Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Discrepancies between clinical needs and helpseeking behaviors in co-occurring posttraumatic stress and alcohol use disorders.

OBJECTIVE: The aim of the study was to compare subjects dually diagnosed with posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) to those with only one or none of these conditions regarding helpseeking needs and behaviors. METHOD: Data from a large community sample (N=3694) were used to assess the associations among lifetime PTSD and AUD, other psychiatric disorders, clinical characteristics and lifetime helpseeking behaviors derived from a semi-structured interview. RESULTS: Comorbid individuals had more severe clinical profiles and were more impaired than individuals with either PTSD or AUD alone or those with no/other psychiatric conditions. However, they did not differ in overall helpseeking behavior from any other group. Those with comorbid PTSD/AUD were even less likely than the other groups to seek help for depression and anxiety disorders through specific treatment facilities or the use of prescribed psychotropic drugs. CONCLUSIONS: Despite a greater need for treatment the comorbid group did not seek more help than the others. Their lower use of prescribed drugs supports the self-medication hypothesis, suggesting that those individuals relieve their symptoms through higher alcohol use instead. Our findings underline the need for health care facilities to encourage helpseeking behavior in the aftermath of stressful life events.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Pluralized life courses? An exploration of the life trajectories of individuals with psychiatric disorders.

BACKGROUND: : Most of the existing research relating to the life courses of people with psychiatric symptoms focuses on the occurrence and the impact of non-normative events on the onsets of crises; it usually disregards the more regular dimensions of life, such as work, family and intimate partnerships that may be related to the timing and seriousness of psychiatric problems. An additional reason for empirically addressing life trajectories of individuals with psychiatric problems relates to recent changes of family and occupational trajectories in relation to societal trends such as individualization and pluralization of life courses.¦AIM: : This paper explores the life trajectories of 86 individuals under clinical supervision and proposes a typology of their occupational, co-residence and intimacy trajectories. The results are discussed in light of the life-course paradigm.¦METHOD: : A multidimensional optimal matching analysis was performed on a sample of 86 individuals under clinical supervision to create a typology of trajectories. The influence of these trajectories on psychiatric disorders, evaluated using a SCL-90-R questionnaire, was then assessed using linear regression modelling.¦RESULTS: : The typologies of trajectories showed that the patients developed a diversity of life trajectories. Individuals who have developed a standard life course with few institutionalization periods reported more symptoms and distress than individuals with an institutionalized life trajectory.¦CONCLUSION: : The results of this study stress that psychiatric patients are social actors who are influenced by society at large and its ongoing process of change. Therefore, it is essential to take into account the diversity of occupational and family trajectories when dealing with individuals in therapeutic settings.

Assessing the associations between mental disorders, cardiovascular risk factors, and cardiovascular disease : the CoLaus/PsyCoLaus study

Background: Cardio-vascular diseases (CVD), their well established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, the pathogenic mechanisms and course determinants of both CVD and mental disorders have only been partially identified.Methods/Design: Comprehensive follow-up of CVRF and CVD with a psychiatric exam in all subjects who participated in the baseline cross-sectional CoLaus study (2003-2006) (n=6'738) which also included a comprehensive genetic assessment. The somatic investigation will include a shortened questionnaire on CVRF, CV events and new CVD since baseline and measurements of the same clinical and biological variables as at baseline. In addition, pro-inflammatory markers, persistent pain and sleep patterns and disorders will be assessed. In the case of a new CV event, detailed information will be abstracted from medical records. Similarly, data on the cause of death will be collected from the Swiss National Death Registry. The comprehensive psychiatric investigation of the CoLaus/PsyCoLaus study will use contemporary epidemiological methods including semi-structured diagnostic interviews, experienced clinical interviewers, standardized diagnostic criteria including threshold according to DSM-IV and sub-threshold syndromes and supplementary information on risk and protective factors for disorders. In addition, screening for objective cognitive impairment will be performed in participants older than 65 years.Discussion: The combined CoLaus/PsyCoLaus sample provides a unique opportunity to obtain prospective data on the interplay between CVRF/CVD and mental disorders, overcoming limitations of previous research by bringing together a comprehensive investigation of both CVRF and mental disorders as well as a large number of biological variables and a genome-wide genetic assessment in participants recruited from the general population.

