor performance in these severely disabled patients while they were in the medication-off state. Serious adverse events were common in this cohort; however, only two patients suffered permanent sequelae.

Aged↗