Yuanjia Wang

Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease

Objective: To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study. Methods: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category. Results: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO ≤ 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P. Conclusions: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset. GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.

Frequency of LRRK2 mutations in early-and late-onset Parkinson disease

Objective: To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD). Methods: We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in the ≤50 age at onset (AAO) category. Results: The LRRK2 G2019S mutation was present in 28 cases with PD (5.6%) and two controls (0.6%) (χ2 = 13.25; p < 0.01; odds ratio 9.18, 95% CI: 2.17 to 38.8). The mutations L1114L, I1122V, R1441C, and Y1699C were not identified. The frequency of the LRRK2 G2019S mutation was 4.9% in 245 cases with AAO ≤50 years vs 6.2% in 259 cases with AAO >50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p < 0.01). Age-specific penetrance to age 80 was 24% and was similar in Jewish and non-Jewish cases. Conclusions: The G2019S mutation is a risk factor in both early- and late-onset Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

Treatment of complicated grief in elderly persons: a randomized clinical trial.

IMPORTANCE Complicated grief (CG) is a debilitating condition, most prevalent in elderly persons. However, to our knowledge, no full-scale randomized clinical trial has studied CG in this population. OBJECTIVE To determine whether complicated grief treatment (CGT) produces greater improvement in CG and depressive symptoms than grief-focused interpersonal psychotherapy (IPT). DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial enrolling 151 individuals 50 years or older (mean [SD] age, 66.1 [8.9] years) scoring at least 30 on the Inventory of Complicated Grief (ICG). Participants were recruited from the New York metropolitan area from August 20, 2008, through January 7, 2013, and randomized to receive CGT or IPT. The main outcome was assessed at 20 weeks after baseline, with interim measures collected at 8, 12, and 16 weeks after baseline. INTERVENTIONS Sixteen sessions of CGT (n = 74) or IPT (n = 77) delivered approximately weekly. MAIN OUTCOMES AND MEASURES Rate of treatment response, defined as a rating from an independent evaluator of much or very much improved on the Improvement subscale of the Clinical Global Impression Scale. RESULTS Both treatments produced improvement in CG symptoms. Response rate for CGT (52 individuals [70.5%]) was more than twice that for IPT (24 [32.0%]) (relative risk, 2.20 [95% CI, 1.51-3.22]; P < .001), with the number needed to treat at 2.56. Secondary analyses of CG severity and CG symptom and impairment questionnaire measures confirmed that CGT conferred a significantly greater change in illness severity (22 individuals [35.2%] in the CGT group vs 41 [64.1%] in the IPT group were still at least moderately ill [P = .001]), rate of CG symptom reduction (1.05 ICG points per week for CGT vs 0.75 points per week for IPT [t633 = 3.85; P < .001]), and the rate of improvement in CG impairment (0.63 work and Social Adjustment Scale points per week with CGT and 0.39 points per week with IPT [t503 = 2.87; P = .004]). Results were not moderated by participant age. CONCLUSIONS AND RELEVANCE Complicated grief treatment produced clinically and statistically significantly greater response rates for CG symptoms than a proven efficacious treatment for depression (IPT). Results strongly support the need for physicians and other health care providers to distinguish CG from depression. Given the growing elderly population, the high prevalence of bereavement in aging individuals, and the marked physical and psychological impact of CG, clinicians need to know how to treat CG in older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01244295.

Pre-meal anxiety and food intake in anorexia nervosa ☆ ☆☆ ★

Anorexia nervosa (AN) is a serious mental illness characterized by reduced caloric intake that often persists after acute weight restoration. This preliminary study assesses the relationship between pre-meal anxiety and food intake in recently weight-restored individuals with AN. We hypothesized that pre-meal anxiety is inversely related to caloric intake in AN. Caloric intake and pre-meal anxiety were measured in three laboratory-based assessments (yogurt snack, multi-item lunch, macaroni and cheese lunch). Anxiety was measured by Spielberger State-Trait Anxiety Inventory (STAI-S) administered prior to the meal. Acutely weight-restored patients with AN were compared with healthy controls (HCs). Associations between anxiety and intake were analyzed first within each meal type separately and then using a model to combine the sample. In the multi-item lunch and the macaroni and cheese lunch, AN ate significantly less than HC (p=0.01, p<0.001). Pre-meal anxiety was significantly correlated with intake among AN, but not HC. In the yogurt snack, there was no significant association between anxiety and intake among patients or controls, and the groups did not differ in caloric intake. The association between pre-meal anxiety and intake among weight-restored individuals with AN suggests a potential target for relapse prevention treatment.

Patient adherence predicts outcome from cognitive behavioral therapy in obsessive-compulsive disorder.