Partial eating disorders among adolescents: a review.

PURPOSE: Many adolescents do not fulfill all the DSM-IV criteria's for anorexia nervosa and bulimia, but do nevertheless suffer from partial eating disorders (EDs). This review focuses on the definition, epidemiology and clinical aspects of these disorders. METHODS: Search on Medline & PsycINFO, review of websites, screening of bibliographies of articles and book chapters. RESULTS: There is still no consensus on the definition of these disorders, which cover a wide range of severity. Affected adolescents often suffer from physical and psychological problems owing to co-morbidity or as a consequence of their eating patterns: chronic constipation, dyspeptic symptoms, nausea, abdominal pain, fatigue, headaches, hypotension, menstrual dysfunction as well as dysthymia, depressive and anxiety disorders, or substance misuse and abuse. In comparison with those who are unaffected, adolescents with partial ED are at higher risk of evolving into full ED. However, most of them evolve into spontaneous remission. Adolescents with partial ED engaged, over a period of several months, in potentially unhealthy weight-control practices, suffering from intense fear of gaining weight and a disturbed body weight/image should be offered therapeutic support. CONCLUSION: Future research should focus on the exact delineation of various subtypes of clinical presentations in partial ED and on evidence-based treatment and follow-up of these various situations.

PsyCoLaUS: santé mentale et maladies cardiovasculaires: association fortuite [PsyCoLaus: mental disorders and cardiovascular diseases: spurious association?].

Cardio-vascular diseases (CVD), their well established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, the mechanisms underlying this association are still poorly understood. The main study questions of PsyCoLaus, the psychiatric arm of CoLaus, are: 1) Do mental disorders increase vulnerability to CVRF and CVD? 2) Do CVRF and CVD promote the development of mental disorders? 3) Do CVRF/ CVD and mental disorders share common pathogenetic processes? The longitudinal project adds a comprehensive psychiatric evaluation to the CoLaus investigation. A better understanding of the psychological, physiological and behavioral links underlying CVD/ CVRF and mental disorders will result in the development of more specific and efficient strategies of prevention and treatment for both psychiatric and CVD/CVRF, two major elements of burden of disease.

Genome-wide association study of co-occurring anxiety in major depression.

OBJECTIVES: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. METHODS: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. RESULTS: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻⁶. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. CONCLUSIONS: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.

Obésite, troubles alimentaires et groupe de parole à l'adolescence [Obesity, eating disorders and the group approach for adolescents].

About a third of obese adolescents also suffer from some kind of eating disorders which have to be recognized and included in the therapeutic frame. Besides this co-morbidity, most of these patients also require a psychological support. The group approach represents an adequate response to these problems, in providing a space for exchanges and an opportunity for mutual support. The group approach may even prove more beneficial than an individual treatment. Involving the parents too reinforces the improvement that adolescents can get from their participation in such groups.

The impact of personality characteristics on the clinical expression in neurodegenerative disorders--a review.

Clinical experience suggests that longstanding personality characteristics as a person's most distinctive features of all are likely to play a role in how someone with dementia copes with his increasing deficiencies. Personality characteristics may have a pathoplastic effect on both behavioral and psychological symptoms (BPS) or on cognition as well as cognitive decline. Cognitive disorders accompanied by BPS are a tremendous burden for both the patient and their proxies. This review suggests that premorbid personality characteristics are co-determinants of BPS in cognitive disorders, but much effort is needed to clarify whether or not specific premorbid personality traits are associated with specific BPS as no strong links have so far emerged. This review further shows that a growing field of research is interested in the links not only between quite short-lived emotional states and cognitive processes, but also between longstanding personality traits and cognition in both healthy individuals and patients with neurodegenerative disorders. Furthermore, a few studies found that specific premorbid personality traits may be risk factors for neurodegenerative diseases. However, research findings in this area remain scarce despite a huge literature on personality and cognitive disorders in general. An important shortcoming that hampers so far the progress of our understanding in these domains is the confusion in the literature between longstanding premorbid personality traits and transient personality changes observed in neurodegenerative diseases. Few studies have based their assessments on accepted personality theories and carefully investigated premorbid personality traits in patients with cognitive disorders, although assessing personality may be complicated in these patients. Studying the impact of personality characteristics in cognitive disorders is an especially promising field of research in particular when concomitantly using neurobiological approaches, in particular structural brain imaging and genetic studies as suggested by as yet rare studies. Improved understanding of premorbid personality characteristics as determinants of both BPS or cognitive capacities or decline is likely to influence our attitudes towards the treatment of demented patients and ultimately to help in alleviating a patient's and their proxies' burden.

