Early weight gain trajectories in first episode anorexia: predictors of outcome for emerging adults in outpatient treatment.

BACKGROUND: Early response to treatment has been shown to be a predictor of later clinical outcomes in eating disorders (EDs). Specifically, early weight gain trajectories in anorexia nervosa (AN) have been shown to predict higher rates of later remission in inpatient treatment. However, no study has, as of yet, examined this phenomenon within outpatient treatment of first episode cases of AN or in emerging adults. METHODS: One hundred seven patients with AN, all between the ages of 16 and 25 and with an illness duration of < 3 years, received treatment via the first episode rapid early intervention in eating disorders (FREED) service pathway. Weight was recorded routinely across early treatment sessions and recovery outcomes (BMI > 18.5 kg/m2 and eating psychopathology) were assessed up to 1 year later. Early weight gain across the first 12 treatment sessions was investigated using latent growth mixture modelling to determine distinct classes of change. Follow-up clinical outcomes and remission rates were compared between classes, and individual and clinical characteristics at baseline (treatment start) were tested as potential predictors. RESULTS: Four classes of early treatment trajectory were identified. Three of these classes (n = 95), though differing in their early change trajectories, showed substantial improvement in clinical outcomes at final follow-up. One smaller class (n = 12), characterised by a 'higher' start BMI (> 17) and no early weight gain, showed negligible improvement 1 year later. Of the three treatment responding groups, levels of purging, depression, and patient reported carer expressed emotion (in the form of high expectations and low tolerance of the patient) determined class membership, although these findings were not significant after correcting for multiple testing. A higher BMI at treatment start was not sufficient to predict optimal clinical outcomes. CONCLUSION: First episode cases of AN treated via FREED fit into four distinct early response trajectory classes. These may represent subtypes of first episode AN patients. Three of these four trajectories included patients with substantial improvements 1 year later. For those in the non-response trajectory class, treatment adjustments or augmentations could be considered earlier, i.e., at treatment session 12.

A key feature of anorexia nervosa (AN) is an unhealthily low body weight. Previous studies show that more weight gained early in inpatient treatment leads to better outcomes. This study tried to see if this was also true for outpatients receiving treatment for the first time. All participants were emerging adults between the ages of 16 and 25 who had been ill for less than 3 years. Weight was recorded across the first 12 weekly treatment sessions. Statistics showed that the patients fit roughly into four different groups in early treatment, each with different starting weights and rates of weight gain in the first 12 treatment sessions. The group a patient belonged to could sometimes be predicted by vomiting behaviours, level of depression, and patients' perception of parental tolerance and expectations at the start of treatment. Out of the four groups, three did relatively well 1 year later, but one small group of patients did not. This small group had a higher starting weight than many of the other groups but did not gain any weight across the first 12 sessions. These patients could benefit from a change or increase in the amount or intensity of treatment after the first 12 treatment sessions.

The amyloid architecture provides a scaffold for enzyme-like catalysts.

Natural biological enzymes possess catalytic sites that are generally surrounded by a large three-dimensional scaffold. However, the proportion of the protein molecule that participates in the catalytic reaction is relatively small. The generation of artificial or miniature enzymes has long been a focus of research because enzyme mimetics can be produced with high activity at low cost. These enzymes aim to mimic the active sites without the additional architecture contributed by the protein chain. Previous work has shown that amyloidogenic peptides are able to self-assemble to create an active site that is capable of binding zinc and catalysing an esterase reaction. Here, we describe the structural characterisation of a set of designed peptides that form an amyloid-like architecture and reveal that their capability to mimic carbonic anhydrase and serve as enzyme-like catalysts is related to their ability to self-assemble. These amyloid fibril structures can bind the metal ion Zn2+via a three-dimensional arrangement of His residues created by the amyloid architecture. Our results suggest that the catalytic efficiency of amyloid-like assembly is not only zinc-dependent but also depends on an active centre created by the peptides which is, in turn, dependent on the ordered architecture. These fibrils have good esterase activity, and they may serve as good models for the evolution of modern-day enzymes. Furthermore, they may be useful in designing self-assembling fibrils for applications as metal ion catalysts. This study also demonstrates that the ligands surrounding the catalytic site affect the affinity of the zinc-binding site to bind the substrate contributing to the enzymatic activity of the assembled peptides.

