Parkinson Disease: Ravina B

Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, Shulman LM, Gronseth G, Weiner WJ, Anonymous00046. · University of Toronto, Canada. · Neurology. · Pubmed #16606910 No free full text.

Abstract: OBJECTIVE: To make evidence-based treatment recommendations for patients with Parkinson disease (PD) with dementia, depression, and psychosis based on these questions: 1) What tools are effective to screen for depression, psychosis, and dementia in PD? 2) What are effective treatments for depression and psychosis in PD? 3) What are effective treatments for PD dementia or dementia with Lewy bodies (DLB)? METHODS: A nine-member multispecialty committee evaluated available evidence from a structured literature review using MEDLINE, and the Cochrane Database of Health and Psychosocial Instruments from 1966 to 2004. Additional articles were identified by panel members. RESULTS: The Beck Depression Inventory-I, Hamilton Depression Rating Scale, and Montgomery Asberg Depression Rating Scale should be considered to screen for depression in PD (Level B). The Mini-Mental State Examination and the Cambridge Cognitive Examination should be considered to screen for dementia in PD (Level B). Amitriptyline may be considered to treat depression in PD without dementia (Level C). For psychosis in PD, clozapine should be considered (Level B), quetiapine may be considered (Level C), but olanzapine should not be considered (Level B). Donepezil or rivastigmine should be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B). CONCLUSIONS: Screening tools are available for depression and dementia in patients with PD, but more specific validated tools are needed. There are no widely used, validated tools for psychosis screening in Parkinson disease (PD). Clozapine successfully treats psychosis in PD. Cholinesterase inhibitors are effective treatments for dementia in PD, but improvement is modest and motor side effects may occur.

Voss T, Ravina B. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Movement and Inherited Neurological Disorders Unit, Rochester, NY 14620, USA. · Curr Neurol Neurosci Rep. · Pubmed #18590614 No free full text.

Abstract: Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder with no cure. Therapies that delay or halt disease progression are urgently needed, but finding such therapies has been difficult. In this article, we review historical and recent clinical trial work in the field of neuroprotection. Several issues have arisen during the search for disease-modifying therapies, including challenges in selecting appropriate therapeutic targets, assessing potential therapies, and selecting the proper patient population to study. Advances in the understanding of PD pathogenesis are presented as they relate to selecting potential therapeutic targets, and issues with preclinical testing are described. We review recent innovations in clinical trial design, including futility studies and delayed-start designs that promise to make clinical testing more efficient. It is hoped that ongoing work in this field will lead to treatments that delay the progression of PD.

Kieburtz K, Ravina B. · University of Rochester Medical Center, Rochester, NY, USA. · Nat Clin Pract Neurol. · Pubmed #17479072 No free full text.

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Biglan KM, Ravina B. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620, USA. · Semin Neurol. · Pubmed #17390255 No free full text.

Abstract: Despite increases in our understanding of the pathophysiology and environmental and genetic influences of illness in Parkinson's disease, neuroprotection remains an elusive goal. No interventions are widely accepted as disease modifying in Parkinson's disease. Continued research identifying novel therapeutic targets is likely to result in several putative neuroprotective agents. Assimilating lessons from previous neuroprotection trials will be critical in developing future trials aimed at efficiently identifying neuroprotective treatments. Ultimately, overcoming the unique challenges of a heterogenous, slowly progressive disorder with multiple potential outcome measures will be necessary to identify treatments that have meaningful effects.

Tilley BC, Palesch YY, Kieburtz K, Ravina B, Huang P, Elm JJ, Shannon K, Wooten GF, Tanner CM, Goetz GC, Anonymous00248. · Department of Biostatistics, Bioinformatics & Epidemiology, Medical University of South Carolina, P.O. Box 250835, Charleston, SC 29425, USA. · Neurology. · Pubmed #16534099 No free full text.

Abstract: Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.

Marsh L, McDonald WM, Cummings J, Ravina B, Anonymous00100. · Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Mov Disord. · Pubmed #16211591 No free full text.

Abstract: 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.

Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A, Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G, Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Neurology. · Pubmed #15668415 No free full text.

Abstract: Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Ravina B, Putt M, Siderowf A, Farrar JT, Gillespie M, Crawley A, Fernandez HH, Trieschmann MM, Reichwein S, Simuni T. · NINDS, Neuroscience Center Rm 2225, 6001 Executive Blvd, Rockville, MD 20892-9257, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15965198 links to  free full text

Abstract: OBJECTIVE: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). METHODS: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). RESULTS: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. CONCLUSIONS: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

Chou KL, Hurtig HI, Stern MB, Colcher A, Ravina B, Newberg A, Mozley PD, Siderowf A. · Parkinson's Disease and Movement Disorders Center, University of Pennsylvania School of Medicine, Pennsylvania Hospital, 330 South Ninth Street, Philadelphia, PA 19107, USA. · Parkinsonism Relat Disord. · Pubmed #15261880 No free full text.

Abstract: We evaluated the diagnostic accuracy of SPECT imaging using [(99m)Tc]TRODAT-1 (TRODAT), a relatively inexpensive technetium-labeled dopamine transporter ligand, in distinguishing 29 patients with early PD from 38 healthy volunteers. Mean TRODAT uptake values were significantly decreased in the caudate (p=0.0097) and anterior and posterior putamen (p < 0.0001) of PD patients compared to controls. Using the posterior putamen as the main region of interest resulted in the greatest accuracy (sensitivity 0.79, specificity 0.92). These findings show that TRODAT imaging can accurately differentiate early PD patients from controls and has the potential to improve the diagnosis of patients with early signs of PD.

