Protein seeding in Alzheimer’s disease and Parkinson’s disease: Similarities and differences

Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide (Aβ) and alpha-synuclein (α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize “seeds” as well as analyze changes in the nervous system in response to exogenous insults.     

Effect of freezing method and storage at − 20 °C and − 70 °C on prothrombin time, aPTT and plasma fibrinogen levels

Clinical and epidemiological trials often involve central laboratory analyses of coagulation tests, including fibrinogen, which requires freezing of the plasma samples. Although rapid freezing by immersion of sample tubes in liquid nitrogen and storage at − 70 °C is recommended, plasma samples are often transferred directly to the storage compartments, and stored at − 20 °C.Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen using a kinetic fibrinogen assay, PT-derived fibrinogen, and an immunoassay were measured in fresh plasma samples from 16 healthy blood donors. In addition, four sets of aliquots were prepared. Set A was transferred directly to a − 20 °C storage compartment, set B was first snap-frozen in liquid nitrogen and then transferred to the − 20 °C compartment. Set C was transferred directly to a − 70 °C freezer, set D was first snap-frozen in liquid nitrogen and then stored at − 70 °C. Aliquots were thawed after one, two, three and four months storage and laboratory assays repeated.PT and aPTT were strongly influenced by freezing and storage. In contrast, freezing had little effect on fibrinogen levels. Differences were below three percent for all variants. Changes were smaller for samples stored at − 70 °C compared to − 20 °C, and for snap-frozen compared to not snap-frozen samples. Frozen and thawed samples generated slightly higher fibrinogen levels compared to fresh samples.Prothrombin time and aPTT should be measured in fresh samples, since freezing has an inconstant and unpredictable effect on the results. In contrast, freezing and storage has little effect on results of fibrinogen assays.A limitation of the study is that only samples from healthy blood donors were used. Plasma samples with abnormal fibrinogen concentration, or with abnormal concentrations of coagulation factors might behave differently.     

Polysialylation and lipopolysaccharide‐induced shedding of E‐selectin ligand‐1 and neuropilin‐2 by microglia and THP‐1 macrophages

Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein‐modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi‐confined polySia, which is depleted in response to lipopolysaccharide (LPS)‐induced activation. Polysialylated neuropilin‐2 (polySia‐NRP2) contributes to this pool but further polySia protein carriers have remained elusive. Here, we use organotypic brain slice cultures to demonstrate that injury‐induced activation of microglia initiates Golgi‐confined polySia expression in situ. An unbiased glycoproteomic approach with stem cell‐derived microglia identifies E‐selectin ligand‐1 (ESL‐1) as a novel polySia acceptor. Together with polySia‐NRP2, polySia‐ESL‐1 is also detected in primary cultured microglia, in brain slice cultures and in phorbol ester‐induced THP‐1 macrophages. Induction of stem cell‐derived microglia, activated microglia in brain slice cultures and THP‐1 macrophages by LPS, but not interleukin‐4, causes polySia depletion and, as shown for stem cell‐derived microglia, a metalloproteinase‐dependent release of polySia‐ESL‐1 and polySia‐NRP2. Moreover, soluble polySia attenuates LPS‐induced production of nitric oxide and proinflammatory cytokines. Thus, shedding of polySia‐ESL‐1 and polySia‐NRP2 after LPS‐induced activation of microglia and THP‐1 macrophages may constitute a mechanism for negative feedback regulation. GLIA 2016 GLIA 2016;64:1314–1330     

L' « Ouverture émotionnelle » dans les Troubles de la dépendance et les Troubles de la personnalité

