Gendered Pathways of Internalizing Problems from Early Childhood to Adolescence and Associated Adolescent Outcomes.

Despite trends indicating worsening internalizing problems, characterized by anxiety and depression, there is dearth of research examining gender differences in developmental trajectories of internalizing problems from early childhood to adolescence. Drawing on the UK Millennium Cohort Study (n = 17,206, 49% female), this study examines trajectories of parent-reported, clinically-meaningful (reflecting the top 10%) internalizing problems from ages 3 to 14 years and their early predictors and adolescent outcomes. Group-based modelling revealed three trajectories when examining boys and girls together, but there were significant gender differences. When examining boys and girls separately, four trajectories were identified including two relatively stable trajectories showing either high or low probabilities of internalizing problems. An increasing trajectory was also found for both boys and girls, showing an increasing probability of internalizing problems which continued to rise for girls, but levelled off for boys from age 11. A decreasing trajectory was revealed for boys, while a moderate but stable trajectory was identified for girls. Boys and girls in the increasing and high probability groups were more likely to report a number of problematic outcomes including high BMI, self-harm, low mental wellbeing, depressive symptoms, and low educational motivation than the low group. Girls on the increasing trajectory also reported more cigarette and cannabis use and early sexual activity at age 14 compared to girls on the low trajectory. Findings suggest that intervention strategies take a systemic view, targeting not only internal feelings, but also behaviours potentially associated with later negative outcomes.

Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood.

Psychotic-like experiences (PLEs) are part of a continuum of psychosis. Previous longitudinal studies highlighted a relationship between peripheral inflammation during childhood and onset of PLEs in adulthood. In this study, we tested if this association is mediated by internalising and externalising symptoms experienced during childhood and adolescence. To test this hypothesis, we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We investigated a subsample of 4525 individuals from this cohort with data on interleukin 6 (IL-6) and C-reactive protein (CRP) in childhood (age 9 years). We measured PLEs at age 18 years, and we used latent growth curve modelling to estimate longitudinal trajectories of internalising and externalising symptoms from ages 9 to 16 years. The individual predicted values of the intercept (set at baseline, 9 years) and the slope (rate of annual change) were then used in the mediation analysis. There was evidence for full mediation by the intercept of internalising symptoms. Our findings suggest that inflammation during childhood may be relevant for the future onset of PLEs via its association with a high level of internalising symptoms. These findings, although obtained from a non-clinical population, provide an additional step in advancing knowledge on the relationship between inflammation and symptoms of the psychosis continuum.

Alemtuzumab significantly improves posterior fossa syndrome presented as a relapse of multiple sclerosis.

BACKGROUND: Posterior fossa syndrome (PFS) is a rare manifestation of ponto-mesencephalic lesions frequently reported in post-surgical pediatric tumors, rarely described as a consequence of vascular, infective or inflammatory lesions. OBJECTIVE: The aim of this article is to report the clinical and neuroradiological characteristics of a patient with an acute PFS presentation as a relapse in relapsing-remitting MS, significantly responsive to Alemtuzumab treatment. CASE REPORT: 24-year-old patient affected by multiple sclerosis developed motor-cognitive and behavioral syndrome related to an extensive ponto-mesencephalic lesion under Fingolimod treatment. CONCLUSION: Our case highlights the significant and rapid effect of Alemtuzumab therapy on both cognitive and motor symptoms occurring during a MS relapse with atypical neuroradiological localization.

Prenatal exposure to tobacco and marijuana and child autonomic regulation and reactivity: An analysis of indirect pathways via maternal psychopathology and parenting.

We examined a conceptual model for the associations of prenatal exposure to tobacco (PTE) and marijuana with child reactivity/regulation at 16 months of age. We hypothesized that PTE would be associated with autonomic reactivity and regulation that these associations would be indirect via maternal anger/hostility, depression/stress, or harsh parenting assessed at 2 months and that these effects would be most pronounced among children exposed to both tobacco and marijuana (PTME). Participants were 247 dyads (81 PTE, 97 PTME, and 69 nonexposed) who were followed up at 2 (N = 247) and 16 months (N = 238) of child age. Results from model testing indicated an indirect association between PTME and autonomic functioning during the second year of life, which was mediated by harsh parenting during caregiver-infant interactions. This study fills an important gap in the literature on PTE, PTME, and autonomic regulation during the toddler years, highlighting the role of maternal parenting as important intervening variables.

