Behavioural and physiological correlates of impulsivity in the domestic dog (Canis familiaris)

Impulsivity is a trait related to inhibitory control which is expressed in a range of behaviours. Impulsive individuals show a decreased ability to tolerate delay of reinforcement, and more impulsive behaviour has been linked to decreased levels of serotonin and dopamine in a number of species. In domestic dogs, impulsivity is implicated in problem behaviours that result from a lack of self control, but currently there are no published studies that assess behavioural and physiological measures of impulsivity in relation to this trait. Impulsivity scores were calculated for 41 dogs using an owner-report assessment, the Dog Impulsivity Assessment Scale (DIAS). Twenty-three of these subjects completed an operant choice task based on a delayed reward paradigm, to assess their tolerance to delay of reinforcement. High Pressure Liquid Chromatography (HPLC) with Fluorometric Detection was used to detect levels of the metabolites of serotonin (5-HIAA) and dopamine (HVA) in the urine of 17 of the subjects. Higher impulsivity scores were found to be significantly correlated with more impulsive behaviour (reduced tolerance to delay of reinforcement) in the behaviour tests and lower levels of urinary 5-HIAA and 5-HIAA/HVA ratio. The results demonstrate convergent validity between impulsivity (as assessed by the DIAS) and behavioural and physiological parameters

Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis

International audienceBACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

K.C.N.K.K. is an SSR National Scholar of Mauritius and acknowledges the Government of Mauritius for funding. J.M.G. is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences. S.C. is supported by the Euan MacDonald Centre, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the Medical Research Council (MRC), Alzheimer’s Society and Alzheimer’s Research UK. A.R.M. is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the MRC and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.Peer reviewedPublisher PD

Disease-Related Changes in the Cerebrospinal Fluid Metabolome in Amyotrophic Lateral Sclerosis Detected by GC/TOFMS

The changes in the cerebrospinal fluid (CSF) metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood and earlier smaller studies have shown conflicting results. The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.Using gas chromatography coupled to mass spectrometry (GC/TOFMS) and multivariate statistical modeling, we simultaneously studied the metabolome signature of ∼120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS) have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS) without superoxide dismutase-1 gene (SOD1) mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.Patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

Molecular Motor Proteins and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons in the brain, brainstem and spinal cord, which is characterized by motor dysfunction, muscle dystrophy and progressive paralysis. Both inherited and sporadic forms of ALS share common pathological features, however, the initial trigger of neurodegeneration remains unknown. Motor neurons are uniquely targeted by ubiquitously expressed proteins in ALS but the reason for this selectively vulnerability is unclear. However motor neurons have unique characteristics such as very long axons, large cell bodies and high energetic metabolism, therefore placing high demands on cellular transport processes. Defects in cellular trafficking are now widely reported in ALS, including dysfunction to the molecular motors dynein and kinesin. Abnormalities to dynein in particular are linked to ALS, and defects in dynein-mediated axonal transport processes have been reported as one of the earliest pathologies in transgenic SOD1 mice. Furthermore, dynein is very highly expressed in neurons and neurons are particularly sensitive to dynein dysfunction. Hence, unravelling cellular transport processes mediated by molecular motor proteins may help shed light on motor neuron loss in ALS

Defining novel functions for cerebrospinal fluid in ALS pathophysiology

Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer's disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS.</p

Tentatives de suicide chez l'enfant et l'adolescent (recherche d'indices biochimiques périphériques et de leurs relations avec les facteurs cliniques)