Emotion processing is supposed to play an important role in psychological dysfunctions in alcohol and drug dependency disorders (DD), as well as in personality disorders (PD). The model of “Emotional Openness” (“Ouverture émotionnelle”) provides a multidimensional framework to analyze problematic patterns of emotion processing. Within this framework, it is suggested that drug- and alcohol-dependent patients as well as borderline and antisocial patients show reduced a) “cognitive/conceptual representation” of affective states; b) “emotion regulation”; and c) “expression and communication of emotion”; but d) increased “awareness of body internal indicators” of affectivity; and e) appropriate psychological treatment is supposed to improve these patterns. Drug-dependent patients with PD comorbidity (in particular borderline or antisocial) are supposed to present even stronger deficits in (a) and (b). The hypotheses are tested with the 36-item DOE questionnaire (“Dimensions of Openness to Emotional experiences”, trait version; [19]), assessing six main dimensions of emotion processing as represented by the subject (French and Italian version). The instrument presents satisfying reliability coefficients (mean alphas of the scales in two recent studies (N = 251; N = 435) vary between 0.74 and 0.82) and good factorial validity (6-factor PCA solutions with varimax rotation solutions in the two samples are highly coherent; the mean of Tucker's congruence coefficients is 0.93). Results of two clinical studies are presented, comparing N = 71 patients (21 drug-dependent without personality disorder; 30 drug-dependent with borderline or antisocial personality; 20 dependent in-patients receiving psychological therapy) with normal control subjects (N = 51 matched; N = 50 reference group), including one pre-post treatment comparison. Results confirm marked deficits of DD patients concerning “conceptual representation” and “emotion regulation”, as well as a reduction of “communication/expression of emotion” but an increased “awareness of body internal indicators” of affectivity. Differences of patients with a double diagnosis correspond to effect sizes of d = -1.33 for cognitive/conceptual representation of emotions and d = -1.25 for emotion regulation; differences in emotion communication and expression are also significant but less important d = -0.44. Awareness of body internal emotion indicators is increased (d = +0.27) but does not differ significantly from the control group. As supposed, patients with a double diagnosis (DD and PD) described significantly stronger deficits in conceptual representation and emotion regulation than the patients with dependency disorder only. In the second study, a group of DD patients receiving multi-component treatment, including individual and group therapeutic intervention, according to the client-centered approach, and working on emotion processing, showed marked differences from the reference group at the beginning of the treatment (d = -0.91 for cognitive/conceptual representation, d = -0.82 for emotion regulation and d = +0.46 for awareness of bodily internal indicators). As supposed, pre-post comparisons indicate improvement with change effect sizes of d = 0.99 for conceptual representation, d = 0.97 for emotion regulation, as well as d = 0.88 for emotion communication and expression. Furthermore, the changes following treatment are highly significant and substantial, except for the awareness of internal bodily indicators, which only slightly decreased. Patients “normalize” their emotion processing following treatment, describing increased conceptual representation and emotion regulation, as well as emotion communication and expression. Results underline the importance of dysfunctional modes of emotion processing in both pathologies, and underline the validity of applying the model and the DOE instrument. They are discussed with reference to the model of alexithymia.     

远程医疗与“周末效应”

<正>1研究介绍1.1研究背景近年来美国卒中死亡率呈逐年下降趋势,但在农村地区其死亡率仍居高不下。远程医疗(telemedicine,TM)的应用可提高偏远地区医疗服务质量及可及性。通过TM指导进行的静脉rt-PA溶栓治疗急性缺血性卒中已被证明是安全的,且其临床结局、并发症及死亡率都与直接前往卒中中心接受治疗的患者相当。有证据表明,就诊日期及时间或可影响卒中结局,患者夜间或周末就诊较工作日工作     

Assessment of progression and prognosis in ‘possible’ and ‘probable’ Alzheimer's disease

Objective. The objective of this study was to assess the rate of progression and clinical predictors of decline in subjects with ‘possible’ and ‘probable’ Alzheimer's disease (AD). Design/setting. The annual rate of change (ARC) for cognitive/functional scales was calculated for 95 subjects with AD attending a memory clinic. Two consecutive ARCs were calculated for a subgroup of 39 subjects. Results. The ARCs were relatively normally distributed; however, there was a large degree of variability. Neither age nor duration of symptoms at presentations were predictive of the rate of decline. However, the data suggested an effect of gender, with males having a greater rate of decline in cognition (p=0·02). Finally, the rate of progression over the first year did not predict the subsequent ARC (p=0·25). Conclusions. The high variability in ARCs observed in this study and poor correlation between consecutive ARCs suggest that neither mean ARC values nor the previous rate of decline can be used to aid clinicians in the assessment of response to acetylcholinesterase inhibitors or other specific treatments for AD. © 1998 John Wiley & Sons, Ltd.     