Atypical resting state neuromagnetic connectivity and spectral power in very preterm children.

BACKGROUND: Children born very preterm often display selective cognitive difficulties at school age even in the absence of major brain injury. Alterations in neurophysiological activity underpinning such difficulties, as well as their relation to specific aspects of adverse neonatal experience, remain poorly understood. In the present study, we examined interregional connectivity and spectral power in very preterm children at school age, and their relationship with clinical neonatal variables and long-term outcomes (IQ, executive functions, externalizing/internalizing behavior, visual-motor integration). METHODS: We collected resting state magnetoencephalographic (MEG) and psychometric data from a cohort at the age of 8 years followed prospectively since birth, which included three groups: Extremely Low Gestational Age (ELGA, 24-28 weeks GA n = 24, age 7.7 ± 0.38, 10 girls), Very Low Gestational Age (VLGA, 29-32 weeks GA n = 37, age 7.7 ± 0.39, 24 girls), and full-term children (38-41 weeks GA n = 39, age 7.9 ± 1.02, 24 girls). Interregional phase synchrony and spectral power were tested for group differences, and associations with neonatal and outcome variables were examined using mean-centered and behavioral Partial Least Squares (PLS) analyses, respectively. RESULTS: We found greater connectivity in the theta band in the ELGA group compared to VLGA and full-term groups, primarily involving frontal connections. Spectral power analysis demonstrated overall lower power in the ELGA and VLGA compared to full-term group. PLS indicated strong associations between neurophysiological connectivity at school age, adverse neonatal experience and cognitive performance, and behavior. Resting spectral power was associated only with behavioral scores. CONCLUSIONS: Our findings indicate significant atypicalities of neuromagnetic brain activity and connectivity in very preterm children at school age, with alterations in connectivity mainly observed only in the ELGA group. We demonstrate a significant relationship between connectivity, adverse neonatal experience, and long-term outcome, indicating that the disruption of developing neurophysiological networks may mediate relationships between neonatal events and cognitive and behavioral difficulties at school age.

Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter.

OBJECTIVE: Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. METHOD: Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9-11, mothers completed a questionnaire assessing psychological symptoms. RESULTS: Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. CONCLUSION: These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.

Multidimensional assessment of impulsivity-related measures in relation to externalizing behaviors.

BACKGROUND: Trait impulsivity is thought to play a key role in predicting behaviors on the externalizing spectrum, such as drug and alcohol use and aggression. Research suggests that impulsivity may not be a unitary construct, but rather multidimensional in nature with dimensions varying across self-report assessments and laboratory behavioral tasks. Few studies with large samples have included a range of impulsivity-related measures and assessed several externalizing behaviors to clarify the predictive validity of these assessments on important life outcomes. METHODS: Community adults (N = 1295) between the ages of 30 and 54 completed a multidimensional assessment of impulsivity-related traits (including 54 self-report scales of personality traits implicated in impulsive behaviors, and four behavioral tasks purporting to assess a construct similar to impulsivity) and reported on five externalizing behavioral outcomes (i.e. drug, alcohol, and cigarette use, and physical and verbal aggression). We ran an exploratory factor analysis on the trait scales, and then a structural equation model predicting the externalizing behaviors from the three higher-order personality factors (i.e. Disinhibition v. Constraint/Conscientiousness, Neuroticism/Negative Emotionality, and Extraversion/Positive Emotionality) and the four behavioral tasks. RESULTS: Relations between the self-report factors and behavioral tasks were small or nonexistent. Associations between the self-report factors and the externalizing outcomes were generally medium to large, but relationships between the behavioral tasks and externalizing outcomes were either nonexistent or small. CONCLUSIONS: These results partially replicate and extend recent meta-analytic findings reported by Sharma et al. (2014) to further clarify the predictive validity of impulsivity-related trait scales and laboratory behavioral tasks on externalizing behaviors.

Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder. METHOD: A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018. RESULTS: There were 706 cases of anti-NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period. CONCLUSION: The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification.

Is It Feasible to Identify Natural Clusters of TSC-Associated Neuropsychiatric Disorders (TAND)?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with multisystem involvement. The lifetime prevalence of TSC-Associated Neuropsychiatric Disorders (TAND) is in the region of 90% in an apparently unique, individual pattern. This "uniqueness" poses significant challenges for diagnosis, psycho-education, and intervention planning. To date, no studies have explored whether there may be natural clusters of TAND. The purpose of this feasibility study was (1) to investigate the practicability of identifying natural TAND clusters, and (2) to identify appropriate multivariate data analysis techniques for larger-scale studies. METHODS: TAND Checklist data were collected from 56 individuals with a clinical diagnosis of TSC (n = 20 from South Africa; n = 36 from Australia). Using R, the open-source statistical platform, mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. RESULTS: Ward's method rendered six TAND clusters with good face validity and significant convergence with a six-factor exploratory factor analysis solution. The "bottom-up" data-driven strategies identified a "scholastic" cluster of TAND manifestations, an "autism spectrum disorder-like" cluster, a "dysregulated behavior" cluster, a "neuropsychological" cluster, a "hyperactive/impulsive" cluster, and a "mixed/mood" cluster. CONCLUSIONS: These feasibility results suggest that a combination of cluster analysis and exploratory factor analysis methods may be able to identify clinically meaningful natural TAND clusters. Findings require replication and expansion in larger dataset, and could include quantification of cluster or factor scores at an individual level.

[A personalized approach to the pulmonary rehabilitation of patients with chronic obstructive pulmonary disease]. / Personalizirovannyi podkhod k legochnoi reabilitatsii bol'nykh khronicheskoi obstruktivnoi bolezn'yu legkikh.

AIM: To elaborate and introduce personalized pulmonary rehabilitation (PR) programs adapted in terms of the types of disease response in patients with chronic obstructive pulmonary disease (COPD) and to evaluate the effectiveness of the programs. SUBJECTS AND METHODS: A total of 85 patients with COPD of more than 2 years' duration (the shortest time frame that was valid to assess the type of disease response) were examined. All the patients underwent adequate physical, instrumental, laboratory, and psychiatric examinations, during which the type of COPD response was determined. Before a rehabilitation cycle, after its termination, and 1, 3, and 6 months later, each patient underwent evaluation of the symptoms of COPD, the frequency of its exacerbations, the level of basic knowledge about COPD according to the author's questionnaire, assessment of the quality of life and the symptoms of anxiety and depression, and functional tests. RESULTS: The final sample included 30 patients who met the inclusion criteria and agreed to voluntarily participate in the PR programs. According to the type of a response to the underlying disease, the patients were divided into 2 polar groups: A) those who were anxious about their illness (excessive apprehension, fears that were associated with the perception of lung disease and that led to distress) and depression (despondency, an agonizing understanding of a possible poor outcome and consequences of the impact of COPD on their lives) and B) those who had a newly diagnosed type of COPD response - hyponosognosia (underestimation of disease severity, perception of the symptoms of COPD as age-related changes, and preservation of the old way of life to the detriment of their health). Effective personalized PR programs were elaborated and applied to both groups. CONCLUSION: Group measures focused on learning how to cope with the disease and its symptoms and on the ability to distinguish its manifestations from the signs of psychological distress and to combat them are effective in patients who are anxious about the disease and depressed (Group A). Individual inpatient activities aimed at the formation and maintenance of motivation, the formation of an image of the disease and its manifestations, and early specialized care for smoking cessation are indicated for patients with hyponosognosia (Group B).

Patient-reported Outcomes in a French Nationwide Survey of Inflammatory Bowel Disease Patients.