Dementia of the eye: the role of amyloid beta in retinal degeneration.

Age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness affecting nearly 50 million individuals globally. The disease is characterised by progressive loss of central vision, which has significant implications for quality of life concerns in an increasingly ageing population. AMD pathology manifests in the macula, a specialised region of the retina, which is responsible for central vision and perception of fine details. The underlying pathology of this complex degenerative disease is incompletely understood but includes both genetic as well as epigenetic risk factors. The recent discovery that amyloid beta (Aß), a highly toxic and aggregate-prone family of peptides, is elevated in the ageing retina and is associated with AMD has opened up new perspectives on the aetiology of this debilitating blinding disease. Multiple studies now link Aß with key stages of AMD progression, which is both exciting and potentially insightful, as this identifies a well-established toxic agent that aggressively targets cells in degenerative brains. Here, we review the most recent findings supporting the hypothesis that Aß may be a key factor in AMD pathology. We describe how multiple Aß reservoirs, now reported in the ageing eye, may target the cellular physiology of the retina as well as associated layers, and propose a mechanistic pathway of Aß-mediated degenerative change leading to AMD.

Typology of obsessive-compulsive symptoms in children and adolescents with anorexia nervosa.

BACKGROUND: Previous studies have shown that symptoms of obsessive compulsive disorder are common in both adults and children and adolescents with anorexia nervosa. Until now, no study has explored the specific obsessive compulsive symptoms shown in children and adolescents with AN. METHOD: In this study we report types of symptoms displayed by young people with AN and explore similarities and differences with adults with AN and with people with OCD. RESULTS: Common obsessions concerned contamination, aggressive and somatic concerns, and common compulsions were related to ordering/arranging, and checking. CONCLUSION: It is important for clinicians to be aware of the obsessions and compulsions they are most likely to encounter when working with these patients. If missed or ignored, such symptoms may interact with eating disorder symptoms and impede treatment.

Establishing a useful distinction between current and anticipated bodily shame in eating disorders.

Previous research has suggested a role for bodily shame in the development of bulimia. The purpose of the present study was to extend this research by exploring a temporal perspective on bodily shame and eating pathology. Specifically, we were interested in whether bodily shame associated with the possibility of future weight gain was important in determining eating disorder symptoms independently of any association with bodily shame associated with current body size. A brief questionnaire designed to measure bodily shame was developed for the purposes of this study and administered to four samples (total n=428) of eating disordered and non-eating disordered women who also completed a number of measures of eating pathology. Factor analysis of the bodily shame scale identified three sub-scales, two measuring feelings of bodily shame (one measuring shame associated with current body size and one measuring shame that is anticipated should the individual gain weight) and a third measuring the perceived unattractiveness of being overweight. Anticipated bodily shame made a significant additional contribution to predicting eating disorder symptoms over and above that made by current bodily shame. A focus on feelings of bodily shame as they are currently experienced may limit the usefulness of this construct in eating disorder research. Since shame can be both punishing and prohibitive, consideration of the anticipation of shame as a consequence of weight gain may be a useful addition to understanding eating disordered behaviours, particularly in relation to symptoms concerning the prevention of weight gain rather than just the achievement of weight loss.

Examining the structure of the mature amyloid fibril.

The pathogenesis of the group of diseases known collectively as the amyloidoses is characterized by the deposition of insoluble amyloid fibrils. These are straight, unbranching structures about 70-120 A (1 A=0.1 nm) in diameter and of indeterminate length formed by the self-assembly of a diverse group of normally soluble proteins. Knowledge of the structure of these fibrils is necessary for the understanding of their abnormal assembly and deposition, possibly leading to the rational design of therapeutic agents for their prevention or disaggregation. Structural elucidation is impeded by fibril insolubility and inability to crystallize, thus preventing the use of X-ray crystallography and solution NMR. CD, Fourier-transform infrared spectroscopy and light scattering have been used in the study of the mechanism of fibril formation. This review concentrates on the structural information about the final, mature fibril and in particular the complementary techniques of cryo-electron microscopy, solid-state NMR and X-ray fibre diffraction.

Specificity in the relationship between depressive and eating disorder symptoms in remitted and nonremitted women.

