Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.     

Sexual abuse in patients with anorexia nervosa and bulimia

Few studies have documented the extent and nature of sexual abuse among women who later come to treatment for anorexia nervosa or bulimia. This comparison study reports on a sample of 158 patients admitted to an eating-disorder unit, of whom 60 gave a history of sexual abuse, compared to 98 with no history of abuse. Fifty percent of the anorexic and bulimic patients had suffered sexual abuse, compared to only 28% of patients admitted with other eating-disorder diagnoses; this was a significant difference (p less than 0.001). Of the four types of abuse surveyed, only those patients suffering rape were likely to have sought help from caregivers prior to admission (p less than 0.001). The authors report on likely perpetrators of abuse, age of first abuse, and frequency of depressive symptoms in the abused population. The data from this study strongly suggest that the possibility of sexual assault or abuse must be assessed and the results included in a comprehensive therapy plan for eating-disorder patients.     

Neurobiology of anorexia and bulimia nervosa

Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders of unknown etiology that most commonly begin during adolescence in women. AN and BN have unique and puzzling symptoms, such as restricted eating or binge-purge behaviors, body image distortions, denial of emaciation, and resistance to treatment. These are often chronic and relapsing disorders, and AN has the highest death rate of any psychiatric disorder. The lack of understanding of the pathogenesis of this illness has hindered the development of effective interventions, particularly for AN. Individuals with AN and BN are consistently characterized by perfectionism, obsessive-compulsiveness, and dysphoric mood. Individuals with AN tend to have high constraint, constriction of affect and emotional expressiveness, ahendonia and asceticism, whereas individuals with BN tend to be more impulsive and sensation seeking. Such symptoms often begin in childhood, before the onset of an eating disorder, and persist after recovery, suggesting they are traits that create a vulnerability for developing an ED. There is growing acknowledgement that neurobiological vulnerabilities make a substantial contribution to the pathogenesis of AN and BN. Considerable evidence suggests that altered brain serotonin (5-HT) function contributes to dysregulation of appetite, mood, and impulse control in AN and BN. Brain imaging studies, using 5-HT specific ligands, show that disturbances of 5-HT function occur when people are ill, and persist after recovery from AN and BN. It is possible that a trait-related disturbance of 5-HT neuronal modulation predates the onset of AN and contributes to premorbid symptoms of anxiety, obsessionality, and inhibition. This dysphoric temperament may involve an inherent dysregulation of emotional and reward pathways which also mediate the hedonic aspects of feeding, thus making these individuals vulnerable to disturbed appetitive behaviors. Restricting food intake may become powerfully reinforcing because it provides a temporary respite from dysphoric mood. Several factors may act on these vulnerabilities to cause AN to start in adolescence. First, puberty-related female gonadal steroids or age-related changes may exacerbate 5-HT dysregulation. Second, stress and/or cultural and societal pressures may contribute by increasing anxious and obsessional temperament. Individuals with AN may discover that reduced dietary intake, by reducing plasma tryptophan availability, is a means by which they can modulate brain 5-HT functional activity and anxious mood. People with AN enter a vicious cycle which accounts for the chronicity of this disorder because caloric restriction results in a brief respite from dysphoric mood. However, malnutrition and weight loss, in turn, produce alterations in many neuropeptides and monoamine function, perhaps in the service of conserving energy, but which also exaggerates dysphoric mood. In summary, this article reviews findings in brain chemistry and neuroimaging that shed new light on understanding the psychopathology of these difficult and frustrating disorders.     

Evaluation of HapMap data in six populations of European descent

We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.European Journal of Human Genetics (2008) 16, 1142-1150; doi:10.1038/ejhg.2008.77; published online 9 April 2008.     

The impact of age, weight and gender on BDNF levels in human platelets and plasma

Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the adult. BDNF is known to be stored in human platelets and to circulate in plasma, but the regulation and function of BDNF in peripheral blood is still poorly understood. In this prospective study, we have examined 140 healthy, non-allergic adults (20-60 years old) to elucidate the impact of age and physical parameters on BDNF levels in human platelets and plasma. There was a wide concentration range of BDNF in serum (median: 22.6 ng/ml), platelets (median: 92.7 pg/10(6) platelets) and plasma (median: 92.5 pg/ml). BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not. When matched for weight, there were no significant gender differences regarding BDNF plasma levels. However, women displayed significantly lower platelet BDNF levels than men. In addition, platelet BDNF levels changed during the menstrual cycle. In conclusion, we demonstrate that parameters such as age or gender have a specific impact on stored and circulating BDNF levels in peripheral blood.     