Isolation and Structural Characterization of <Emphasis Type="Italic">Drosophila</Emphasis> TDVDHVFLRFamide and FMRFamide-Containing Neural Peptides

An extract of adult Drosophila melanogaster was separated by gel exclusion, ion exchange, and reversed-phase chromatography. Four peptides, each with an -ArgPheNH2 C-terminal sequence, were identified by radioimmunoassay. The primary sequences were determined by Edman degradation and confirmed by mass spectrometry and sequence-specific radioimmunoassay. Three of the peptides are encoded by Drosophila proFMRFamide: AspProLysGlnAspPheMetArgPheNH2 (DPKQDFMRFamide), ThrProAlaGluAspPheMetArgPheNH2 (TPAEDFMRFamide), and SerAspAsnPheMetArgPheNH2 (SDNFMRFamide). A novel Drosophila peptide ThrAspValAspHisValPheLeuArgPheNH2 (TDVDHVFLRFamide) was also isolated. TDVDHVFLRFamide is structurally related to peptides isolated from chicken, cockroach, locust, and snail; the cockroach, fruitfly, and locust peptides differ only by the N-terminal amino acid residue. Two Drosophila neural genes, dsk and FMRFamide, are known to encode -ArgPheNH2-containing peptides; however, neither encodes TDVDHVFLRFamide, indicating that Drosophila contains another precursor encoding -ArgPheNH2 peptides.     

‘Born to …’— Genetics and Behaviour

In its ascendancy, the study of human genetics is shifting from the inheritance of physical structure to that of behaviour and personality; seeking the secret machinery which joins the inherited code to the quirk of character. At the start of the century human behaviour was thought to be largely learned and to stem from upbringing, the blank slate of personality being moulded by parents and events. What had been learned could be unlearned and this accorded with the idea of free will expressed in Cassius' claim that ‘the fault, dear Brutus, is not in our stars, but in ourselves, that we are underlings’. Now, at the century's close, the influence of breeding is back in fashion, bringing the implacable effects of genetic determinism and bad blood. The implications for the successes and failings of the ‘normal’ population are far-reaching. In learning disability, many of these ideas are contained in the concept of the ‘behavioural phenotype’.     

Une phénoménologie de la dépendance à l'alcool. Une expérience primordiale de la « nostrité »

The phenomenological approach to alcoholism interestingly focuses on specific dynamics of interpersonal relationships displaying the founding of the Self from a primary “us” and its original basis in the human feast. Priorities for treatment intervention recommend to involve social setting and relationships of the patients, reaching their active participation to a motivational and long term group treatment, underlying the specific therapeutic effect of world exchanges. Biopsychosocial determination of alcoholism could be primarily based on components of interpersonal relationships. Regarding social background, drinking is one of the most famous supports for the achievement of the feast, a founding marker of present time. Taking an existential point of view, the feast appears as the heart of mankind because it presents a primary “us”, a plural state which indicates the beginning and founding of the Self from the others. During the feast, we regularly have to reach our Self from the “us” while avoiding two main dangers, drunkenness, an increase in the dizziness of upright verticality, and addiction, an opposite vertical surrender to alcohol and falling into in the alcoholic relapse, both situations imply a spatial domination and the disappearance of others. Treatment programs of alcohol addicts need to integrate the necessity of reaching the existential basic trust from the support of a group to the appropriation of the community which can be defined as an original “usness”.     

Expertises pour la sécurité sociale : méthodologie et spécificités

Mental disorders represent in France for the Social Security the second post of spending in consumption of care with 11,4 billion euro, that is 10,6% of the spending, behind the diseases of the circulatory system. They stay in the rank of the pathologies justifying the allocation of a disability pension, representing 26,7% of invalids. It is to say the importance of the psychiatric expertise for the Social Security. This type of expertises is particular among the expertises in psychiatry because the objective of the expertise is to establish an arbitrage between the position of CPAM's doctor and his regular doctor. Effectively, except legal flaw, the opinion of the expert imposes upon the parts (parties). The realization of the expertise and its editorial staff are detailed in their specificities. Problem specific of the psychiatry are approached as well as the functions (offices) of the expert which are well beyond arbitrator's role towards a function of teacher and intermediary.