OBJECTIVE: There is a strong association between eating disorders and depression. However, because both eating disorder symptoms and depression are multifactorial, this study explored the relationship between these two disorders in women with eating disorders and women in remission. METHOD: Two hundred and eight (mostly female) volunteers with a history of eating disorders participated. They completed a self-report questionnaire of eating disorder symptoms, the Short Evaluation for Eating Disorders (SEED), and a questionnaire measuring depression, the Beck Depression Inventory (BDI). RESULTS: According to the SEED, 57 volunteers were classified as being in remission and 151 were classified as being ill. Those who were in remission were significantly less depressed overall than those who were still ill with 72% of the former falling in the "not depressed" or "mildly depressed" categories and 73% of the latter falling in the "moderately" or "severely depressed" categories. Factor analyses of the SEED and BDI identified three subscales of eating disorder symptoms (dietary restriction, bulimia, and body mass index [BMI]/menstruation) and two subscales of depression (cognitive and somatic/affective). Dietary restriction and bulimia, but not BMI/menstruation, were uniquely associated with the cognitive symptoms of depression. However, none of the eating disorder symptoms were uniquely associated with the somatic/affective symptoms of depression. DISCUSSION: Although eating disorders and depression share considerable comorbidity, a specific association is restricted to that between the cognitive and behavioral symptoms of eating disorders and the cognitive symptoms of depression.

Assembly of Alzheimer's amyloid-beta fibrils and approaches for therapeutic intervention.

Amyloid plaques are the principal features of Alzheimers disease (AD) pathology and are considered to be a major factor in the disease process. These fibrillar deposits are composed primarily of the 40-42 residue amyloid-beta (Abeta) peptide which is a proteolytic product of a larger membrane precursor protein. Electron microscopy and X-ray diffraction have revealed that the mature amyloid fibrils are assembled as a highly beta-sheet polymer that has a well-defined protofilament quaternary structure. This organization is observed for amyloid fibrils from a wide variety of disorders and appears to represent a structural superfamily. Amyloid plaques also contain a number of other components such as proteoglycans that contain highly sulfated glycosaminoglycan (GAG) chains. These amyloid-associated elements may contribute to the aggregation and/or stabilization of Abeta as insoluble fibrils. We have recently developed an aggressive model for Abeta plaque formation in transgenic mice that exhibits an "early-onset" phenotype. Immunocytochemistry has demonstrated that even with this rapid progression, Abeta deposits within the neuropil and cerebrovascular system all co-localize with heparan sulfate proteoglycans (HSPG). These findings indicate a number of structural features that can be targeted as potential sites for the development of amyloid inhibitors. In addition, the use of small compounds that interfere with the proteoglycan-amyloid pathway may be effective therapeutic agents that can be assessed through the use of these transgenic models.

Osteoporosis in young people. Research and treatment in eating disorders.

We still have much to learn about BMD problems in eating disorders. Much progress has been made in the past 10 years; most clinicians and many patients and their families are now aware of the problem. More research is crucial, however, the authors suggest focusing on three areas: 1. Treatment and prevention: Such studies are difficult to conduct for similar reasons to the difficulties in conducting treatment trials of therapy for AN. First, the relative rarity of the condition makes it difficult to recruit subjects; second, drop-out rates are higher because of ambivalence; and third, the population is heterogeneous both in terms of symptoms and cause. 2. Better understanding of bone turnover in AN. More studies are needed to examine turnover of bone in patients with AN using biochemical markers. In particular, prospective studies are needed to examine the effects of refeeding, weight gain, and treatments such as calcium supplementation. 3. Long-term course of bone density. It would be particularly instructive to examine this in individuals with a short or long history of AN. It would also be useful to study women approaching menopause who had an episode of AN in their teens or early twenties compared with women who were of normal weight during this period.

Identification of a novel human islet amyloid polypeptide beta-sheet domain and factors influencing fibrillogenesis.

