We performed a placebo-controlled trial of CEP-1347, an inhibitor of neuronal apoptotic cell death, in patients with early Parkinson's disease (PD) to determine whether long-term therapy would slow disability progression. This also provided an opportunity to monitor cancer incidence in a large cohort of PD patients followed prospectively including periods before and after patients developed disability requiring dopaminergic therapy. This was a multicenter study of 806 patients with early PD, without disability requiring dopaminergic therapy, assigned randomly to placebo or one of three doses of CEP-1347. Patients were monitored for an average of 1.8 years (1,467 patient-years) with routine cancer screening evaluations and annual skin examinations by a dermatologist. There was no significant excess of cancers among patients taking CEP-1347 compared with placebo for any cancer type (all P > 0.1). Nonmelanoma skin cancers were the most common cancer type observed. The incidence of melanomas was 20.9 times that predicted in the general population. Most melanomas occurred in patients who had never taken dopaminergic therapy. We found no evidence that CEP-1347 affected cancer incidence within 2 years of follow-up. Melanoma occurrence in our PD patients was greater than predicted compared with the general population and was unrelated to dopaminergic therapy. Clinical surveillance of PD patients for melanoma may be warranted.
This chapter addresses the principles of research study design. It provides an in-depth description of commonly used study designs to address research objectives. It presents information about study designs for descriptive epidemiology (i.e., studies of disease incidence, prevalence, and mortality rates) and analytic epidemiology (i.e., randomized trials, prospective cohort studies, retrospective cohort studies, cross-sectional studies, case-control studies). It describes the measures of effect that reflect the associations between health predictors and neurologic outcomes (odds ratios, relative risks). The second part of the chapter describes common study biases that can adversely affect study validity (sampling error, selection bias, confounding) and how to avoid these biases in the design and conduct of clinical and epidemiological studies.
Abstract This chapter begins with a discussion of the taxonomy of primary brain tumors, with a focus on gliomas, meningiomas, and grading systems for these tumors. It discusses methodological challenges for studies of brain tumor incidence including variations in diagnostic practices. It summarizes descriptive epidemiology studies of brain tumor incidence and mortality by age, sex, histologic type, and ethnicity. Factors associated with survival are discussed including histologic grade, tumor location, and extent of surgical resection. Much work remains to discover the causes of the majority of human brain tumors, as established risk factors account for only a small proportion of these tumors. The chapter critiques evidence regarding possible risk factors for brain tumors, including genetic predisposition, ionizing radiation, chemical carcinogen exposure, electromagnetic fields, infections, head trauma, smoking, and diet.
This study investigates risk factors associated with mechanical loosening of cemented total hip arthroplasties. Mechanical failure was evaluated using survivorship analysis on all arthroplasties performed at the authors' institution by the Orthopedic Service from March 1971 until September 1983. Failure was defined as the necessity for replacement of one or more components for any reason other than infection. The failure rate was approximately 1.7% per year and, at 12 years, 20% of the hips had failed. Variables evaluated as potential risk factors for arthroplasty revision included weight, gender, age, surgeon, preoperative functional status, prosthetic type, and diagnosis. A Cox proportional hazard analysis indicated that weight (p less than 0.015) and age (p = 0.087) are important determinants of hip failure. The use of regression trees identified subsets of patients at differing risks for failure. Patients who weighed less than 75.22 kg had the best outcome with a 90% survival to 12 years. Patients weighing more than 75.22 kg are at varying risk depending on their age. These data define a subset of special-risk patients not previously described. Patients weighing more than 75.22 kg who were older than 75.4 years had a revision rate of 73% by eight years.
Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease.In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT).Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls.In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
Abstract This chapter begins with a discussion of the taxonomy of seizure disorders and the clinical features of epilepsy that pose methodological challenges in clinical and epidemiologic studies. Descriptive studies of incidence and prevalence are described for the following seizure types: partial, generalized tonic-clonic, myoclonic, and absence seizures. Risk factors for epilepsy are discussed in the context of case-control and cohort designs, and evidence is summarized regarding the role of non-genetic risk factors (traumatic brain injury, infections, cerebrovascular disease, brain tumors, degenerative CNS diseases, and developmental deficits). The chapter discusses factors associated with prognosis and mortality of epilepsy, as well as common causes of death in epilepsy patients. The final section addresses evidence for familial aggregation and genetic causes of seizures.