Predictive markers of HIV-related weight loss and determination of differences between populations with weight loss stratified by opportunistic processes

OBJECTIVE: To describe factors predictive of >10% weight loss among enrolled participants in clinical trials of the AIDS Clinical Trial Group (ACTG). DESIGN: A retrospective analysis of data from selected ACTG antiretroviral clinical trials completed prior to 1996 (ACTG 116, 117, 155, 175, and 241), which did not include protease inhibitors. METHODS: Data were analyzed in Cox proportional hazards models to determine significant predictors for >10% weight loss while on study. Weight loss occurring within 30 days before or after an opportunistic infection (OI) was defined as "OI-associated." Both univariate and multivariate models were considered; gender-specific models were also analyzed to provide insight into potential gender differences in predictors of weight loss. RESULTS: We found that substantial weight loss is a frequent occurrence among those enrolled in clinical trials of antiretroviral agents; approximately 15% of subjects in the studies considered experienced >10% weight loss. CD4 cell count and HIV-1 RNA at week 8, Karnofsky score, and injection drug use status were significant multivariate predictive markers for weight loss associated with an OI; baseline weight, hemoglobin, triglycerides, and gender were additional predictors for weight loss not associated with an OI. CONCLUSIONS: This is the first study to characterize the association between baseline viral load and future weight loss. Baseline and week 8 immunologic parameters as well as measures of baseline symptomatology were significant predictors of weight loss associated and not associated with an OI.     

No association between polymorphisms in the BDNF gene and age at onset in Huntington disease

Background

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) is an attractive candidate for modifying age at onset (AO) in Huntington disease (HD). In particular, the functional Val66Met polymorphism appeared to exert a significant effect. Here we evaluate BDNF variability with respect to AO of HD using markers that represent the entire locus.

Methods

Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients.

Results

Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO.

Conclusion

We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO.     

遗传因素和机械因素与膝骨性关节炎发病年龄的关系

目的 研究中国汉族人群膝骨性关节炎发病年龄与相关的易感基因和体重指数(body mass index,BMI)的关系.方法 临床选择膝骨性关节炎患者863例,年龄匹配的对照组999人,临床资料完整.应用TaqMan探针法和聚丙烯酰胺凝胶电泳法对转化生长因子-5(growth differentiation factor 5,GDF5)5'非翻译区域的单核苷酸基因多态性(single nucleotide polymorphism,SNP)(+104T/C;rs143383)、ASPN基因天冬氨酸(D)重复序列多态性进行基因分型,采用SPSS17.0统计软件进行计算,分析骨性关节炎患者发病年龄与易致病等位基因和BMI之间的关系.结果 膝骨性关节炎患者与年龄匹配对照组之间BMI差异有统计学意义(P＜0.01),肥胖(BMI≥25)是膝骨性关节炎发病的高危因素(P＜0.01);骨关节炎组随年龄增大BMI有增大的趋势,Pearson相关系数为0.15,P＜0.01;为分析不同发病年龄阶段BMI分布的情况,膝骨性关节炎组及对照组按年龄35～70岁(5岁为一组)分组,发现骨关节炎组发病年龄早的患者BMI较发病年龄较晚者小,差异有统计学意义(F=2.497,P=0.011),而对照组内差异无统计学意义(F=0.786,P=0.56);TT(GDF5)和D14(ASPN)致病易感等位基因在膝骨性关节炎患者中年龄分布不同,较年轻发病患者易致病等位基因人群携带率明显高于较年长发病患者(P＜0.05).结论 发病年龄较小的膝骨性关节炎患者受遗传因素作用更大,而发病年龄较大的患者机械因素起更重要作用.     

Energy intake and body composition in anorexia and bulimia nervosa

Energy intake during the weight gain phase and the weight maintenance phase was examined in three groups of inpatients: 64 anorectic restrictors (AN-R), 37 anorectic bulimics (AN-B), and 74 normal-weight bulimics (BN). The influence of body composition and other variables such as weight, exercise, and bingeing and purging frequencies on energy intake was analyzed. Eating disorder subgroups were found to differ in energy intakes to gain weight and to maintain weight within a target weight range. Anorectic restrictors consumed significantly more energy to gain weight than did the anorectic bulimics (a mean of 3055 kcals per day vs. a mean of 2788 kcal per day). Energy intake for weight gain was inversely related to admission body mass index (BMI) and to admission fat-free mass. Bingeing and purging frequencies did not predict caloric intake for either weight gain or maintenance for anorectics. Energy intake of the anorectic patients when they were maintaining weight within a target weight range did not differ between restrictors and anorectic bulimics (means of 2204 and 2134 kcal/day, respectively). Energy needed to maintain weight within a target weight range was predicted by the amount of fat-free mass at target weight and by the mean number of calories ingested per week during weight gain. Bulimics consumed fewer calories than either of the two anorectic groups during the weight maintenance phase (1538 kcal/day). Other than BMI at hospital admission, bulimics' energy intakes were unrelated to all demographic and eating disorder-related variables, including body composition.     

Psychiatric comorbidity in anorexia and bulimia nervosa: nature,prevalence, and causal relationships

Eating disorders are complex, multifactorially determined phenomena. When individuals with eating disorders present for treatment with comorbid conditions, case conceptualization is further complicated and, as a result, it may be difficult to determine optimal psychological or pharmacological treatment. This article reviews the evidence of the association between eating disorders (anorexia nervosa [AN] and bulimia nervosa [BN]) and Axis I depression, obsessive-compulsive disorder (OCD), substance abuse, and Axis II personality disorders, for the purposes of increasing awareness about the different options for case conceptualization. Although other diagnoses comorbid with eating disorders are of interest to clinicians (e.g., posttraumatic stress disorder [PTSD] and social phobia), their comprehensive review is currently premature due to a lack of empirical scrutiny. Finally, future directions for research, including suggestions for the use of particular assessment tools and more sophisticated research designs, are discussed.     

