Shannon L. Rhodes

Meta-analysis: surgical treatment of obesity.

Context The effectiveness of surgical therapy in the treatment of obesity is unclear. Contribution Many published studies of obesity surgery have significant limitations, and case series make up much of the evidence. Evidence is complicated by the heterogeneity of procedures studied. However, surgery can result in substantial amounts of weight loss (20 to 30 kg) for markedly obese individuals. One cohort study documented weight loss for 8 years with associated improvements in comorbid conditions, such as diabetes. Complications of surgery appear to occur in about 20% of patients. Implications Those considering surgical treatment for obesity should understand that, although patients who have surgery can lose substantial amounts of weight, the evidence base for these treatments is limited. The Editors The prevalence of obesity in the United States is reaching epidemic proportions. An estimated 30% of individuals met the criteria for obesity in 19992002 (1, 2), and many industrialized countries have seen similar increases. The health consequences of obesity include heart disease, diabetes, hypertension, hyperlipidemia, osteoarthritis, and sleep apnea (3-7). Weight loss of 5% to 10% has been associated with marked reductions in the risk for these chronic diseases and with reducing the incidence of diabetes (8-14). The increasing numbers of obese individuals have led to intensified interest in surgical treatments to achieve weight loss, and a variety of surgical procedures have been used (Figure 1). Bariatric surgery was first performed in 1954 with the introduction of the jejunoileal bypass, which bypasses a large segment of small intestine by connecting proximal small intestine to distal small intestine. With this procedure, weight loss occurs secondary to malabsorption from reduction of upstream pancreatic and biliary contents. However, diarrhea and nutritional deficiencies were common, and this procedure was discontinued because of the complication of irreversible hepatic cirrhosis. With the development of surgical staplers came the introduction of gastroplasty procedures by Gomez in 1981 (15) and Mason in 1982 (16). In these early procedures, the upper portion of the stomach was stapled into a small gastric pouch with an outlet (that is, a stoma) to the remaining distal stomach, which limited the size of the meal and induced early satiety. These procedures were prone to staple-line breakdown or stoma enlargement and were modified in turn by the placement of a band around the stoma (vertical banded gastroplasty). Figure 1. Surgical procedures. The first gastric bypass was reported in 1967 by Mason and Ito (17). It combined the creation of a small gastric pouch with bypassing a portion of the upper small intestine. Additional modifications resulted in the Roux-en-Y gastric bypass (RYGB), a now common operation that involves stapling the upper stomach into a 30-mL pouch and creating an outlet to the downstream small intestine. The new food limb joins with the biliopancreatic intestine after a short distance. This procedure, performed laparoscopically or by using an open approach, generates weight loss by limiting gastric capacity, causing mild malabsorption, and inducing hormonal changes. A second common technique, particularly outside of the United States, is the laparoscopic adjustable gastric band. This device is positioned around the uppermost portion of the stomach and can be adjusted to allow tailoring of the stoma outlet, which controls the rate of emptying of the pouch and meal capacity. Another procedure, preferred by a number of surgeons, is the biliopancreatic bypass, which combines a limited gastrectomy with a long Roux limb intestinal bypass that creates a small common channel (that is, an intestine where food and biliopancreatic contents mix). This procedure can be combined with a duodenal switch, which maintains continuity of the proximal duodenum with the stomach and uses a long limb Roux-en-Y bypass to create a short common distal channel. These latter 2 procedures generate weight loss primarily through malabsorption. Recent worldwide survey data from 2002 and 2003 show that gastric bypass is the most commonly performed weight loss procedure (65.1%) (18). Slightly more than half of gastric bypasses are done laparoscopically. Overall, 24% of cases are laparoscopic adjustable band procedures; 5.4% are vertical banded gastroplasties; and 4.9% are biliopancreatic diversion, with or without the duodenal switch. In California, the number of bariatric cases increased 6-fold between 1996 and 2000 (19), from 1131 cases to 6304; an estimated 140000 procedures were performed in the United States in 2004. With this escalation in the number of procedures, there have been reports of high postoperative complication rates (20-24). Because of these reports and the increasing use of obesity surgery, we were asked to review the literature to estimate the effectiveness of bariatric