Abstract Background and Objectives In Parkinson’s disease (PD), Alzheimer’s disease (AD) co-pathology is common and clinically relevant. However, the longitudinal progression of AD cerebrospinal fluid (CSF) biomarkers – β-amyloid 1-42 (Aβ 42 ), phosphorylated tau 181 (p-tau 181 ) and total tau (t-tau) – in PD is poorly understood, and may be distinct from clinical AD. Moreover, it is unclear if CSF p-tau 181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ 42 . First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN PD ) using CSF Aβ 42 (A), p-tau 181 (T), and serum NfL (N), and tested ATN PD prediction of longitudinal cognitive decline in PD. Methods Participants were selected from the Parkinson’s Progression Markers Initiative (PPMI) cohort, clinically-diagnosed with sporadic PD or as normal Controls, and followed annually for 5 years. Linear mixed effects models (LMEM) tested the interaction of diagnosis with longitudinal trajectories of analytes (log-transformed, FDR-corrected). In PD, LMEMs tested how baseline ATN PD status (AD [A+T+N±] vs . not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank-transformed, FDR-corrected). Results Participants were 364 PD and 168 Controls, with comparable baseline mean (±SD) age (PD=62±10; Control=61±11]; Mann-Whitney-Wilcoxon: p =0.40) and gender distribution (PD=231 males [63%]; Control=107 males [64%]; chi-square: p =1.0). PD had overall lower CSF p-tau 181 (β=-0.16, 95%CI=-0.23 – -0.092, p =2.2e-05) and t-tau than Controls (β=-0.13, 95%CI=-0.19 – -0.065, p =4.0e-04), but not Aβ 42 ( p =0.061) or NfL ( p =0.32). Over time, PD had greater increases in serum NfL than Controls (β=0.035, 95%CI=0.022 – 0.048, p =9.8e-07); PD slopes did not differ from controls for CSF Aβ 42 ( p =0.18), p-tau 181 ( p =1.0) or t-tau ( p =0.96). Using ATN PD , PD classified as A+T+N± (n=32; 9%) had consistently worse cognitive decline, including on global MoCA (β=-73, 95%CI=-110 – -37, p =0.00077), than all other ATN PD statuses including A+ alone (A+T-N-; n=75; 21%). Discussion In early PD, CSF p-tau 181 and t-tau were low compared to Controls and did not increase over 5 year follow-up. Even so, classification using modified ATN PD (incorporating CSF p-tau 181 with CSF Aβ 42 and serum NfL) may identify biologically-relevant subgroups of PD to improve prediction of cognitive decline in early PD.
ISEE-0473 Background and Objective: Pesticide exposure may increase PD risk, but detailed data are lacking. Using data from the AHS, an ∼89,000 member cohort of licensed pesticide applicators and their spouses enrolled in Iowa and North Carolina in 1993–1997, we found that self-reported PD was associated with cumulative lifetime use of pesticides and with factors affecting pesticide exposure, including high-intensity exposures and inadequate use of personal protective equipment. Because this study was limited by reliance on self-reported PD, we conducted a further study based on confirmed diagnoses. Methods: The Farming and Movement Evaluation (FAME) study is a case-control study of PD nested within the AHS. PD diagnoses were confirmed by movement disorder specialists. We enrolled 115 confirmed PD cases and 383 age-, sex-, and state-matched controls. Using structured interviews, we collected information on lifetime use of pesticides implicated in PD by prior human studies or by experimental models or mechanistic hypotheses. We collected additional information on other factors affecting exposure, including application methods and use of personal protective equipment. Data were analyzed by unconditional logistic regression with adjustment for age, sex, state, and cigarette smoking. Results: We found that PD risk was associated with exposure to specific pesticides and confirmed and extended our earlier work on factors affecting exposure. Conclusions: These results add to evidence supporting an association between pesticide exposure and PD risk. They recapitulate experimental models and may shed light on mechanisms involved in PD pathophysiology.
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