Mental disorders in offspring of parents with bipolar and major depressive disorders.

OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS:   These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.

Risk of mental disorders in children of parents with alcohol or heroin dependence: a controlled high-risk study.

Aim: To assess the specific effect of alcohol dependence (AD) or heroin dependence (HD) in patients and their spouses on the risk of psychopathology in their 276 6.0- to 17.9- year-old children (mean 11.3 years). Methods: The sample included 101 offspring of patients with AD, 23 of patients with HD, and 152 of medical controls, as well as their 2 parents. Participants were assessed using semistructured diagnostic interviews and family history reports by psychologists blind to patient diagnoses. Results: Children of HD and AD patients had largely elevated rates of recurrent major depressive disorder. Children of HD patients were also at an increased risk for attention deficit hyperactivity disorder and substance use disorders (SUD). There were interactions between SUD in the 2 parents to increase the risk of SUD in offspring. Conclusions: These results emphasize the need for prompt identification and treatment of these children and highlight the need to pay clinical attention not only to the patient, but also to the co-parent in order to optimize prevention in offspring.

VEGF is a mediator of retinal pigment epithelium permeability leading to photoreceptor cell death in light-induced retinal degeneration : gene therapy strategy to prevent AMD-disorders

ABSTRACTIn normal tissues, a balance between pro- and anti-angiogenic factors tightly controls angiogenesis. Alterations of this balance may have pathological consequences. For instance, concerning the retina, the vascular endothelial growth factor (VEGF) is a potent pro-angiogenic factor, and has been identified has a key player during ocular neovascularization implicated in a variety of retinal diseases. In the exudative form (wet-form) of age-related macular degeneration (AMD), neovascularizations occurring from the choroidal vessels are responsible for a quick and dramatic loss of visual acuity. In diabetic retinopathy and retinopathy of prematurity, sprouting from the retinal vessels leads to vision loss. Furthermore, the aging of the population, the increased- prevalence of diabetes and the better survival rate of premature infants will lead to an increasing rate of these conditions. In this way, anti-VEGF strategy represents an important therapeutic target to treat ocular neovascular disorders.In addition, the administration of Pigmented Epithelial growth factor, a neurotrophic and an anti- angiogenic factor, prevents photoreceptor cell death in a model of retinal degeneration induced by light. Previous results analyzing end point morphology reveal that the light damage (LD) model is used to mimic retinal degenerations arising from environmental insult, as well as aging and genetic disease such as advanced atrophic AMD. Moreover, light has been identified as a co-factor in a number of retinal diseases, speeding up the degeneration process. This protecting effect of PEDF in the LD retina raises the possibility of involvement of the balance between pro- and anti-angiogenic factors not only for angiogenesis, but also in cell survival and maintenance.The aim of the work presented here was to evaluate the importance of this balance in neurodegenerative processes. To this aim, a model of light-induced retinal degeneration was used and characterized, mainly focusing on factors simultaneously controlling neuron survival and angiogenesis, such as PEDF and VEGF.In most species, prolonged intense light exposure can lead to photoreceptor cell damage that can progress to cell death and vision loss. A protocol previously described to induce retinal degeneration in Balb/c mice was used. Retinas were characterized at different time points after light injury through several methods at the functional and molecular levels. Data obtained confirmed that toxic level of light induce PR cell death. Variations were observed in VEGF pathway players in both the neural retina and the eye-cup containing the retinal pigment epithelium (RPE), suggesting a flux of VEGF from the RPE towards the neuroretina. Concomitantly, the integrity of the outer blood-retinal-barrier (BRB) was altered, leading to extravascular albumin leakage from the choroid throughout the photoreceptor layer.To evaluate the importance of VEGF during light-induced retinal degeneration process, a lentiviral vector encoding the cDNA of a single chain antibody directed against all VEGF-A isoforms was developed (LV-V65). The bioactivity of this vector to block VEGF was validated in a mouse model of laser-induced choroidal neovascularization mediated by VEGF upregulation. The vector was then used in the LD model. The administration of the LV-V65 contributed to the maintenance of functional photoreceptors, which was assessed by ERG recording, visual acuity measurement and histological analyses. At the RPE level, the BRB integrity was preserved as shown by the absence of albumin leakage and the maintenance of RPE cell cohesion.These results taken together indicate that the VEGF is a mediator of light induced PR degeneration process and confirm the crucial role of the balance between pro- and anti-angiogenic factors in the PR cell survival. This work also highlights the prime importance of BRB integrity and functional coupling between RPE and PR cells to maintain the PR survival. VEGF dysregulation was already shown to be involved in wet AMD forms and our study suggests that VEGF dysregulation may also occur at early stages of AMD and could thus be a potential therapeutic target for several RPE related diseases.RESUMEDans les différents tissues