Multimodal brain predictors of current weight and weight gain in children enrolled in the ABCD study ®

Multimodal neuroimaging assessments were utilized to identify generalizable brain correlates of current body mass index (BMI) and predictors of pathological weight gain (i.e., beyond normative development) one year later. Multimodal data from children enrolled in the Adolescent Brain Cognitive Development Study® at 9-to-10-years-old, consisted of structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), resting state (rs), and three task-based functional (f) MRI scans assessing reward processing, inhibitory control, and working memory. Cross-validated elastic-net regression revealed widespread structural associations with BMI (e.g., cortical thickness, surface area, subcortical volume, and DTI), which explained 35% of the variance in the training set and generalized well to the test set (R² = 0.27). Widespread rsfMRI inter- and intra-network correlations were related to BMI (R²_train = 0.21; R²_test = 0.14), as were regional activations on the working memory task (R²_train = 0.20; (R² _test = 0.16). However, reward and inhibitory control tasks were unrelated to BMI. Further, pathological weight gain was predicted by structural features (Area Under the Curve (AUC)_train = 0.83; AUC_test = 0.83, p < 0.001), but not by fMRI nor rsfMRI. These results establish generalizable brain correlates of current weight and future pathological weight gain. These results also suggest that sMRI may have particular value for identifying children at risk for pathological weight gain.     

Assessment of psychological predictors of weight loss: How and what for?

Obesity is a multifactorial disease and the prominent factors playing a role in its pathogenesis are biological, environmental and psychological. There is a growing interest in understanding psychological functioning of obese subjects and the influence of psychological factors on treatment outcome. The aim of the present narrative review is to critically analyze the current literature, in order to point out the most common psychological constructs studied in obesity and to give an overview of the main existing tools investigating psychological features which have been considered significant for the prediction of success in weight loss and maintenance programs in obese patients. In this framework, the most common psychological constructs studied are: self-motivation, self-efficacy, locus of control, health related quality of life, self-esteem, self-control, concerns about body image, outcome expectations, and personality traits. These features have been explored through a wide variety of psychometric instruments. However, as an overall, studies evaluating the association between psychological features and treatment outcome failed to give consistent results. A possible explanation may consist on the fact that many tools widely used to explore psychological features were not specifically designed for obese patients and none of them was comprehensive of all possible psychological features involved. The identification of well-defined sub-groups of patients and the validation of more reliable and comprehensive tools, specifically designed for obese subjects, should be forecasted in order to reach a better knowledge of psychological functioning of obese individuals and to improve the outcome of weight loss programs.     

Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)β(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)β(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)β(2)- and α(7)-selective agonists. Localization of α(4)β(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)β(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)β(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)β(2)- and α(7)-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)β(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)β(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)β(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)β(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.     

The causes of the syndromes of Landry (1859) and of Guillain, Barré and Strohl (1916)

Post-infectious and post-vaccinal peripheral neuritis or encephalomyelitis have frequently been considered the human equivalents of experimental allergic neuritis (EAN) or encephalomyelitis (EAE). The major basis for these comparisons between diseases in humans and experimental animals rests on the classical observations of "paralytic accidents" of Pasteur-type vaccination against rabies. These old observations in humans injected with brain tissue indicate a remarkable heterogeneity of periphéral as well as central nervous system syndromes, quite in contrast with the remarkable specificity for either peripheral or central involvement in most experimental animals. The syndromes of Landry (1859) and of Guillain, Barré and Strohl (1916) differ clinically and pathologically, the latter a purely peripheral neuritis and the former a mixture of transverse myelitis and facial neuritis. Each can be caused by many different factors, including 1) direct infection by wild or attenuated rabies virus, 2) direct auto-sensitization by myelin antigens in the vaccine and 3) indirect or cross-reactive sensitization by viral or bacterial antigenic determinants (epitopes) with sufficient chemical homology with aminoacid sequences in central or peripheral myelin antigens to be recognized as immunological homologies.     