BACKGROUND: Patient reported-outcomes [PROs] are a major therapeutic goal in inflammatory bowel disease [IBD]. METHODS: Between January and June 2014, patients affiliated with the French national IBD association filled out six self-questionnaires: quality of life 9QoL, according to the Short Inflammatory Bowel Disease Questionnaire [SIBDQ] and the Short-Form-36 Questionnaire [SF-36] v2); fatigue (the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]); work productivity (the Work Productivity and Activity Impairment [WPAI] questionnaire); disability [the I nflammatory Bowel Disease Disability Index]; and anxiety/depression (the Hospital Anxiety and Depression scale [HADS]). Associated factors were identified by univariate and multivariate logistic regression analyses. RESULTS: Datasets were obtained from 1185 IBD patients. Around half of patients reported poor QoL [SIBDQ <45: 53.3%], severe fatigue [FACIT-F <30: 47.4%] and/or depression [HAD-D >7: 49.4%]. One-third of the patients reported anxiety [HAD-A >7: 30.3%] and/or moderate [22.4%] or severe [11.9%] disability. About half of them reported presenteeism and moderate-to-severe loss of work productivity and loss of activity. Poor QoL, severe fatigue, severe disease-related disability, and/or high WPAI were all associated with female gender, unemployment, and disease activity. Poor QoL, severe fatigue, and high WPAI were also associated with the use of tumour necrosis factor antagonists. A history of surgery was associated with poor QoL, whereas age was associated with severe fatigue. Severe depression was associated with female gender and disease activity. CONCLUSIONS: The disease burden is very high in IBD, with poor QoL, fatigue, work impairment, and depression in half of patients. Marked disability and anxiety were reported by one-third of patients.

Developmental effects of fractionated low-dose exposure to gamma radiation on behaviour and susceptibility of the cholinergic system in mice.

PURPOSE: To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. MATERIALS AND METHODS: Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 µg/kg b.w.) twice daily on postnatal day (PND) 10, 10-11, 10-12 or 10-13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. RESULTS: Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. CONCLUSIONS: The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.

[The role of the nucleus accumbens in psychiatric disorders].

The nucleus accumbens is the most inferior part of the striatum and is mainly connected to the limbic system. It is neurochemically and immunohistochemically divided into a shell laterally and a core medially. As a functionally central structure between amygdala, basal ganglia, mesolimbic dopaminergic regions, mediodorsal thalamus and prefrontal cortex, the nucleus accumbens appears to play a modulative role in the flow of the information from the amygdaloid complex to these regions. Dopamine is a major neurotransmitter of the nucleus accumbens and this nucleus has a modulative function to the amygdala-basal ganglia-prefrontal cortex circuit. Together with the prefrontal cortex and amygdala, nucleus accumbens consists a part of the cerebral circuit which regulates functions associated with effort. It is anatomically located in a unique way to serve emotional and behavioral components of feelings. It is considered as a neural interface between motivation and action, having a key-role in food intake, sexual behavior, reward-motivated behavior, stress-related behavior and substance-dependence. It is involved in several cognitive, emotional and psychomotor functions, altered in some psychopathology. Moreover it is involved in some of the commonest and most severe psychiatric disorders, such as depression, schizophrenia, obsessive-compulsive disorder and other anxiety disorders, as well as in addiction, including drugs abuse, alcoholism and smoking. Nucleus accumbens has also a role in other psychiatric disorders such as bipolar disorder, attention deficit/ hyperactivity disorder and post-traumatic stress disorder. Because of its rich dopaminergic projections, this nucleus has been subject of many studies in animals as well as in humans, connecting its malfunction with the disturbed reward process observed in depression. Neuromodulation interventions targeting the nucleus accumbens are nowadays applied in strictly selected patients suffering from treatment-resistant depression, obsessive-compulsive disorder, Tourette syndrome and addiction to drugs or alcohol. Specifically, bilateral and unilateral (right) deep brain stimulation of the nucleus accumbens has been applied in obsessive-compulsive patients resulting into significant improvement of their symptoms and their quality of life. Nucleus accumbens deep brain stimulation has been also associated with antidepressant and anxiolytic effect, as well as quality of life improvement in patients suffering from severe resistant depression. Finally, this minimally invasive stereotactic procedure has been proved beneficial for all phenotypic components of the Tourette syndrome, with remarkable reduction of the syndrome's motor manifestations, including tics.