Human islet amyloid polypeptide (hIAPP) accumulates as pancreatic amyloid in type 2 diabetes and readily forms fibrils in vitro. Investigations into the mechanism of hIAPP fibril formation have focused largely on residues 20 to 29, which are considered to comprise a primary amyloidogenic domain. In rodents, proline substitutions within this region and the subsequent beta-sheet disruption, prevents fibril formation. An additional amyloidogenic fragment within the C-terminal sequence, residues 30 to 37, has been identified recently. We have extended these observations by examining a series of overlapping peptide fragments from the human and rodent sequences. Using protein spectroscopy (CD/FTIR), electron microscopy and X-ray diffraction, a previously unrecognised amyloidogenic domain was localised within residues 8 to 20. Synthetic peptides corresponding to this region exhibited a transition from random coil to beta-sheet conformation and assembled into fibrils having a typical amyloid-like morphology. The comparable rat 8-20 sequence, which contains a single His18Arg substitution, was also capable of assembling into amyloid-like fibrils. Examination of peptide fragments corresponding to residues 1 to 13 revealed that the immediate N-terminal region is likely to have only a modulating influence on fibril formation or conformational conversion. The contributions of charged residues as they relate to the amyloid-forming 8-20 sequence were also investigated using IAPP fragments and by assessing the effects of pH and counterions. The identification of these principal amyloidogenic sequences and the effects of associated factors provide details on the IAPP aggregation pathway and structure of the peptide in its fibrillar state.

From genetics to pathology: tau and alpha-synuclein assemblies in neurodegenerative diseases.

The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule-associated protein tau or the protein alpha-synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the alpha-synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and alpha-synuclein can cause neurodegeneration.

Perceptual illusions in eating disorders: rigid and fluctuating styles.

This study investigated perceptual styles in anorexia nervosa (AN) and bulimia nervosa (BN) using a perceptual set task. We hypothesised that, consistent with personality style research. AN patients might be more rigid in style than those with BN or no eating disorder. We found that once an illusion had been established, participants with AN and BN showed more illusions than non-ED women. However, while AN patients responded rigidly, giving the same response repeatedly, BN patients were more likely to change their responses. The study suggests interesting differences to be followed up in future research. Differences in rigid and fluctuating perceptual styles may have implications for understanding the phenomenology of eating disorders, and have implications for treatment.

Molecular structure of a fibrillar Alzheimer's A beta fragment.

Amyloid-beta (Abeta) peptide deposition as fibrillar senile plaques is a key element in the pathology of Alzheimer's disease. Here we present a high-resolution structure of an Abeta amyloid fibril using magnetically aligned preparations of a central Abeta domain which forms representative amyloid fibrils. Diffraction analysis of these samples revealed Bragg reflections on layer lines consistent with a preferred orientation, as opposed to the typical symmetry associated with fibers. These crystalline properties permitted a molecular replacement approach based upon a beta-hairpin motif resulting in a structure of the fibrillar Abeta peptide. This detailed molecular structure of Abeta in its fibrous state provides clues as to the mechanism of amyloid assembly and identifies potential targets for controlling the aggregation process.

Nucleated conformational conversion and the replication of conformational information by a prion determinant.

Prion proteins can serve as genetic elements by adopting distinct physical and functional states that are self-perpetuating and heritable. The critical region of one prion protein, Sup35, is initially unstructured in solution and then forms self-seeded amyloid fibers. We examined in vitro the mechanism by which this state is attained and replicated. Structurally fluid oligomeric complexes appear to be crucial intermediates in de novo amyloid nucleus formation. Rapid assembly ensues when these complexes conformationally convert upon association with nuclei. This model for replicating protein-based genetic information, nucleated conformational conversion, may be applicable to other protein assembly processes.

Presenilin structure, function and role in Alzheimer disease.

Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the beta-amyloid precursor protein. Although the underlying mechanism by which presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid beta-peptides. Furthermore, presenilins interact with beta-catenin to form presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.

Alzheimer's amyloid fibrils: structure and assembly.

Structural studies of Alzheimer's amyloid fibrils have revealed information about the structure at different levels. The amyloid-beta peptide has been examined in various solvents and conditions and this has led to a model by which a conformational switching occurs from alpha-helix or random coil, to a beta-sheet structure. Amyloid fibril assembly proceeds by a nucleation dependent pathway leading to elongation of the fibrils. Along this pathway small oligomeric intermediates and short fibrillar structures (protofibrils) have been observed. In cross-section the fibril appears to be composed of several subfibrils or protofilaments. Each of these protofilaments is composed of beta-sheet structure in which hydrogen bonding occurs along the length of the fibre and the beta-strands run perpendicular to the fibre axis. This hierarchy of structure is discussed in this review.

