Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders?

The response to stimulant drugs of 48 boys with attention deficit/hyperactivity disorder was measured following dextroamphetamine, methylphenidate, and placebo in a double-blind crossover study. To distinguish lack of behavioral improvement from adverse drug effects, a day hospital setting and a wide dose range were used. Both drugs were highly and equally efficacious for the group as a whole, and frequently one drug or the other was superior for an individual child, or adverse effects occurred only on one of the stimulants. Only one of the 48 boys (2%) was discharged without the recommendation for continued stimulant drug treatment. "Nonresponse" appears to be extremely rare when both stimulants and a wide range of doses are given.     

Could Wallerian degeneration contribute to "leuko-araiosis" in subjects free of any vascular disorder?

To determine the possible role of Wallerian degeneration secondary to the grey matter neuronal loss in the pathogenesis of "leuko-araiosis", computerised tomography (CT) of the brain was studied in 98 normotensive and non diabetic subjects free of cardiac diseases: 32 with Alzheimer's disease, 36 with Parkinson's disease, eight with progressive supranuclear palsy, and 22 controls. In Alzheimer's disease, leuko-araiosis scores were greater than in control subjects. Leuko-araiosis was more prominent in anterior periventricular areas in Parkinson's disease and progressive supranuclear palsy, and in posterior periventricular areas in Alzheimer's disease. In two patients with Alzheimer's disease and leuko-araiosis, necropsy revealed diffuse white matter pallor, mild fibrillary astrocytosis, and in one patient limited hyaline thickening of small white matter vessels, without any infarction or hypertensive change. Changes were more severe in white matter close to cortical areas with a great density of neurofibrillary tangles. Leuko-araiosis was more severe or more widespread in Alzheimer's disease than in Parkinson's disease, progressive supranuclear palsy and normal ageing. Differences in the location of leuko-araiosis between the four groups might be due to differences in the location of the grey matter disorder and Wallerian degeneration rather than amyloid in Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy and normal ageing. Wallerian degeneration might be another cause of leuko-araiosis in neuro-degenerative disorders beside previously reported extra-cerebral predisposing factors and amyloid angiopathy.     

MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection

OBJECTIVE: The authors assessed selective basal ganglia involvement in a subgroup of children with obsessive-compulsive disorder (OCD) and/or tics believed to be associated with streptococcal infection. METHOD: Using computer-assisted morphometric techniques, they analyzed the cerebral magnetic resonance images of 34 children with presumed streptococcus-associated OCD and/or tics and 82 healthy comparison children who were matched for age and sex. RESULTS: The average sizes of the caudate, putamen, and globus pallidus, but not of the thalamus or total cerebrum, were significantly greater in the group of children with streptococcus-associated OCD and/or tics than in the healthy children. The differences were similar to those found previously for subjects with Sydenham's chorea compared with normal subjects. CONCLUSIONS: These results support the hypothesis that there is a distinct subgroup of subjects with OCD and/or tics who have enlarged basal ganglia. These findings are consistent with the hypothesis of an autoimmune response to streptococcal infection.     

Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors

OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined. METHOD: Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments. RESULTS: Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.     

Impaired cholinergic function in cell lines derived from the cerebral cortex of normal and trisomy 16 mice

Murine trisomy 16 is an animal model of human Down's syndrome. We have successfully established permanently growing cell lines from the cerebral cortex of normal and trisomy 16 foetal mice using an original procedure. These lines, named CNh (derived from a normal animal) and CTb (derived from a trisomic foetus), express neuronal markers. Considering that Down's syndrome exhibits cholinergic deficits, we examined cholinergic function in these lines, using incorporation of [3H]-choline and fractional release studies. After 1, 3 and 5 min of [3H]-choline incubation, CTb cell uptake was lower by approximately 50% compared to controls. Hemicholinium-3 significantly reduced the incorporation of [3H]-choline in both CNh and CTb cells at high concentration (10 microM), suggesting high-affinity choline transport. However, CTb cells exhibited greater sensitivity to the blocker. For fractional release experiments, the cells were stimulated by K+ depolarization, glutamate or nicotine. When depolarized, CTb cells showed a 68% reduction in fractional release of [3H]-acetylcholine compared to CNh cell line, and a 45% reduction when stimulated by nicotine. Interestingly, glutamate induced similar levels of release in both cell types. The results indicate the existence of cholinergic dysfunction in CTb cells when compared to CNh, similar to that reported for primary cultures of trisomy 16 brain tissue (Fiedler et al. 1994, Brain Res., 658, 27-32). Thus, the CTb cell line may serve as a model for the study of Down's syndrome pathophysiology.     