surgery relative to nonsurgical therapy for weight loss and reduction in preoperative obesity-related comorbid conditions. We were also asked to compare outcomes of surgical techniques. This paper is part of a larger evidence report titled Pharmacological and Surgical Treatment of Obesity, which was prepared for the Agency for Healthcare Research and Quality and is available at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.19289. Methods Literature Search and Selection We began with an electronic search of MEDLINE on 16 October 2002, followed by a search of EMBASE and subsequent periodic search updates (on 22 May, 2 June, 12 June, and 3 July 2003). We also assessed existing reviews of surgical therapy for obesity (10, 25, 26). Three reviewers independently reviewed the studies, abstracted data, and resolved disagreements by consensus (2 reviewers per study). The principal investigator settled any unresolved disagreements. We focused on studies that assessed surgery and used a concurrent comparison group. This category includes randomized, controlled trials (RCTs); controlled clinical trials; and cohort studies. A brief scan of the literature showed that these types of studies were rare. Therefore, we also elected to include case series with 10 or more patients, since these studies can be used to assess adverse events and could potentially augment the efficacy data from comparative studies. Publication bias is one potential limitation of analyzing the available literature because poor or negative results are not as likely to be reported as are successes or positive results. Extraction of Study-Level Variables We abstracted data from the articles, including number of patients and comorbid conditions, adverse events, types of outcome measures, and time from intervention until outcome. Detailed data were also collected on characteristics of the study samples, including median age, percentage of women, median baseline weight (in kilograms or body mass index [BMI]), percentage of patients with comorbid conditions at baseline (diabetes, hypertension, dyslipidemia, and sleep apnea), percentage of improvement or resolution of preexisting comorbid conditions, and median follow-up time. We also recorded whether the case series studies reported on consecutive patients. Choice of Outcomes The main outcomes of interest were weight loss, mortality, complication rates, and control of obesity-related comorbid conditions. We used the most commonly reported measurement of weight loss, that is, kilograms, which allowed us to include the greatest number of studies. Among 111 surgical studies reporting weight loss, 43 reported weight loss in kilograms or pounds, 17 reported excess weight loss or some variant, 46 reported both of these outcomes, and 5 reported neither. A total of 89 studies had sufficient data to be included in the weight loss analysis. Because weight loss achieves health benefits primarily by reducing the incidence or severity of weight-related comorbid conditions, we also compared the effects on these outcomes. Quality of life, an important outcome in assessing tradeoffs between benefits and risks, was reported infrequently. Statistical Analyses Because we included both comparative studies and case series, we conducted several types of analyses. The vast number of types of surgical procedures and technical variations required that we aggregate those that were clinically similar and identify the comparisons that were of most interest to the clinical audience. On the basis of discussions with bariatric surgeons, we categorized obesity surgery procedures by procedure type (for example, gastric bypass, vertical banded gastroplasty), laparoscopic or open approach, and specific surgical details such as length of Roux limb (see the larger evidence report for details). Analysis of the Efficacy of Surgical Weight Loss We extracted the mean weight loss and standard deviation at 12 postoperative months and at the maximum follow-up time (36 months). These times were chosen because they are clinically relevant and are most commonly reported. Of the 89 weight loss studies, 71 reported baseline BMI (average, 47.1 kg/m2), 16 reported baseline weight in kilograms or pounds (average, 123.3 kg), and 2 did not report either. The average age of patients was 38 years, and more than three quarters were women. For comparative studies that reported a within-study comparison of 2 procedures, a mean difference was calculated. Mean differences were pooled by using a random-effects model, and 95% CIs were estimated; the same method was used to determine a pooled mean weight loss for each group considering all studies combined. However, mean difference in weight loss was not calculated. Analysis of Surgery Mortality We recorded the number of deaths observed and the total number of patients in each procedure group. If the study self-identified the deaths as early or postoperative or as occurring within 30 days of the surgery, we termed these early deaths. If the