Olanzapine-induced weight gain in anorexia nervosa: Involvement of leptin and ghrelin secretion?

BACKGROUND: Olanzapine (OLA) administration has been reported to induce weight gain in experimental animals and humans, through not yet fully defined mechanisms of action. Aim of this study was to determine whether in patients with Anorexia Nervosa (AN) OLA induces weight gain through the modulation of the hunger-satiety regulatory peptides leptin and ghrelin. METHODS: Twenty anorexic probands received a 3 months course of cognitive-behavioral psychotherapy and programmed nutritional rehabilitation, combined with OLA PO (2.5 mg for 1 month and 5 mg for 2 months) in ten patients and with placebo PO (PL) in the other 10. Weight, measured as body mass index (BMI), leptin and ghrelin plasma values were monitored before starting the therapy and then monthly for 3 months. Plasma leptin was measured by ELISA, and plasma ghrelin by radioimmunoassay. RESULTS: BMI increased significantly but not differently in both treatment groups. Leptin and ghrelin secretion did not change during the course of the treatments. No correlations were observed between BMI values and leptin and ghrelin levels. CONCLUSIONS: Our data suggest that the weight gain observed in our OLA-treated patients was not linked to drug administration. Moreover, leptin and ghrelin secretions were not responsible for BMI changes.     

Persistent depressive symptomatology and inflammation: To what extent do health behaviours and weight control mediate this relationship?

We examined if persistent depressive symptoms are associated with markers of inflammation (C-Reactive Protein-CRP) and coagulation (fibrinogen), and if this association can be partly explained by weight control and behavioural risk factors (smoking, alcohol, physical activity). The study sample included 3609 men and women (aged 60.5 ± 9.2 years) from The English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Depressive symptoms (using the 8-item CES-D scale), health behaviours (smoking, alcohol, physical activity), body weight, and central adiposity were assessed at baseline and 2 years follow up. CRP and fibrinogen were assessed at follow up. At baseline 12.7% of the sample reported elevated depressive symptomatology, which persisted in 6.1% of participants at follow up. Baseline CES-D score was associated with CRP (β = .035, SE = .0066) and fibrinogen (β = .023, SE = .0060) measured 2 years later. Using simple mediation analysis we observed both a direct association of depressive symptoms on CRP (β = .013, SE = .0066) and indirect mediating effects through behavioural risk factors (β for total indirect effect β = .022, SE = .0023). For fibrinogen there were no direct effects of depression, and the association was entirely explained through indirect mediating effects of health behaviours. The presence of recurrent elevated depressive symptomatology at both time points was more strongly associated with CRP and fibrinogen. In summary, the association between depressive symptoms and low grade inflammation can be partly explained by behavioural risk factors. The presence of persistent depression appears to be associated with the greatest risk of elevated inflammation.     

Isolation and characterization of twenty polymorphic microsatellite markers for the endangered Dupont′s lark (Chersophilus duponti) and cross-amplification in crested lark (Galerida cristata) and thekla lark (Galerida theklae)

We developed twenty microsatellite markers for the Dupont′s lark (Chersophilus duponti), one of the most endangered European bird species, and tested in two related, more widely distributed species: crested lark (Galerida cristata) and thekla lark (Galerida theklae). 14 markers amplified and were polymorphic in Dupont′s lark, 11 in crested lark and 6 in thekla lark. Microsatellite variability analyses were carried out on Dupont′s lark (N = 23–28 individuals), crested lark (N = 9–10) and thekla lark (N = 14) populations in NE Spain showing moderate/high diversity, ranging from 1 to 13 alleles per locus. The mean allelic richness in Dupont’s lark was 6.21 and expected and observed heterozygosities ranged from 0.195 to 0.848 and from 0.071 to 0.889, respectively. Crested and thekla larks showed moderate/high diversity with a mean allelic richness of 4.36 and 4.67, respectively. This microsatellite set could be useful for population genetic studies of lark species widely differing in population fragmentation and conservation status across the Old World.     

