No effect of acute tryptophan depletion on verbal declarative memory in young persons with ADHD.

OBJECTIVE: Animal experiments and studies in adults have shown that the neurotransmitter serotonin (5-HT) plays an important role in learning and memory processes. However, data on this relationship in young persons are scarce, and neurodietary research in this age group is limited compared with the extensive literature on adults. Here, we aimed to explore the effects of a diminished central nervous 5-HT synthesis, which is achieved by acute tryptophan depletion (ATD) Moja-De , on memory function in young males with attention deficit hyperactivity disorder (ADHD). METHOD: Twenty-two male patients with ADHD (ages 9-15 years, mean 10.95 ± 1.17 years) received ATD, thus diminishing central nervous 5-HT synthesis, and a tryptophan-balanced amino acid load (BAL) in a randomized, double-blind, within-subject, crossover design study. Approximately 1.7 h after administration of ATD/BAL, verbal declarative memory was assessed using the 'Auditory Verbal-Learning-Test' (AVLT). RESULTS: There were no significant effects of ATD administration on verbal declarative memory function. CONCLUSION: In this study, changes in 5-HT neurotransmission were not associated with specific aspects of verbal declarative memory in young persons with ADHD. Future studies with healthy control groups that address effects of covarying attentional processes are warranted.

Diminished 5-HT functioning in CBCL pediatric bipolar disorder-profiled ADHD patients versus normal ADHD: susceptibility to rapid tryptophan depletion influences reaction time performance.

OBJECTIVE: There is a current debate on characterizing children with pediatric bipolar disorder (PBD) through a profile within the child behaviour checklist (CBCL), and on the involvement of the 5-HT system in the underlying neurobiological processes of PBD. The aim of the present paper was to investigate reaction time performance in patients with CBCL-PBD and to discriminate ADHD from ADHD with CBCL-PBD with respect to diminished 5-HT functioning and reaction time. METHODS: Twenty-two patients with ADHD received the rapid tryptophan depletion test (RTD) thus lowering the central-nervous 5-HT synthesis rate within a placebo-controlled double-blind within-subject crossover design. Reaction time was assessed using a competitive reaction time game with low and high provocation after both depletion and placebo intake. The study sample was divided into high and low scorers according to their CBCL-PBD scores. RESULTS: Comparing those six patients with the highest and clinically significant CBCL-PBD scores versus those six patients with the lowest, patients with a high CBCL-PBD score showed a slower reaction time under RTD compared to patients with low CBCL-PBD scores after high provocation. CBCL-'aggression' discriminated between the two groups. CONCLUSIONS: The results suggest alterations in 5-HT functioning in CBCL-PBD-spectrum patients, and 'aggression' as a potential moderator variable to ADHD.

Soluble forms of intercellular adhesion molecule-1 (ICAM-1) block lymphocyte attachment to cerebral endothelial cells.

Serum levels of circulating ICAM-1 are increased in various disorders including inflammatory diseases of the central nervous system (CNS). We recently described an association between high sICAM-1 levels in the serum of patients with multiple sclerosis and disease activity. The functional consequences of increased circulating adhesion molecules are not fully understood. This may simply arise as a consequence of inflammation or may have immune modulating properties. ICAM-1 plays an important role in the recruitment of activated lymphocytes to sites of inflammation within the CNS. We therefore tested the ability of soluble forms of ICAM-1 to prevent adhesion of activated lymphocytes to cerebral endothelial cells. Mitogen-activated blood mononuclear cells (PBMC) as well as PBMCs from patients with active multiple sclerosis adhered to cerebral endothelial cell cultures in vitro. This adhesion could be blocked if lymphocytes were preincubated with a recombinant form of soluble ICAM-1. In addition, serum from patients with active multiple sclerosis and high sICAM-1 levels blocked adhesion in a dose-dependent manner which was abrogated by pre-adsorption to an anti ICAM-1 antibody. Since soluble forms of ICAM-1 are able to block lymphocyte adhesion to cerebral endothelial cells, they may provide new therapeutic tools to interfere with the pathogenesis of inflammatory diseases of the CNS.

Cerebral endothelial cells are a major source for soluble intercellular adhesion molecule-1 in the human central nervous system.