Meta-analysis: chronic disease self-management programs for older adults

Context Do self-management programs improve outcomes of adults with chronic conditions? Contribution This meta-analysis summarizes data from 53 randomized, controlled trials of self-management interventions for adults with diabetes mellitus, hypertension, or osteoarthritis. Self-management helped reduce hemoglobin A1c and blood pressure levels in diabetes and hypertension, respectively, but had minimal effect on pain and function in patients with arthritis. The authors could not identify any self-management program characteristics that predicted successful outcomes. Cautions The authors found evidence of possible publication bias. Implications Self-management programs may improve some outcomes in patients with some chronic diseases, but how to design an optimal program is not yet clear. The Editors Chronic diseases are conditions that are usually incurable. Although often not immediately life-threatening, they place substantial burdens on the health, economic status, and quality of life of individuals, families, and communities (1). In 1995, 79% of noninstitutionalized persons who were 70 years of age or older reported having at least 1 of 7 of the most common chronic conditions affecting this age group: arthritis, hypertension, heart disease, diabetes mellitus, respiratory disease, stroke, and cancer (1). Of these 7 conditions, arthritis is most prevalent, affecting more than 47% of individuals 65 years of age and older (2). Hypertension affects 41% of this population, and 31% of this group has some form of heart disease (of which ischemic heart disease and a history of myocardial infarction are major components). Diabetes mellitus affects approximately 10% of persons 65 years of age and older and increases the risk for other chronic conditions, including ischemic heart disease, renal disease, and visual impairment (2). Enthusiasm is growing for the role of self-management programs in controlling and preventing chronic disease complications (3-5). Despite this enthusiasm, experts do not agree on the definition of what constitutes a chronic disease self-management program, which elements of self-management programs are essential regardless of the clinical condition, or which elements are important for specific conditions. Several recent reviews on chronic disease self-management interventions have been published, including 2 Cochrane collaborations (6-13). Almost all have been disease-specific. One Cochrane review (12) concluded that there was insufficient evidence to assess the benefit of dietary treatment for type 2 diabetes mellitus programs, but exercise programs led to improved hemoglobin A1c values. A second Cochrane review of self-management for hypertension (11) used unpooled results to conclude that a reduction in the frequency of medication dosage increased adherence. There was not, however, consistent evidence of decreased blood pressure. Almost all previous reviews have been disease-specific or addressed specific intervention components within specific disease conditions (14-17). Two recent reviews assessed self-management programs across conditions. The first review provided a qualitative evaluation of self-management interventions across 3 conditions: type 2 diabetes mellitus, arthritis, and asthma (18). This review, which presented an overall optimistic assessment of self-management interventions, did not, however, include a quantitative synthesis of the data, nor did it address the issue of publication bias. The second review quantitatively assessed 71 trials (both randomized and nonrandomized) that included a self-management education program for patients with asthma, arthritis, diabetes mellitus, hypertension, and miscellaneous other conditions. Meta-analysis found statistically significant benefits for some outcomes within conditions. The authors could not detect meaningful differences in the effectiveness of the programs because of the varying intervention characteristics, such as the use of a formal syllabus, the type of program facilitator, the number of program sessions in which patients participated, and the duration of the program (19). In our review, we sought to quantitatively assess chronic disease self-management programs for older adults within and across disease conditions. We used empirical data from the literature to address 2 research questions: First, do chronic disease self-management programs result in improved disease-related outcomes for specific chronic diseases of high prevalence in older adults? Second, if self-management interventions are effective, are there specific components that are most responsible for the effect, within or across disease conditions? To address these questions, we focused on evaluating the effect of self-management programs for the 3 chronic conditions that have been most commonly studied in controlled trials of older adults: osteoarthritis, diabetes mellitus, and hypertension. Methods Conceptual Model Because there is no accepted definition of what constitutes a chronic disease self-management program, we used an intentionally broad definition to avoid prematurely excluding relevant studies. On the basis of a conceptual framework derived from the clinical literature and from discussions with social scientists with expertise in self-management, we defined chronic disease self-management as a systematic intervention that is targeted toward patients with chronic disease. The intervention should help them actively participate in either or both of the following: self-monitoring (of symptoms or of physiologic processes) or decision making (managing the disease or its impact through self-monitoring). We attempted to understand the characteristics particular to chronic disease self-management programs that may be most responsible for their effectiveness. On the basis of the literature and expert opinion, we postulated 5 hypotheses regarding the effectiveness of chronic disease self-management programs that feature the following characteristics: Tailoring. Patients who receive interventions tailored to their specific needs and circumstances are likely to derive more benefit than those receiving interventions that are generic. roup setting. Patients are more likely to benefit from interventions received within a group setting that includes others affected by the same condition than from an intervention provided in some other setting. Feedback. Patients are more likely to derive benefit from a cycle of intervention followed by some form of individual review with the provider of the intervention than from interventions where no such review exists. Psychological emphasis. Patients are more likely to derive benefit from a psychological intervention than from interventions where there is no psychological emphasis. Medical care. Patients who receive interventions directly from their medical providers (physicians or primary care providers) are more likely to derive benefit than those who receive interventions from nonmedical providers. Outcome Measures From the literature, we identified outcomes of interest to include the following: clinical outcomes, such as pain and function for osteoarthritis; measures that have strong links to clinical outcomes, such as hemoglobin A1c levels, fasting blood glucose levels, and patient weight for diabetes and blood pressure for hypertension; and intermediate outcomes, such as knowledge, feeling of self-efficacy, and health behaviors that are postulated to be related to clinical outcomes. Databases for Literature Search We used several databases and published documents to identify existing research and potentially relevant evidence for this report. For our primary source of citation information from 1980 until 1995, we used An Indexed Bibliography on Self-Management for People with Chronic Disease (20), published by the Center for Advancement of Health in association with the Group Health Cooperative of Puget Sound; we obtained any studies not listed in the bibliography (including those published later than 1995) by searching MEDLINE, PsycINFO, and CINAHL. We also used the Cochrane Library (its database of systematic reviews and the central register of controlled trials); the Assessment of Self-Care Manuals, published by the Evidence-based Practice Center at the Oregon Health Sciences University (21); and 77 other previously completed reviews relevant to this project. We retrieved all relevant documents referenced in these publications, and we updated our search in September 2004. Each review discussed at least 1 intervention aimed at chronic disease self-management. We also searched the Health Care Quality Improvement Projects database, maintained by the U.S. Centers for Medicare & Medicaid Services. This database contains reports known as narrative project documents, each of which describes an individual research project conducted by a Medicare Peer Review Organization; most projects in this database are not published elsewhere. Each report includes the projects background, aims, quality indicators, collaborators, sampling methods, interventions, measurement, and results. A complete description of our literature search has been reported elsewhere (22). Article Selection and Data Abstraction Two trained physician reviewers, working independently, conducted the article selection, quality assessment, and data abstraction; disagreements were resolved by consensus or third-party adjudication. Articles were not masked. We included all randomized trials that assessed the effects of an intervention or interventions relative to either a group that received usual care or a control group among the elderly and for our 3 conditions. Most studies compared their intervention with usual care or with a control intervention designed to account for the added attention received in the intervention (such as attending classes on vehicle safety instead of attending classes on self-management). Because our analysis was funded by the Centers for M