Simuni T, Jaggi JL, Mulholland H, Hurtig HI, Colcher A, Siderowf AD, Ravina B, Skolnick BE, Goldstein R, Stern MB, Baltuch GH. · Parkinson's Disease and Movement Disorders Center, Pennsylvania Hospital, Philadelphia, USA. · J Neurosurg. · Pubmed #11990805 No free full text.

Abstract: 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.

Gill DJ, Freshman A, Blender JA, Ravina B. · Department of Neurology, University of Rochester, Rochester, NY, USA. · Mov Disord. · Pubmed #18381646 No free full text.

Abstract: Cognitive impairment is common in Parkinson's disease (PD) and can occur early in the disease course. No effective screening test exists for detection of early or mild cognitive impairment in PD. We examined the Montreal Cognitive Assessment (MoCA) as a screening tool for cognitive dysfunction in PD. The test-retest intraclass correlation coefficient was 0.79 and the interrater intraclass correlation coefficient was 0.81. The correlation coefficient between the MoCA and a neuropsychologic battery was 0.72. The MoCA is reliable and valid in the PD population and warrants further study as a screening tool for cognitive dysfunction.

Ravina B, Camicioli R, Como PG, Marsh L, Jankovic J, Weintraub D, Elm J. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. · Neurology. · Pubmed #17581943 links to  free full text

Abstract: BACKGROUND: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. METHODS: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. RESULTS: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). CONCLUSIONS: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, Aarsland D, Babcock D, Cummings J, Endicott J, Factor S, Galpern W, Lees A, Marsh L, Stacy M, Gwinn-Hardy K, Voon V, Goetz C. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA. · Mov Disord. · Pubmed #17266092 No free full text.

Abstract: There are no standardized diagnostic criteria for psychosis associated with Parkinson's disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV-TR. PDPsy has a well-characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinson's disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Guimaraes P, Kieburtz K, Goetz CG, Elm JJ, Palesch YY, Huang P, Ravina B, Tanner CM, Tilley BC. · Dept of Biostatistics, Bioinformatics & Epidemiology, Medical University of South Carolina, 135 Cannon St. Suite 303, Charleston, SC 29425, USA. · Clin Trials. · Pubmed #16422311 No free full text.

Abstract: 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.

Fujita M, Ichise M, Zoghbi SS, Liow JS, Ghose S, Vines DC, Sangare J, Lu JQ, Cropley VL, Iida H, Kim KM, Cohen RM, Bara-Jimenez W, Ravina B, Innis RB. · Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 1, Room B3-10, I Center Drive, MSC-0135, Bethesda, MD, USA. ,gov · Ann Neurol. · Pubmed #16374823 links to  free full text

Abstract: 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.

Elm JJ, Goetz CG, Ravina B, Shannon K, Wooten GF, Tanner CM, Palesch YY, Huang P, Guimaraes P, Kamp C, Tilley BC, Kieburtz K, Anonymous00019. · Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston, SC 29425, USA. · Ann Neurol. · Pubmed #15668964 No free full text.

Abstract: 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.

Johnson J, Hague SM, Hanson M, Gibson A, Wilson KE, Evans EW, Singleton AA, McInerney-Leo A, Nussbaum RL, Hernandez DG, Gallardo M, McKeith IG, Burn DJ, Ryu M, Hellstrom O, Ravina B, Eerola J, Perry RH, Jaros E, Tienari P, Weiser R, Gwinn-Hardy K, Morris CM, Hardy J, Singleton AB. · Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA. · Neurology. · Pubmed #15304594 No free full text.

Abstract: The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

Hague S, Rogaeva E, Hernandez D, Gulick C, Singleton A, Hanson M, Johnson J, Weiser R, Gallardo M, Ravina B, Gwinn-Hardy K, Crawley A, St George-Hyslop PH, Lang AE, Heutink P, Bonifati V, Hardy J, Singleton A. · Molecular Genetics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Ann Neurol. · Pubmed #12891685 No free full text.

Abstract: 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.

Siderowf A, Ravina B, Glick HA. · Departments of Neurology, University of Pennsylvania School of Medicine, Philadelphia, USA. · Neurology. · Pubmed #12105315 No free full text.

Abstract: 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.

Putt ME, Ravina B. · Department of Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, 621 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA · Control Clin Trials. · Pubmed #11943439 No free full text.

Abstract: 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.

Bronstein J, Carvey P, Chen H, Cory-Slechta D, DiMonte D, Duda J, English P, Goldman S, Grate S, Hansen J, Hoppin J, Jewell S, Kamel F, Koroshetz W, Langston JW, Logroscino G, Nelson L, Ravina B, Rocca W, Ross GW, Schettler T, Schwarzschild M, Scott B, Seegal R, Singleton A, Steenland K, Tanner CM, Van Den Eeden S, Weisskopf M. · UCLA School of Medicine, Los Angeles, California, USA. · Environ Health Perspect. · Pubmed #19165397 links to  free full text

Abstract: BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. METHODS: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. RESULTS: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. CONCLUSIONS: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.