Immunohistological analysis of tissue sections from human brain revealed that intercellular adhesion molecule-1 (ICAM-1) is mainly expressed on endothelial cells of small vessels, including the subependymal vessels of the choroid plexus. In addition, it is expressed on cerebrospinal fluid (CSF) cells in patients with inflammatory diseases of the central nervous system. Stimulation of confluent monolayers of adult human cerebral endothelial cells with lipopolysaccharide (LPS) or recombinant human tumor necrosis factor-alpha (TNF-alpha) could induce expression and secretion of soluble ICAM-1 in a dose dependent manner. In addition, sICAM-1 was also present in the supernatant from U251 glioma cells. No sICAM was detected in the culture supernatant from activated blood or CSF lymphocytes. Cerebral endothelial cells are therefore a likely source for sICAM-1 in the CSF.

Tumor-related venous obstruction and development of peritumoral brain edema in meningiomas.

OBJECTIVE: The exact pathogenesis of peritumoral brain edema (PTBE) in meningiomas is still unknown. A number of different pathophysiological hypotheses have been considered. A detrimental effect of tumor-related venous obstruction has been suggested as one pathogenetic mechanism. We sought to characterize the significance of venous stasis in the development of PTBE in meningiomas. METHODS: Angiograms for 134 patients with 136 intracranial meningiomas were analyzed. Pathological changes affecting cortical veins, sylvian veins, bridging veins, deep veins, transmedullary veins, and dural sinuses were evaluated. From preoperative computed tomographic scans, the total tumor volume, the tumor/PTBE volume ratio (edema index [EI]), and the location of the edema were determined. For statistical evaluation, meningiomas associated with pathological venous drainage were compared with size-matched controls. RESULTS: The edema incidence and the mean EI were not different for meningiomas with unselected signs of obstructed venous drainage, compared with controls. In particular, lesions with involvement of cortical veins, bridging veins, and dural sinuses showed no higher edema incidence. However, meningiomas associated with venous changes in sylvian veins (EI = 4.9 versus EI = 2.7; P < 0.004) and with dysplastic transmedullary veins (EI = 3.3 versus EI = 1.7; P < 0.04) showed significantly higher mean EI values, compared with meningiomas without involvement of these vessels. CONCLUSION: Our data suggest that tumor-related venous obstruction does not play an essential role in the development of PTBE for the majority of meningiomas. For a small subgroup of meningiomas with involvement of sylvian veins or development of dysplastic transmedullary veins, changes in venous drainage may aggravate preexisting PTBE.

The importance of pial blood supply to the development of peritumoral brain edema in meningiomas.

In a retrospective analysis, the authors studied the pial and dural blood supplies in 74 intracranial meningiomas and quantified their associated peritumoral brain edema (PTBE). The extent and localization of pial blush in relation to the total tumor volume were determined angiographically. The amount of edema and tumor size were calculated using computerized tomography. The edema-tumor volume ratio was defined as Edema Index (EI). There were 49 meningiomas with PTBE; of those tumors, 46 were supplied by pial vessels, and three were supplied exclusively by dural vessels. Tumors without PTBE showed no pial blush. The mean EI in meningiomas with pial blush was significantly larger (EI = 3) than in meningiomas without pial supply (EI = 1.1; p < 0.0001). Meningiomas with a smaller pial supply than dural supply had a significantly smaller mean EI than tumors with a pial supply equal to or greater than the dural supply (EI = 2.9 vs. EI = 3.7; p < 0.015). In 69.9% of cases with pial blood supply, major portions of the edema were located adjacent to the tumor region supplied by pial vessels. Edema index differences among tumors of different subgroups, as defined by size or histology, were significantly related to the pial supply in each subset. Thus, pial blood supply may be associated with the development of PTBE in meningiomas.

Differences in zinc status and the leptin axis in anorexic and recovered adolescents and young adults: a pilot study.