Present-day trends in adolescents' health

The trends in teenagers' health in the past decade have been studied. A total of 2442 pupils from general and vocational training schools have been examined. There have been increases in morbidity and in the incidence of social diseases, there has been a decrease in their physical development. Methodological approaches to examining the health status in this age group are presented. Examining the procedures developed for monitoring adolescents' health has shown that they yield positive results.     

Phospholipid composition and levels are altered in Down syndrome brain

Individuals chronically exposed to low levels of organophosphate insecticides may present with subtle impairments in cognition. In addition, low level diisopropylflurophosphate (DFP) exposure (0.25 mg/kg per day for 2 weeks) in rats resulted in protracted working memory impairment [29]. The current studies attempt to show a temporal relationship between the DFP-induced impairment in performance of a spatial memory task and the protracted decrease in the expression of cholinergic receptors and acetylcholinesterase in specific brain regions. Cholinergic receptors labeled with the ligands [(3)H]epibatidine and [(3)H]AFDX-384 were affected to a much greater extent and for a longer period of time than were both acetylcholinesterase activities and cholinergic receptors labeled with [(3)H]QNB. Pre-testing administration of nicotine was shown to completely reverse this DFP-induced impairment in memory-related task performance. Additionally, prophylaxis with pyridostigmine bromide (PB) caused DFP-treated animals to exhibit near normal levels of memory-related task performance. These results are consistent with the development of a protracted phase of learning impairment to sub-acute DFP exposure, which may involve the loss of hippocampal nicotinic receptors, and may be prevented or reversed by PB or nicotine, respectively.     

A continuous fluorometric assay for phospholipase A(2) activity in brain cytosol

Alterations in phospholipase A₂ (PLA₂) activity have been implicated in Alzheimer disease and other neurological disorders, although brain PLA₂ activity is currently measured using lengthy, non-continuous assays. We describe herein a rapid, continuous assay in which we measured PLA₂ activity in mouse brain cytosol (CB-57). Brains were homogenized in HEPES buffer (pH 7.5) and the cytosolic fraction was prepared by centrifugation at 25 000×g for 20 min, followed by centrifugation of the supernatant at 100 000×g for 60 min. Cytosolic protein content was determined using the Bradford assay. Pyrene labeled phosphatidylcholine was added to 50 μg of cytosolic protein in Tris buffer (pH 8.0) containing fatty acid free-bovine serum albumin for a final assay volume of 2 ml. Assay temperature was maintained at 30±1°C. The excitation wavelength was 345 nm and emission was measured at 377 nm. Fluorescence intensity was converted to molar concentrations using a standard curve. Under these conditions, bromoenol lactone inhibited up to 58% of the PLA₂ activity with an IC₅₀ of 0.5 μM. In a separate experiment, lack of appreciable alternative acylhydrolase activity was verified chromatographically. Using this method, brain PLA₂ activity can be measured in a continuous, rapid, and sensitive manner.     

Brain myo-inositol level is elevated in Ts65Dn mouse and reduced after lithium treatment

The segmental trisomy Ts65Dn mouse is a novel model of Down syndrome (DS). The purpose of this study was to measure brain levels of myo-inositol (ml), N-acetylaspartate (NAA), and other metabolites in Ts65Dn mice using in vivo 1H magnetic resonance spectroscopy (MRS), and to determine whether lithium (Li) treatment alters brain ml level. The ratio of ml over total creatine (Cr), ml/Cr, was significantly elevated (mean change +38%), while NAA/Cr was significantly decreased (mean change -18%) in Ts65Dn mice (n=5) compared with control mice (n= 7). This is consistent with 1H MRS findings in DS human adults. Brain ml/Cr of the entire sample group (n= 12) was reduced (mean change -15%) following Li treatment, supporting the Li-induced ml depletion hypothesis.