Intestinal inflammation influences α-MSH reactive autoantibodies: relevance to food intake and body weight

Autoantibodies reacting with alpha-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, are involved in regulation of feeding. In this work we studied if intestinal inflammation (mucositis) may influence α-MSH autoantibodies production relevant to food intake and body weight. Mucositis and anorexia were produced in Sprague-Dawley rats by methotrexate (MTX, 2.5mg/kg/day, for three days, subcutaneously). Plasma levels of total IgG and of α-MSH autoantibodies were measured during and after MTX-induced mucositis and were compared with pair-fed and ad libitum-fed controls. Effects of intraperitoneal injections of rabbit anti-α-MSH IgG (3 or 10 μg/day/rat) on MTX-induced anorexia and on plasma α-MSH peptide concentration were separately studied. Here we show that in MTX rats, intestinal mucositis and anorexia were accompanied by decreased plasma levels of both total IgG and of α-MSH autoantibodies while refeeding was characterized by their elevated levels. In spite of similar food intake in MTX and pair-fed rats, recovery of body weight was delayed by at least 1 week in the MTX group. During refeeding and body weight deficit in MTX rats, α-MSH IgG autoantibody levels correlated negatively with food to water intake ratios. Injections of anti-α-MSH IgG induced a dose-dependent attenuation of food intake and body weight regain in MTX-treated rats accompanied by increased concentrations of α-MSH peptide which correlated positively with plasma levels of α-MSH autoantibodies. These data show that intestinal inflammation, independently from food restriction, affects general humoral immune response which may influence food intake and body weight control via modulation of α-MSH plasma concentration by α-MSH reactive autoantibodies.     

Is the CCK2 receptor essential for normal regulation of body weight and adiposity?

Cholecystokinin (CCK) is a gastrointestinal satiety signal released from the duodenum to terminate feeding, via CCK1 receptors. CCK2 receptors are considered to be involved in anxiety. CCK2 receptor knockout mice have increased body weight and food intake. Little is known regarding the effects of CCK2 receptor deficiency on adipose distribution and hypothalamic feeding regulators such as neuropeptide Y (NPY), a powerful stimulator of feeding. Adult (10 week) CCK2 receptor knockout and wild-type mice were anaesthetized and killed by decapitation. Brain sections, organs and fat tissue were dissected. Plasma leptin, insulin and brain NPY content were measured by radioimmunoassay. Female CCK2 receptor knockout mice weighed more than control mice (22.0 +/- 0.2 vs. 19.9 +/- 0.4 g, P < 0.05), with this difference being less marked in male mice (26.4 +/- 0.4 vs. 25.6 +/- 0.6 g). Fat masses in all locations sampled were significantly smaller in CCK2 receptor knockout mice of both genders (P < 0.05), resulting in lower plasma leptin and insulin levels. NPY concentrations were significantly increased in arcuate nucleus and anterior hypothalamus in both male and female CCK2 receptor knockout mice, and total hypothalamic NPY content was increased by 7 and 9% in males and females, respectively (P < 0.05). CCK2 receptor deletion was associated with increased body weight and hypothalamic NPY content, but reduced fat masses and plasma leptin and insulin. Increased NPY might contribute to increased food intake in CCK2 receptor knockout mice. Further work needs to focus on the metabolic changes.     

Studies of HLA associations in male and female patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

HLA associations are found to differ with the gender of the patient in some autoimmune diseases. Here we have investigated whether there are gender-related HLA associations in Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), both of which occur more frequently in male patients than in females. In GBS, no particular HLA associations were noted, except for a slight negative association in both males and females for carriage of HLA-DR5. In CIDP, the gene frequency and the frequency of individuals positive for HLA-DR2 were greater in female patients than female controls, although this was statistically significant only for the gene frequency. Furthermore more female CIDP patients were homozygous for DR2, than male CIDP patients, or male or female controls and patients with GBS. This suggests that sex-related factors may interact with the risk associated with carriage of HLA-DR2 for development of CIDP.     