BACKGROUND: Evidence from animal studies suggests that leptin metabolism is associated with zinc (Zn) status. However, research investigating this relationship in adolescents and young adults with anorexia nervosa (AN) is scarce; the present study aims to fill that gap. METHODS: Serum concentrations of leptin, the soluble leptin receptor (sOB-R) and the free leptin index (FLI) were obtained in healthy control subjects (n=19), acutely ill individuals (n=14) and recovered patients with AN (n=15). Serum Zn concentrations noted in previous research data were also incorporated for all groups. RESULTS: Leptin, FLI and Zn concentrations were higher in recovered subjects with AN when compared with acutely ill AN patients. Remitted patients showed higher sOB-R concentrations but no difference in FLI compared with the control group. Leptin and FLI were lower in the acutely ill patients compared with the control subjects, who showed no differences in Zn concentrations. Zn concentrations were not correlated with leptin, sOB-R or FLI concentrations in any of the three investigated subgroups. CONCLUSIONS: The present investigation does not entirely support an association between Zn, Leptin and FLI concentrations in subjects with AN, possibly due to limited statistical power. Further research and replication of the present findings related to the interaction between leptin and Zn is warranted. However, with respect to serum leptin levels the data of the present investigation indicate that acutely ill and remitted patients with AN differ as regards serum leptin concentrations and FLI, which is in line with previous research.

No association between affective and behavioral dysregulation and parameters of thyroid function in youths.

OBJECTIVE: Evidence from adults suggests that changes in thyroid function are associated with the development of bipolar disorder (BD) and severe mood dysregulation. A dysregulation profile based on the Child Behavior Checklist (CBCL-DP) describes a phenotype with severe mood problems in youth. The present study investigated whether altered thyroid functioning in youths is associated with the severe mood dysregulation symptoms characterized by the CBCL-DP. METHODS: We analyzed the thyroid function data from 262 children and adolescents (n = 262 for serum TSH, n = 148 for free triiodothyronine [fT3] and n = 153 for free thyroxine [fT4]) with their CBCL-DP composite score. We created and compared high CBCL-DP and low CBCL-DP subgroups with regard to their serum TSH, fT3 and fT4 concentrations as well as the presence or absence of subclinical hypothyroidism. RESULTS: We did not detect between-group differences in serum TSH, fT3 and fT4 concentrations, nor were there significant correlations between youths' CBCL-DP scores and their serum TSH, fT3 and fT4 concentrations for either the whole sample or any subgroup. Post-hoc power analyses indicated that adequate to moderate power existed to detect between-group differences in fT3 and fT4 concentrations, respectively, but that larger TSH samples would be required to detect the same differences in those concentrations. LIMITATIONS: This study had a retrospective design, fewer females than males, and reduced power with respect to TSH concentrations. CONCLUSIONS: The present investigation does not support the association between elevated serum-TSH concentrations and severe mood dysregulation in youths. However, these findings should be confirmed in future large-scale studies.

Reduced serotonergic functioning changes heart rate in ADHD.

Reduced mean heart rate (HR) was shown to be a biophysiological marker for aggression, which in turn was proven to be related to changed serotonergic neurotransmission. A total of 16 ADHD-diagnosed boys were subjected to rapid tryptophan depletion (RTD) and a placebo in a double-blind within-subject crossover-design. Mean HR was assessed under RTD/placebo. Low impulsive patients behaving aggressively under RTD showed a lowered HR under RTD versus placebo. Diminished 5-HT functioning was associated with lowered HR and aggressive behaviour.

Reduced number of taste papillae in patients with eating disorders.

Taste affects dietary behavior and in turn taste response and food preferences are altered in eating disorders. Fungiform papillae on the tongue are the first line of the gustatory apparatus to provide information about taste. Aim of this study is determination of their number in patients with eating disorders. Twenty-seven female adolescents with eating disorders and 16 age-matched healthy female controls were examined. Tongues were stained with blue food coloring and the number of fungiform papillae was quantified using digital photography and image processing. Patients with restrictive type eating disorders showed a more distinct reduction (p < 0.001) of fungiform papillae than patients with vomiting and/or binge eating (p < 0.05), compared with those of healthy control subjects. Causes may be an initially disturbed development of fungiform papillae or secondary to changes in eating behavior which may be mutually causative.

CBCL-pediatric bipolar disorder phenotype: severe ADHD or bipolar disorder?