The protofilament substructure of amyloid fibrils.

Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes the usually fatal, acquired and hereditary systemic amyloidoses and is associated with the pathology of Alzheimer's disease, type 2 diabetes and the transmissible spongiform encephalopathies. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. We have previously demonstrated that transthyretin amyloid fibrils contain four constituent protofilaments packed in a square array. Here, we have used cross-correlation techniques to average electron microscopy images of multiple cross-sections in order to reconstruct the sub-structure of ex vivo amyloid fibrils composed of amyloid A protein, monoclonal immunoglobulin lambda light chain, Leu60Arg variant apolipoprotein AI, and Asp67His variant lysozyme, as well as synthetic fibrils derived from a ten-residue peptide corresponding to the A-strand of transthyretin. All the fibrils had an electron-lucent core but the packing arrangement comprised five or six protofilaments rather than four. The structural similarity that defines amyloid fibres thus exists principally at the level of beta-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.

Direct visualisation of the beta-sheet structure of synthetic Alzheimer's amyloid.

Amyloid fibrils are a major pathological feature of Alzheimer's disease as well as other amyloidoses including the prion diseases. They are an unusual phenomenon, being made up of different, normally soluble proteins which undergo a profound conformational change and assemble to form very stable, insoluble fibrils which accumulate in the extracellular spaces. In Alzheimer's disease the amyloid fibrils are composed of the A beta protein. Knowledge of the structure of amyloid is essential for understanding the abnormal assembly and deposition of these fibrils and could lead to the rational design of therapeutic agents for their prevention or disaggregation. Here we reveal the core structure of an Alzheimer's amyloid fibril by direct visualisation using cryo-electron microscopy. Synthetic amyloid fibrils composed of A beta residues 11 to 25 and 1 to 42 were examined. The A beta (11-25) fibrils are clearly composed of beta-sheet structure that is observable as striations across the fibres. The beta-strands run perpendicular to the fibre axis and the projections show that the fibres are composed of beta-sheets with the strands in direct register. This observation has implications not only for the further understanding of amyloid, but also for the development of cryo-electron microscopy for direct visualisation of secondary structure.

Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation.

Filamentous inclusions made of alpha-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in alpha-synuclein. We report here the assembly properties and secondary structure characteristics of recombinant alpha-synuclein. Carboxy-terminally truncated human alpha-synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T alpha-synuclein, and rat and zebra finch alpha-synuclein. Wild-type human alpha-synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins beta- and gamma-synuclein only assembled after several weeks of incubation. Synthetic human alpha-synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of alpha-synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that alpha-synuclein undergoes a conformational change from random coil to beta-sheet structure during assembly. X-ray diffraction and electron diffraction of the alpha-synuclein assemblies showed a cross-beta conformation characteristic of amyloid.

Protofilaments, filaments, ribbons, and fibrils from peptidomimetic self-assembly: implications for amyloid fibril formation and materials science.

Deciphering the mechanism(s) of ß-sheet mediated self-assembly is essential for understanding amyloid fibril formation and for the fabrication of polypeptide materials. Herein, we report a simple peptidomimetic that self-assembles into polymorphic ß-sheet quaternary structures including protofilaments, filaments, fibrils, and ribbons that are reminiscent of the highly ordered structures displayed by the amyloidogenic peptides Aß, calcitonin, and amylin. The distribution of quaternary structures can be controlled by and in some cases specified by manipulating the pH, buffer composition, and the ionic strength. The ability to control ß-sheet-mediated assembly takes advantage of quaternary structure dependent pK(a) perturbations. Biophysical methods including analytical ultracentrifugation studies as well as far-UV circular dichroism and FT-IR spectroscopy demonstrate that linked secondary and quaternary structural changes mediate peptidomimetic self-assembly. Electron and atomic force microscopy reveal that peptidomimetic assembly involves numerous quaternary structural intermediates that appear to self-assemble in a convergent fashion affording quaternary structures of increasing complexity. The ability to control the assembly pathway(s) and the final quaternary structure(s) afforded should prove to be particularly useful in deciphering the quaternary structural requirements for amyloid fibril formation and for the construction of noncovalent macromolecular structures.