Newer antipsychotic drugs and obesity in children and adolescents. How should we assess drug‐associated weight gain?

OBJECTIVE: Antipsychotic drugs may contribute to weight gain in children and adolescents. METHOD: We used Medline's PubMed in the pediatric age using key words 'weight gain' and 'obesity', for each newer antipsychotic drug. RESULTS: We found 21 articles linking weight gain and obesity with newer antipsychotic drugs among youths. Risperidone was the most commonly cited agent. Weight gain from olanzapine was the largest among the more commonly prescribed newer agents. All studies reported absolute weight gain. Only a few studies used the better measure of body mass index (BMI). None incorporated growth charts to allow for changes in weight and height over time because of growth. CONCLUSION: Weight gain may be a major problem when prescribing newer antipsychotic drugs in the pediatric population. Risperidone is associated with less weight gain than olanzapine. Published reports and studies have not utilized state-of-the-art techniques using BMI with readily available growth charts.     

Are freezing of gait (FOG) and panic related?

We studied 109 consecutive patients who were unselected for freezing of gait (FOG), anxiety, depression, or panic attacks. All patients completed a panic assessment, the Hamilton Anxiety Scale and the Hamilton Depression Scale. Patients were divided into those with FOG or no FOG based on their answer to the FOG question on the Activities of Daily Living part of the UPDRS. Patients with FOG were more disabled, had more "wearing off", dyskinesia, leg dystonia, and postural instability. They were also more anxious and more likely to panic. FOG, in many patients, is increased by anxiety and panic.     

Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients

RAGE (receptor for advanced glycation end-products) participates in the influx transport of glycated Aβ (amyloid beta) from the blood to the brain. Because little is known of the RAGE operating in brain barriers such as those in the choroid plexus and ependyma, the aim of the present study was to examine the immunodistributions of RAGE and Aβ peptides in the choroid plexus where the blood-cerebrospinal fluid barrier (B-CSF) is located, and in ependyma of the brain ventricles associated with functions of the cerebrospinal fluid-brain barrier (CSF-B). The study was performed on patients over 65 years successfully resuscitated after cardiac arrest with survival a few weeks. The control group consisted of age-matched individuals who were not resuscitated and died immediately after cardiac arrest. In resuscitated patients, but not in controls, RAGE receptors were localized in choroid plexus (CP) epithelial cells and in ependymal cells bordering the brain ventricles. These cells form the B-CSF and CSF-B barriers. The presence of Aβ was detected within the CP blood vessels and in the basement membrane of the CP epithelium. In numerous cytoplasmic vacuoles of CP epithelial and ependymal cells Aβ protein was found and our observations suggest that the contents of those vacuoles were undergoing progressive digestion. The results demonstrated that CP epithelium and ependymal cells, equipped with RAGE receptors, not only play an important role in the creation of amyloid deposits in the brain but are also places where Aβ may be utilized. The RAGE transportation system should be a main target in the therapy of brain amyloidosis, a well-known risk factor of Alzheimer disease.     

Selective naming (and comprehension) deficits in Alzheimer's disease?

The study addresses the issue of the selective preservation of verbs in Alzheimer's disease (AD). Twenty three AD patients and age-matched controls named pictures of objects and actions and took part in a word-picture verification task. The results for picture naming revealed that both patients and controls were faster and produced more target responses for objects than actions. In the comprehension task, accuracy levels were comparable for nouns and verbs, but response times were longer for verbs. Although patients were more error prone and had longer latencies in both tasks than controls, the only qualitative difference in performance between the groups was in response to trials with semantically related foils in the word-picture verification task. Patients were particularly error prone in this condition. We conclude that the results do not provide support for the notion that verbs are selectively preserved in AD. They also do not provide conclusive evidence for claims that depressed naming and comprehension is (always) due to loss of semantic knowledge or inadequate access to semantic knowledge. Finally, we discuss the findings in relation to comparable investigations in patients with semantic dementia.     

Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other?

BACKGROUND: Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME. SUMMARY POINTS: We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.