Wrist Actigraphy: A Simple Way to Record Motor Activity in Elderly Patients with Dementia and Apathy or Aberrant Motor Behavior.

INTRODUCTION: In dementia, behavioral psychological symptoms are frequent and variable. OBJECTIVE: To assess the value of wrist actigraphy as a measure of disorder in motor behavior especially apathy, aberrant motor behavior, agitation and anxiety. METHODS: Cross sectional observational study of consecutive patients older than 75 years admitted to an intermediate care unit of a geriatric hospital ward during a two-year period. Psycho behavioral symptoms and cognitive status were assessed using the NPI scale and MMSE and diagnosis of dementia was done using DSMIV criteria. A wrist actigraph was worn for 10 days to record motor activity, sleep time and number of periods of sleep. RESULTS: 183 patients were included. Among patients with dementia, a significant decrease in motor activity was recorded in those with apathy from 9h to 12h and 18h to 21h (p <0.05) and in those with anxiety from 21h to 24h (p <0.05). Aberrant motor behavior in dementia was associated with a significant increase in motor activity from 21h to 24h (p <0.01). Agitation was not associated with a significant differences in motor activity. CONCLUSIONS: Wrist actigraphy can be used to record motor activity in elderly patients with dementia especially in those with apathy and aberrant motor behavior.

The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.

Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

Prolonged hyperoxia preconditioning attenuates behavioral symptoms of 6-hydroxydopamine-induced Parkinsonism.

OBJECTIVES: Several lines of evidences show that hyperoxia preconditioning provides neuronal protection against central nervous system ischemic damages. Common pathways including mitochondrial dysfunction, apoptosis, and caspase activation are involved in acute neurodegeneration (e.g. after cerebral ischemia) and chronic neurodegeneration (e.g. neuronal death in Parkinson's disease). The aim of the present research was to study the effect of hyperoxia preconditioning on 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. METHODS: Male Wistar rats were first subjected to either air with high oxygen concentration (>90%) or atmospheric air for prolonged (24 hours) or intermittent (six consecutive days, 4 hours each day) periods and then 6-OHDA was injected into their left striatums by stereotaxic surgery. Development and severity of the 6-OHDA-induced Parkinsonism was assessed using apomorphine-induced rotational test, elevated body swing test, and rotarod test within 2-5 weeks after the surgery. RESULTS: Significant data obtained in rats treated with prolonged hyperoxia, but not the intermittent hyperoxia. In these rats, the number of apomorphine-induced rotations was ∼60% lower than that in control and sham groups. Rats belonging to the prolonged hyperoxia group also showed considerably better motor performance and learning pattern in rotarod test. These results were confirmed by the data obtained in the elevated body swing test. DISCUSSION: Our findings show that the prolonged hyperoxia preconditioning attenuates the behavioral symptoms of 6-OHDA-induced Parkinsonism. Considering the well-known correlation between dopaminergic neuronal death in the substantia nigra and the behavioral symptoms of 6-OHDA-induced Parkinsonism, it could be speculated that the prolonged hyperoxia preconditioning induces the mechanisms that provide dopaminergic neuroprotection against Parkinsonism-induced toxins.

Observations on intelligence and behavior in 15 patients with Legius syndrome.

Legius syndrome is a RAS-MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full-scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1.

Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review.