L-type calcium channel blockers and Parkinson disease in Denmark

This study was undertaken to investigate L‐type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood–brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk.

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinsons disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNPs main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2dfu200a=u200a10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (ORu200a=u200a0.43; Pu200a=u200a6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplicationu200a=u200a0.59, PReplicationu200a=u200a10−3; ORPooledu200a=u200a0.51, PPooledu200a=u200a7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (Pu200a=u200a3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (Pu200a=u200a6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and ORu200a=u200a0.41, Pu200a=u200a3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

α-Synuclein Genetic Variants Predict Faster Motor Symptom Progression in Idiopathic Parkinson Disease

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57–10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96–2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend u200a=u200a0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.

Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease

Objective: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study. Methods: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinsons Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation. Results: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. Conclusion: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression.

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease

IMPORTANCEnCognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.nnnOBJECTIVEnTo determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.nnnDESIGN, SETTING, AND PARTICIPANTSnWe studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.nnnMAIN OUTCOMES AND MEASURESnNine variables derived from 7 psychometric tests.nnnRESULTSnThe APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc]u2009= 6.0 × 10(-5)), Delayed Recall (P =u2009.001; Pc =u2009.009), and Recognition Discrimination Index (P =u2009.004; Pc =u2009.04); a semantic verbal fluency test (P =u2009.002; Pc =u2009.02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P =u2009.002; Pc =u2009.02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P =u2009.005; Pc =u2009.045) and the semantic verbal fluency (P =u2009.005; Pc =u2009.045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.nnnCONCLUSIONS AND RELEVANCEnOur data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Serum Metabolomics of Slow vs. Rapid Motor Progression Parkinson’s Disease: a Pilot Study

Progression of Parkinson’s disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD.

α-Synuclein Gene May Interact with Environmental Factors in Increasing Risk of Parkinson’s Disease

Background: Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans. Methods: We used a population-based approach to examine whether the risk of Parkinson’s disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking. Results/Conclusions: Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years. More importantly, while analyses of interactions were limited by small cell sizes, risk due to SNCA variations seemed to vary with pesticide exposure and smoking, especially in younger onset cases, suggesting an age-of-onset effect.