Cette thèse rend compte des résultats d'une étude en situation réelle portant sur des enfants et adolescents ayant effectués une tentative de suicide et admis à l'hôpital pédiatrique R. Debré. Nous sommes partis de l'hypothèse que des anomalies biologiques similaires à celles décrites chez des adultes ayant effectué une tentative de suicide pouvaient être mise en évidence chez les enfants et adolescents suicidaires. Dans un premier temps, les caractéristiques psychopathologiques et cliniques de ces jeunes suicidaires ont été déterminés par un pédipsychiatre. Dans un second temps, une baisse des paramètres sérotoninergiques, une baisse des taux de cholestétol sanguins et des taux bas d'œstrogènes circulant chez les filles pubères, ont été recherchés chez les jeunes suicidaires comparés à des témoins appariés de façon optimale. Au niveau de la clinique, on retrouve très fréquemment chez les mêmes sujets la coexistence d'une symptomatologie dépressive, souvent majeure, et des traits de tempéraments impulsifs. Au niveau de la biologie, il semblerait se distinguer deux sous groupes biologiquement différents parmi les suicidaires, se caractérisant par un degré d'impulsivité différent. La comparaison des différents paramètres sérotoninergiques entre les jeunes suicidaires et leurs témoins appariés ne montre pas globalement de différence significative, excepté pour le tryptophane plasmatique. Chez les impulsifs, la dépression est associée à un taux d'œstradiol bas et réciproquement chez les noms impulsifs, la dépressions est associée à un taux d'œstradiol plus élevé. Cependant, notre échantillon un peu faible (30 sujets contre 50 initialement prévus) incite à poursuivre le recrutement, pour pouvoir exploiter au mieux les résultats biologiques obtenus sur in plan statistique.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Suicide : autopsie psychologique, outil de recherche en prévention

Le suicide constitue un problème majeur de santé publique. Il traduit uncomportement autodestructeur qui est l’aboutissement d’une situation decrise, souvent insuffisamment perçue par l’entourage et le corps médical. Ilconcerne toutes les catégories d’âge et les deux sexes. Les tentatives desuicide sont quant à elles au moins 10 fois plus fréquentes que les suicidesaboutis et sont des gestes souvent réitérés.Selon les estimations de l’Organisation Mondiale de la Santé, environ unmillion de personnes meurent par suicide chaque année dans le monde et lephénomène ne cesse globalement d’augmenter. Ce fléau touche tous les pays,à des degrés divers. Les taux de suicide varient pour le sexe masculin de0,5/100 000 à la Jamaïque à 75,6 en Lituanie et pour le sexe féminin de 0,2 àla Jamaïque à 16,8 au Sri Lanka.3En France, on estime à près de 11 000 le nombre de suicides par an. Ilreprésente environ 2 % des décès annuels et se situe dans une moyenne hautepar rapport aux autres pays européens. C’est la deuxième cause de mortalitéchez les 15-44 ans après les accidents de la circulation et la première chez les30-39 ans. Bien que la part du suicide diminue ensuite sensiblement avecl’âge, le nombre de décès par suicide est quant à lui fortement accru ; les tauxde suicides aboutis sont six fois plus élevés dans la population âgée de plus de85 ans par comparaison aux 15-24 ans. En 1999, dernière année pour laquellela prévalence est connue, les taux en population générale étaient de26,1/100 000 pour les hommes et 9,4 pour les femmes. Par ailleurs, il existede fortes disparités géographiques, avec une accentuation de la prévalence dusuicide dans les régions situées au nord-ouest de l’hexagone.C’est à partir des données de mortalité que l’on peut évaluer la situation d’unpays par rapport aux autres pays de la communauté internationale en matièrede suicide ou mettre en évidence le poids du suicide dans les causes de décèsdans certaines catégories de la population, par exemple les adolescents. A cetitre, l’élaboration des données statistiques concernant la population décédéepar suicide nécessite la prise en considération des causes médicales du décèstelles qu’elles sont reportées sur les certificats de décès. L’éventualité del’absence de mention explicite de suicide peut résulter en une sousestimationde la prévalence des décès par suicide. Des enquêtes ponctuellesauprès d’instituts médico-légaux et par le CépiDC de l’Inserm ont évalué à20 % la « sous-déclaration » de suicides en France pour l’année 1998.(...