BACKGROUND: In children with pediatric bipolar disorder (PBD), a consistent pattern of elevations in hyperactivity, depression/anxiety, and aggression has been identified on the child behavior checklist (CBCL-PBD profile). The aim of the present study was to estimate the prevalence of the CBCL-PBD profile in a child psychiatric sample, and to determine ICD-10 diagnoses in CBCL-PBD patients. METHODS: We studied a sample of 939 consecutively referred children and adolescents, aged 4-18 years. ICD-10 discharge diagnoses were established in consensus conferences. The CBCL 4-18 was completed by parents as part of the diagnostic routine. RESULTS: A total of 62 subjects (6.6%; 95% CI=5.2-8.4) met criteria for the CBCL-PBD phenotype. More than 75% of CBCL-PBD subjects were clinically diagnosed with disruptive behavior disorders (ADHD, ODD, and CD). Two patients (0.2% of the total sample) received a formal diagnosis of bipolar disorder, but did not show the CBCL-PBD phenotype. CONCLUSIONS: A considerable number of children in Germany are referred to psychiatric care with a mixed phenotype of aggression, anxiety, depression and attention problems. Our study demonstrated a comparable prevalence and similar clinical characteristics as reported from other countries using different diagnostic approaches. However, the CBCL-PBD phenotype does not correspond with clinical consensus diagnoses of bipolar disorder, but with severe disruptive behavior disorders.

Diminished serotonergic functioning in hostile children with ADHD: tryptophan depletion increases behavioural inhibition.

INTRODUCTION: Serotonergic (5-HT) functioning has been shown to account for a variety of behavioural characteristics, in particular aggressive and impulsive behaviour. This study explored the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of brain 5-HT synthesis on behavioural inhibition in passive avoidance learning assessed in a computerized go/no-go task. METHODS: 22 male patients with an ICD-10 diagnosis of ADHD were administered RTD within an amino acid drink lacking tryptophan, the natural precursor of 5-HT, thus lowering the central nervous 5-HT synthesis rate in a placebo-controlled double-blind within-subject crossover-design. 4 hours after RTD/placebo intake the patients were subjected to a go/no-go task for assessment of behavioural inhibition. RESULTS: Highly hostile aggressive patients showed increased inhibition errors under RTD compared to placebo. Low hostile aggressive patients showed lower rates of inhibition errors and thus better performance under RTD compared to placebo. DISCUSSION: The data suggest that in ADHD levels of trait-aggressive characteristics influence the susceptibility to changed behavioural inhibition after an acute 5-HT dysfunction. The detected influence of 5-HT could also be relevant as regards behavioural inhibition being subject to a developmental change in 5-HT functioning.

Serotonin-induced platelet intracellular Ca2+ response in patients with anorexia nervosa.

INTRODUCTION: Serotonin (5-HT) is involved in the regulation of food intake. In anorexia nervosa there is a disturbance in 5-HT function. The stimulation of 5-HT(2)-receptors in platelets is a useful peripheral model to investigate the cascade of signal transduction and neuronal functioning. METHODS: 25 anorexic female patients between the ages of 11 and 18 years with a mean body mass index (BMI) of 13.9+/-1.3 kg/m(2) participated in this study. The 21 healthy female controls revealed a mean BMI of 20.5+/-2.7 kg/m(2). 5-HT stimulated intracellular Ca(2+) response of the platelets was obtained using the Fura-2 method at the time of admission, during therapy and when the target BMI was reached. RESULTS: We found a significant (p<0.01) decrease in 5-HT-induced Delta[Ca(2+)](i) at admission and a significant (p<0.05) increase of Delta[Ca(2+)](i) during treatment in patients with anorexia nervosa. Anorexic patients with and without comorbid depression had a comparable Ca(2+) release. However, low and high Ca(2+) responders showed a different course of Delta[Ca(2+)](i). The treatment with antidepressants led to a significant increase of Delta[Ca(2+)](i) in those patients with concomitant depression. DISCUSSION: Since the course of Delta[Ca(2+)](i) is not related to BMI or the presence of comorbid depression, we conclude that serotonergic transmission or signaling pathways could be disturbed in patients suffering from anorexia nervosa. One inference of this preliminary study is that administration of antidepressants may be more effective in patients with concomitant depression.

[The importance of choline and different serum parameters for the course of the anorexia nervosa]. / Die Bedeutung von Cholin und verschiedenen Serumparametern für den Verlauf der Anorexia nervosa.