Costello syndrome is a rare rasopathy resulting from germline mutations of the proto-oncogene HRAS. Its phenotype includes severe failure-to-thrive, cardiac abnormalities, a predisposition to benign and malignant tumors, hypotonia, and developmental delay. Costello syndrome is associated with cognitive impairment, including intellectual functioning generally in the mild to moderate range of disability, commensurate adaptive functioning, and increased anxiety. Relative strengths have been found for nonverbal fluid reasoning (FR). Gender effects have been reported, with females showing better adaptive functioning across domains. Developmentally, nonverbal skills plateau in late childhood/early adolescence, whereas the rate of vocabulary acquisition may increase in adolescence into early adulthood. Here we review the literature assessing cognitive, adaptive, and behavioral functioning in Costello syndrome, and we provide data from an ongoing longitudinal study. Severity of cognitive impairment may depend upon the specific HRAS mutation, as three individuals with the p.G13C change showed average nonverbal FR skills and borderline-to-low average overall nonverbal IQ. Further, separation anxiety is more common in Costello syndrome than in the general population, affecting 39% of this cohort, and males are more often overly anxious than females. Interrelations between anxiety and cognitive and adaptive functioning were found, pointing to functional difficulties as a likely source of stress and anxiety. Taking into account data from animal models, cognitive and behavioral changes likely originate from abnormal differentiation of neuronal precursor cells, which result in structural and functional brain differences.

Voxel-based morphometry findings in Alzheimer's disease: neuropsychiatric symptoms and disability correlations - preliminary results

INTRODUCTION: The role of structural brain changes and their correlations with neuropsychiatric symptoms and disability in Alzheimer's disease are still poorly understood. OBJECTIVE: To establish whether structural changes in grey matter volume in patients with mild Alzheimer's disease are associated with neuropsychiatric symptoms and disability METHODS: Nineteen Alzheimer's disease patients (9 females; total mean age =75.2 y old +4.7; total mean education level =8.5 y +4.9) underwent a magnetic resonance imaging (MRI) examination and voxel-based morphometry analysis. T1-weighted images were spatially normalized and segmented. Grey matter images were smoothed and analyzed using a multiple regression design. The results were corrected for multiple comparisons. The Neuropsychiatric Inventory was used to evaluate the neuropsychiatric symptoms, and the Functional Activities Questionnaire and Disability Assessment for Dementia were used for functional evaluation RESULTS: A significant negative correlation was found between the bilateral middle frontal gyri, left inferior temporal gyrus, right orbitofrontal gyrus, and Neuropsychiatric Inventory scores. A negative correlation was found between bilateral middle temporal gyri, left hippocampus, bilateral fusiform gyri, and the Functional Activities Questionnaire. There was a positive correlation between the right amygdala, bilateral fusiform gyri, right anterior insula, left inferior and middle temporal gyri, right superior temporal gyrus, and Disability Assessment for Dementia scores CONCLUSIONS: The results suggest that the neuropsychiatric symptoms observed in Alzheimer's disease patients could be mainly due to frontal structural abnormalities, whereas disability could be associated with reductions in temporal structures.

Increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. This condition has been associated with cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM are incompletely understood. Glutamate and other metabolites such as lactate have been implicated in its pathogenesis. In the present study, we investigated the involvement of glutamate in the behavioral symptoms of CM. Seventeen female C57BL/6 mice (20-25 g) aged 6-8 weeks were infected with P. berghei ANKA by the intraperitoneal route using a standardized inoculation of 10(6) parasitized red blood cells suspended in 0.2 mL PBS. Control animals (N = 17) received the same volume of PBS. Behavioral and neurological symptoms were analyzed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. Glutamate release was measured in the cerebral cortex and cerebrospinal fluid of infected and control mice by fluorimetric assay. All functional categories of the SHIRPA battery were significantly altered in the infected mice at 6 days post-infection (dpi) (P ≤ 0.05). In parallel to CM symptoms, we found a significant increase in glutamate levels in the cerebral cortex (mean ± SEM; control: 11.62 ± 0.90 nmol/mg protein; infected at 3 dpi: 10.36 ± 1.17 nmol/mg protein; infected at 6 dpi: 26.65 ± 0.73 nmol/mg protein; with EGTA, control: 5.60 ± 1.92 nmol/mg protein; infected at 3 dpi: 6.24 ± 1.87 nmol/mg protein; infected at 6 dpi: 14.14 ± 0.84 nmol/mg protein) and in the cerebrospinal fluid (control: 128 ± 51.23 pmol/mg protein; infected: 301.4 ± 22.52 pmol/mg protein) of infected mice (P ≤ 0.05). These findings suggest a role of glutamate in the central nervous system dysfunction found in CM.