OBJECTIVE To examine the effects of patient adherence on outcome from exposure and response prevention (EX/RP) therapy in adults with obsessive-compulsive disorder (OCD). METHOD Thirty adults with OCD were randomized to EX/RP (n = 15) or EX/RP augmented by motivational interviewing strategies (n = 15). Both treatments included 3 introductory sessions and 15 exposure sessions. Because there were no significant group differences in adherence or outcome, the groups were combined to examine the effects of patient adherence on outcome. Independent evaluators assessed OCD severity using the Yale-Brown Obsessive Compulsive Scale. Therapists assessed patient adherence to between-session EX/RP assignments at each session using the Patient EX/RP Adherence Scale (PEAS). Linear regression models were used to examine the effects of PEAS scores on outcome, adjusting for baseline severity. The relationship between patient adherence and other predictors of outcome was explored using structural equation modeling. RESULTS Higher average PEAS ratings significantly predicted lower posttreatment OCD severity in intent-to-treat and completer samples. PEAS ratings in early sessions (5-9) also significantly predicted posttreatment OCD severity. The effects of other significant predictors of outcome in this sample (baseline OCD severity, hoarding subtype, and working alliance) were fully mediated by patient adherence. CONCLUSIONS Patient adherence to between-session EX/RP assignments significantly predicted treatment outcome, as did early patient adherence and change in early adherence. Patient adherence mediated the effects of other predictors of outcome. Future research should develop interventions that increase adherence and then test whether increasing adherence improves outcome. If effective, these interventions could then be used to personalize care.

Inflammatory Markers and Longitudinal Lung Function Decline in the Elderly

Longitudinal studies examining associations of the inflammatory markers fibrinogen and C-reactive protein (CRP) with lung function decline are sparse. The authors examined whether elevated fibrinogen and CRP levels were associated with greater longitudinal lung function decline in the elderly. The Cardiovascular Health Study measured fibrinogen and CRP in 5,790 Whites and African Americans from four US communities aged 65 years or older in 1989-1990 or 1992-1993. Spirometry was performed in 1989-1990 and 4, 7, and 16 years later. Fibrinogen and CRP were inversely associated with lung function at baseline after adjustment for multiple potential confounders. In mixed models, the rate of decline in forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) ratio with increasing age was faster among those with higher baseline fibrinogen (-0.032%/year per standard deviation higher fibrinogen (95% confidence interval: -0.057, -0.0074)) but not among those with higher CRP (-0.0037%/year per standard deviation higher CRP (95% confidence interval: -0.013, 0.0056)). Longitudinal analyses for FEV(1) and FVC yielded results in the direction opposite of that hypothesized, possibly because of the high mortality rate and strong inverse association of FEV(1) and FVC but not FEV(1)/FVC with mortality. An alternative approach to missing data yielded similar results. In conclusion, higher levels of fibrinogen, but not CRP, independently predicted greater FEV(1)/FVC decline in the elderly.

Challenges Using Motivational Interviewing as an Adjunct to Exposure Therapy for Obsessive-Compulsive Disorder

Exposure and response prevention (EX/RP) is an efficacious treatment for obsessive-compulsive disorder (OCD). However, patients often do not adhere fully to EX/RP procedures. Motivational interviewing (MI) has been shown to improve treatment adherence in other disorders. This pilot study used a randomized controlled design to examine whether MI can be successfully added to EX/RP and whether this intervention (EX/RP+MI) could improve patient adherence to between-session EX/RP procedures relative to EX/RP alone. Thirty adults with OCD were randomized to 18 sessions of EX/RP or EX/RP+MI. Therapists rated patient adherence at each exposure session. Independent evaluators assessed change in OCD and depressive symptoms, and patients completed self-report measures of readiness for change and quality of life. The two treatment conditions differed in degree of congruence with MI but not in conduct of EX/RP procedures. Both groups experienced clinically significant improvement in OCD symptoms, without significant group differences in patient adherence. There are several possible reasons why EX/RP+MI had no effect on patient adherence compared to standard EX/RP, each of which has important implications for the design of future MI studies in OCD. We recommend that MI be further evaluated in OCD by exploring alternative modes of delivery and by focusing on patients less ready for change than the current sample.

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Objective: Estimates of the penetrance of LRRK2 G2019S vary widely (24%–100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. Methods: The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available. Results: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18–0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73–4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10–0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18–0.40; HR male to female: 0.74, 95% CI 0.27–1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11–0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04–0.10; HR male to female: 2.40, 95% CI 1.50–4.15, p < 0.001). Conclusion: Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.

Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical) or different types of components (e.g., some are continuous and others are categorical). We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

Olanzapine versus placebo for out-patients with anorexia nervosa

BACKGROUND Anorexia nervosa (AN) is a serious psychiatric illness associated with significant morbidity and mortality. There is little empirical support for specific treatments and new approaches are sorely needed. This two-site study aimed to determine whether olanzapine is superior to placebo in increasing body mass index (BMI) and improving psychological symptoms in out-patients with AN. METHOD A total of 23 individuals with AN were randomly assigned in double-blind fashion to receive olanzapine or placebo for 8 weeks together with medication management sessions that emphasized compliance. Weight, other physical assessments and measures of psychopathology were collected. RESULTS End-of-treatment BMI, with initial BMI as a covariate, was significantly greater in the group receiving olanzapine [F(1, 20)=6.64, p=0.018]. Psychological symptoms improved in both groups, but there were no statistically significant group differences. Of the 23 participants, 17 (74%) completed the 8-week trial. Participants tolerated the medication well with sedation being the only frequent side effect and no adverse metabolic effects were noted. CONCLUSIONS This small study suggests that olanzapine is generally well tolerated by, and may provide more benefit than placebo for out-patients with AN. Further study is indicated to determine whether olanzapine may affect psychological symptoms in addition to BMI.