de l'organisme, l'angiogenèse est strictement contrôlée par une balance entre les facteurs pro- et anti-angiogéniques. Des modifications survenant dans cette balance peuvent engendrer des conséquences pathologiques. Par exemple, concernant la rétine, le facteur de croissance de l'endothélium vasculaire (VEGF) est un facteur pro-angiogénique important. Ce facteur a été identifié comme un acteur majeur dans les néovascularisations oculaires et les processus pathologiques angiogéniques survenant dans l'oeil et responsables d'une grande variété de maladies rétiniennes. Dans la forme humide de la dégénérescence maculaire liée à l'âge (DMLA), la néovascularisation choroïdienne est responsable de la perte rapide et brutale de l'acuité visuelle chez les patients affectés. Dans la rétinopathie diabétique et celle lié à la prématurité, l'émergence de néovaisseaux rétiniens est la cause de la perte de la vision. Les néovascularisations oculaires représentent la principale cause de cécité dans les pays développés. De plus, l'âge croissant de la population, la progression de la prévalence du diabète et la meilleure survie des enfants prématurés mèneront sans doute à l'augmentation de ces pathologies dans les années futures. Dans ces conditions, les thérapies anti- angiogéniques visant à inhiber le VEGF représentent une importante cible thérapeutique pour le traitement de ces pathologies.Plusieurs facteurs anti-angiogéniques ont été identifiés. Parmi eux, le facteur de l'épithélium pigmentaire (PEDF) est à la fois un facteur neuro-trophique et anti-angiogénique, et l'administration de ce facteur au niveau de la rétine dans un modèle de dégénérescence rétinienne induite par la lumière protège les photorécepteurs de la mort cellulaire. Des études antérieures basées sur l'analyse morphologique ont révélé que les modifications survenant lors de la dégénération induite suite à l'exposition à des doses toxiques de lumière représente un remarquable modèle pour l'étude des dégénérations rétiniennes suite à des lésions environnementales, à l'âge ou encore aux maladies génétiques telle que la forme atrophique avancée de la DMLA. De plus, la lumière a été identifiée comme un co-facteur impliqué dans un grand nombre de maladies rétiniennes, accélérant le processus de dégénération. L'effet protecteur du PEDF dans les rétines lésées suite à l'exposition de des doses toxiques de lumière suscite la possibilité que la balance entre les facteurs pro- et anti-angiogéniques soit impliquée non seulement dans les processus angiogéniques, mais également dans le maintient et la survie des cellules.Le but de ce projet consiste donc à évaluer l'implication de cette balance lors des processus neurodégénératifs. Pour cela, un modèle de dégénération induite par la lumière à été utilisé et caractérisé, avec un intérêt particulier pour les facteurs comme le PEDF et le VEGF contrôlant simultanément la survie des neurones et l'angiogenèse.Dans la plupart des espèces, l'exposition prolongée à une lumière intense peut provoquer des dommages au niveau des cellules photoréceptrices de l'oeil, qui peut mener à leur mort, et par conséquent à la perte de la vision. Un protocole préalablement décrit a été utilisé pour induire la dégénération rétinienne dans les souris albinos Balb/c. Les rétines ont été analysées à différents moments après la lésion par différentes techniques, aussi bien au niveau moléculaire que fonctionnel. Les résultats obtenus ont confirmé que des doses toxiques de lumière induisent la mort des photorécepteurs, mais altèrent également la voie de signalisation du VEGF, aussi bien dans la neuro-rétine que dans le reste de l'oeil, contenant l'épithélium pigmentaire (EP), et suggérant un flux de VEGF provenant de ΙΈΡ en direction de la neuro-rétine. Simultanément, il se produit une altération de l'intégrité de la barrière hémato-rétinienne externe, menant à la fuite de protéine telle que l'albumine, provenant de la choroïde et retrouvée dans les compartiments extravasculaires de la rétine, telle que dans la couche des photorécepteurs.Pour déterminer l'importance et le rôle du VEGF, un vecteur lentiviral codant pour un anticorps neutralisant dirigée contre tous les isoformes du VEGF a été développé (LV-V65). La bio-activité de ce vecteur a été testé et validée dans un modèle de laser, connu pour induire des néovascularisations choroïdiennes chez la souris suite à l'augmentation du VEGF. Ce vecteur a ensuite été utilisé dans le modèle de dégénération induite par la lumière. Les résultats des électrorétinogrammes, les mesures de l'acuité visuelle et les analyses histologiques ont montré que l'injection du LV-V65 contribue à la maintenance de photorécepteurs fonctionnels. Au niveau de l'EP, l'absence d'albumine et la maintenance des jonctions cellulaires des cellules de l'EP ont démontré que l'intégrité de la barrière hémato-rétinienne externe est préservée suite au traitement.Par conséquent, tous les résultats obtenus indiquent que le VEGF est un médiateur important impliquée dans le processus de dégénération induit par la lumière et confirme le rôle cruciale de la balance entre les facteurs pro- et anti-angiogéniques dans la survie des photorécepteurs. Cette étude révèle également l'importance de l'intégrité de la barrière hémato-rétinienne et l'importance du lien fonctionnel et structurel entre l'EP et les photorécepteurs, essentiel pour la survie de ces derniers. Par ailleurs, Cette étude suggère que des dérèglements au niveau de l'équilibre du VEGF ne sont pas seulement impliqués dans la forme humide de la DMLA, comme déjà démontré dans des études antérieures, mais pourraient également contribuer et survenir dans des formes précoces de la DMLA, et par conséquent le VEGF représente une cible thérapeutique potentielle pour les maladies associées à des anomalies au niveau de l'EP.