A quantitative study of body-related attitudes in patients with anorexia and bulimia nervosa.

The Ben-Tovim Walker Body Attitudes Questionnaire (BAQ) is a psychometrically sound self-report instrument for assessing women's attitudes towards their own bodies. The BAQ responses of a large sample of patients with eating disorders (ED) diagnosed in accordance with DSM-III-R criteria were compared with those from a normative population and from diverse groups of psychiatrically and physically ill patients. The ED group was distinct, and showed extreme responses in the area of weight and shape concerns. But a better discrimination between the ED and other populations was achieved using subscales that related to 'body disparagement' (an intense loathing of the body) and 'attractiveness', rather than to weight and shape concerns. ED patients may have a more pervasive disturbance in body-related attitudes than is currently widely accepted. Patients with anorexia and bulimia nervosa showed very similar attitudes despite the symptomatic differences between the groups.     

Availability of information on young onset dementia for patients and carers in six European countries

Objectives

To identify information available in six European countries (England, France, Germany, Netherlands, Portugal, Sweden) that addresses the specific needs of people with young onset dementia (YOD) and their carers, and identify gaps.

Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings

We describe a retrospective study of 4 cases of sporadic fatal infectious mononucleosis (IM), 1 case of fatal IM, and 1 case of sporadic severe IM. Patients were 26 months to 17 years old; 3 were male. Five died of complications of IM. All 5 of these patients had the Epstein-Barr virus (EBV) present in examined tissue specimens; EBV was monoclonal in 3 patients and biclonal in 1. EBV clonality studies were not performed in the remaining patient. All 5 patients also had monoclonal gene rearrangements. The sixth patient survived despite a life-threatening clinical course; EBV was oligoclonal, and gene rearrangements were not detected. EBV clonality and gene rearrangement studies may be usefulfor predicting which patients with clinically aggressive IM are at highest risk for fatal outcome. Patients in whom IM has a fatal outcome are more likely to have monoclonal or biclonal EBV and immunoglobulin heavy chain or T-cell receptor gene rearrangements. In contrast, patients with nonfatal IM may lack monoclonal EBV and monoclonal rearrangements of the aforementioned genes. The reasons EBV induces a monoclonal proliferation only in some patients remain to be elucidated.     

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in Parkinson's disease and age of onset

Given the implications with respect to neuronal survival and the decreased level of the protein in the striatal region in Parkinson's disease (PD), brain-derived neurotrophic factor (BDNF) may be a candidate gene conferring susceptibility to PD. In a recent study of a Japanese population, a functional BDNF Val66Met polymorphism was associated with PD, however, an analogous investigation of a western population did not replicate this finding. In the present study of a Chinese sample, we have investigated the associations between the BDNF polymorphism and susceptibility to PD and PD onset age. The distribution of the BDNF genotypes and alleles did not differ significantly comparing PD patients and controls. Further, the onset age was not significantly different comparing the three BDNF genotype groups. Thus, our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of PD in the Chinese population. Other BDNF genetic variants, and the association of these variants with PD symptomatology or treatment response, may merit further investigation.     

Cognitive theory in anorexia nervosa and bulimia nervosa: progress, development and future directions

Important developments have taken place in cognitive theory of eating disorders (EDs) (and also in other disorders) since the review paper published by M.J. Cooper in 1997. The relevant empirical database has also expanded. Nevertheless, cognitive therapy for anorexia nervosa and bulimia nervosa, although helpful to many patients, leaves much to be desired. The current paper reviews the relevant empirical evidence collected, and the theoretical revisions that have been made to cognitive models of eating disorders, since 1997. The status and limitations of these developments are considered, including whether or not they meet the criteria for "good" theory. New theoretical developments relevant to cognitive explanations of eating disorders (second generation theories) are then presented, and the preliminary evidence that supports these is briefly reviewed. The lack of integration between cognitive theories of EDs and risk (vulnerability) factor research is noted, and a potential model that unites the two is noted. The implications of the review for future research and the development of cognitive theory in eating disorders are then discussed. These include the need for study of cognitive constructs not yet fully integrated (or indeed not yet applied clinically) into current theories and the need for cognitive theories of eating disorders to continue to evolve (as they have indeed done since 1997) in order to fully integrate such constructs. Treatment studies incorporating these new developments also urgently need to be undertaken.     

Intellect,perceptual characteristics,and weight gain in anorexia nervosa

Studied weight gain in a group of primary anorexics by examining two popular psychodiagnostic measures, the Wechsler and Rorschach, for indices that may predict improvement. Twenty-seven successively admitted anorexics to a behavior modification weight gain program at NIMH were studied. Using weight gain as a continuous criterion, multiple regression analyses indicated that perceptual-personality variables did not have any predictive power. Cognitive focusing skills, as measured by the Arithmetic and Digit Span subtests of the Wechsler, were found to account for roughly half of the variance and to be good predictors of weight gain.