Malnutrition in anorexia nervosa was simulated in an animal starvation study. Female rats aged 11 to 13 weeks received a hypocaloric standard diet or a hypocaloric choline reduced diet. Weight reduction lasted for 12 to 20 weeks and was between 30 % to 40 % of initial weight. Several animals were refed after weight reduction up to 6 to 12 weeks with a standard or a choline enriched diet ad libitum. Serum parameters and membrane fluidity of the CNS were measured after weight reduction or after refeeding. Weight reduction leads to a significant decrease of serum protein, triglycerides (Z = -3.53 resp. -3.42; p < 0.001) and an increase of membrane fluidity in the CNS (Z = -2.83; p < 0.001). Long-term diet with marked weight reduction and following refeeding causes a catabole metabolic situation with significant increase of urea/creatinine-ratio. Choline enriched refeeding after diet results in normalization of serum parameters and membrane fluidity of the CNS. Choline enrichment leads to a significant increase of serum protein (Z = -2.03; p < 0.01). Besides we found a negative correlation between serum protein and urea/creatinine-ratio (r (S) = -0.47; p < 0.001; n = 64). This is possibly caused by a reduced protein catabolism or an increased protein anabolism. Furthermore membrane fluidity in the CNS correlates with serum protein (r (S) = 0.65; p < 0.001; n = 41) and with serum creatinine levels (r (S) = 0.58; p < 0.001; n = 42). We conclude that these serum parameters are potential predictors for cell function in the starved brain and consequently for the course of anorexia nervosa. We furthermore hypothesize that choline enriched nutrition after starvation improves the stabilization of cerebral membranes and the metabolic situation in anorexia nervosa.

Abundant minute myotubes in a patient who later developed centronuclear myopathy.

Centronuclear myopathy (CNM) is a congenital myopathy which manifests itself as a severe neonatal (also termed myotubular myopathy), early-onset, or adult form. The histological pattern of each is marked by a considerable number of nuclei of muscle fibers being internally placed. Owing to their remote resemblance to myotubes, and their expression of developmentally regulated proteins, most authors now favor the concept that myogenesis is arrested or delayed in this disease. We here present two muscle biopsy specimens of a patient with early-onset CNM, taken at the age of 5 months and 14 years, respectively. The first biopsy sample contained internally placed nuclei in 7% of the muscle fibers, abundant minute myotubes, and hypertrophic muscle fibers. The second biopsy sample showed internally placed nuclei in 40% of the muscle fibers, and hypotrophic fibers. We suggest that the histological findings in early-onset CNM are the result of a complex dynamic process, which includes a delay in maturation.

Peritumoural brain oedema in intracranial meningiomas: influence of tumour size, location and histology.

Peritumoural brain oedema was examined retrospectively in 175 patients with 179 intracranial meningiomas. The influence of tumour size, location and histology were investigated. Tumour volume and localization, and the presence of peritumoural brain oedema (PTBOe) were determined by computed tomography (CT). The oedema-tumour volume ratio was defined as Oedema Index (Oel). All patients underwent microsurgical removal of the tumour. Surgically resected meningiomas were classified histopathologically based on criteria of the new World Health Organization (WHO) classification. A close relationship was found between the tumour size and the incidence of peritumoural oedema: with increasing size of the tumour the incidence of oedema also rises, the oedema index, however decreases. Frontobasal and temporobasal meningiomas showed a significant increase in the oedema incidence and the mean oedema index. If major parts of the surface of meningiomas were adjacent to subarachnoid cisterns only a slight tendency for the development of oedema was observed. WHO-III-meningiomas showed a significantly higher oedema incidence (61.1% vs. 94.4%; p < 0.004) and mean oedema index (Oel = 2.7 vs. 3.7; p < 0.0009) than WHO-I-meningiomas. Brain tissue was affected in 59 cases. 19 meningiomas with infiltration into adjacent brain parenchyma revealed a statistically significant increase in oedema incidence (94.7% vs. 51.7%; p < 0.0003) and mean oedema index (Oel = 3.9 vs. Oel = 2.2; p < 0.0001) when compared to tumours without any brain tissue involvement in the histopathological specimens. Tumours with large volume, fronto-temporo-basal location and anaplastic histology were not only associated with the highest incidence of oedema formation but also presented with an overproportionate infiltrative growth. Thus, a disruption of the arachnoid or a true brain infiltration may be an essential factor for the development of a PTBOe.