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study.

BackgroundNiemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort.MethodsClinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and period prevalence rates for neurological, psychiatric and visceral symptoms associated with NP-C disease. The NP-C suspicion index was calculated for the time of neurological disease onset and the time of diagnosis.ResultsThe shortest median diagnostic delay was noted for vertical supranuclear gaze palsy (2y). Ataxia, dysarthria, dysphagia, spasticity, cataplexy, seizures and cognitive decline displayed similar median diagnostic delays (4¿5y). The longest median diagnostic delay was associated with hepatosplenomegaly (15y). Highest period prevalence rates were noted for ataxia, dysarthria, vertical supranuclear gaze palsy and cognitive decline. The NP-C suspicion index revealed a median score of 81 points in nine patients at the time of neurological disease onset which is highly suspicious for NP-C disease. At the time of diagnosis, the score increased to 206 points.ConclusionA neurologic-psychiatric disease pattern represents the most characteristic clinical manifestation of NP-C and occurs early in the disease course. Visceral manifestation such as isolated hepatosplenomegaly often fails recognition and thus highlights the importance of a work-up for lysosomal storage disorders. The NP-C suspicion index emphasizes the importance of a multisystem evaluation, but seems to be weak in monosymptomatic and infantile NP-C patients.

Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.

α-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable β-sheet enriched toroid-shaped α-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured α-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by α-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.