Journal of Neural Transmission-supplement最新文献

The present article provides a review of a series of studies in children with attention deficit hyperactivity disorder (ADHD) concerning (1) the effects of methylphenidate on various attentional functions, (2) the stimulant-induced changes of both qualitative and quantitative (i.e. kinematic) aspects of handwriting, (3) the interaction between conscious control of handwriting and fluency of handwriting movements, and (4) possible therapeutic approaches to graphomotor disturbances. Children with ADHD showed impairments in various aspects of attentional functioning. Pharmacological treatment of ADHD children with methylphenidate resulted in marked improvements of various components of attentional functioning. In comparison to the performance following the withdrawal of methylphenidate, children with ADHD on methylphenidate displayed a significant improvement in task accuracy in the areas of vigilance, divided attention, selective attention (inhibition, focused attention and integration of sensory information) and flexibility. However, the comparison with healthy children revealed considerable deficits regarding vigilance, divided attention, flexibility and selective attention (focused attention and integration of sensory information) in children with ADHD on methylphenidate. The comparison of writing movements of children on and off methylphenidate revealed that medication resulted in a better handwriting, but a deterioration in handwriting fluency as assessed by kinematic analysis. Children with ADHD may use their increased attentional capacities to focus on skills (e.g. handwriting) that are independent of conscious control or may even be disturbed by attention. The findings summarized in this paper indicate, therefore, that administration of methylphenidate alone is insufficient in the treatment of children with ADHD. Children with ADHD may benefit from instructions on how to best use their improved attentional capacities.

Therapeutic Drug Monitoring (TDM) is a tool to optimise antidepressant pharmacotherapy improving efficacy and avoiding side effects. The Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP)-TDM group has worked out consensus guidelines to make progress in the use of TDM which in spite of its obvious advantages, is far from optimal in everyday clinical practice. Research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration. Main indications of TDM compromise control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic predisposition particularity concerning the drug metabolism, children, adolescents and elderly patients. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed, implications on pharmacoeconomics aspects are discussed. The need to improve the implementation of TDM in routine patient care is emphasized.

Data about therapeutic drug monitoring (TDM) of psychotropic medications are often obtained from samples of highly selected individuals, who may not be representative for the average psychiatric patient. These data therefore may have limitations with regard to their transferability to everyday clinical practice. Therefore studies under naturalistic conditions are important to clarify the full clinical relevance of TDM. We retrospectively evaluated all TDM-analyses of the tricyclic antidepressants (TCA) amitriptyline and clomipramine during a 12-month period in an unselected sample of patients in a standard clinical setting. We especially examined the relationship between serum levels on one hand and clinical response and adverse effects on the other hand. In patients with amitriptyline, responders showed a significantly higher serum level than non-responders, whereas in patients with clomipramine a serum level within the recommended therapeutic range was associated with clinical response. We also found significantly higher serum concentrations in patients with adverse effects compared to patients without adverse effects in the clomipramine group. No such relationship could be shown in patients treated with amitriptyline. Our results suggest that therapeutic ranges in naturalistic settings in some ways differ from those obtained in controlled clinical settings and that TDM studies in everyday clinical practice are necessary and beneficial.

The aim of this study was to analyze motor inhibition and facilitation of adult ADHD patients using double pulse transcranial magnetic stimulation (TMS). Twenty-six right handed adult ADHD patients according to DSM-IV were investigated and compared to 26 age and sex-matched controls. In the left hemisphere, mean motor inhibition was 0.53 +/- 0.33 (mean +/- SD) in ADHD patients and 0.34 +/- 0.16 (mean +/- SD) in controls (p = 0.012). There were no significant differences in motor excitability concerning facilitation or in the right hemisphere. Decreased motor inhibition correlated with a higher symptom score derived from the Wender Reimherr Interview (WRI) (p = 0.28; p = 0.04) and also with self rated hyperactivity/impulsivity symptoms (p = 0.30; p = 0.03). In conclusion, decreased motor inhibition in adult ADHD corroborate similar findings in children with ADHD (Moll et al., 2000) and reflect disturbed impulsivity and hyperactivity on a neurophysiological level.

In this study we investigated differences in the gene expression profiling of the brains of rhesus macaques that were uninfected or infected with SIV in the asymptomatic stage or AIDS. The main aim was to use biostatistical methods to classify brain gene expression following SIV infection, without consideration of the biological significance of the individual genes. We also used data from animals treated with different pharmacological substances such as dopaminergic drugs, N-methyl-D-aspartate (NMDA) antagonists or antioxidants during the early stage of infection as these animals exhibited an accelerated or attenuated neuropsychiatric disease progression. We found macaque subspecies to be a more important factor for disease classification based on gene expression profiling than clinical symptoms or neuropathological findings. It is noteworthy that SIV-infected pharmacologically-treated. Chinese animals clustered near uninfected animals independent on the outcome of the treatment, whereas untreated SIV infected animals were clustered in a separate subtree. It is clear from this study that NeuroAIDS is a diverse disease entity and that SIV brain genes can be differentially regulated, depending on the disease type as well as changed dependent on the monkey subspecies.

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).

Catecholaminergic neurons of the primate substantia nigra (SN) pars compacta (SNc) and the locus coeruleus contain neuromelanin (NM) granules as characteristic structures underlying the pigmentation of these brain areas. Due to a phylogenetic appearance NM granules are absent in the rodent brain, but gradually become present in primates until they reach a maximal expression in humans. Although a possible mechanism of pigment formation may be autoxidation of the NM precursors dopamine or noradrenalin, several groups have suggested an enzymatic formation of NM mediated by tyrosinase or a related enzyme. Since tyrosinase mRNA is suggested to be expressed in the SN of mice and humans, we reinvestigated the expression of tyrosinase in the human SNc and the locus coeruleus at the protein level by immunohistochemistry and Western blot analysis, but could not detect tyrosinase in these brain regions.

The nature of intracellular communication and integration in the central nervous system remained a source of controversy long after it had been accepted that the brain is intrinsically involved in the reception of external and internal sensory impressions, in the control of both voluntary and involuntary physiological functions, and in the processes associated with consciousness and psychic function in humans. The role of the specific chemistry of the brain in these functions was specifically addressed only in the 20th century, although chemical examination of brain tissue can be traced at least as far back as 1719 to Hensing's Cerebri examen chemicum. Throughout the 1940s and 1950s evidence accumulated from a variety of laboratories that certain chemical substances, such as acetylcholine, noradrenaline and histamine, might be involved in central nervous system neurotransmission, but conclusive evidence for such communication was difficult to obtain. Commencing with Carlsson's 1957 paper on the anti-reserpine effects of DOPA and culminating in the successful amelioration of parkinsonian akinesia by Birkmayer and Hornykiewicz via administration of L-DOPA in 1961, followed by the identification of specific nervous tracts which utilized dopamine as a transmitter, chemical neurotransmission in the brain was ultimately demonstrated through a combination of pharmacological, physiological and clinical research. Neurochemistry had thereby graduated from a branch of general physiology to being centrally involved in models of central nervous system function.

It is believed that oxidative stress plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer's disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity against peroxyl (ORAC(-ROO)*) and hydroxyl (ORAC(-OH)*) free radical was measured in three different brain regions (hippocampus, cerebellum, and brain stem) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased antioxidant capacity has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy. Also, these abnormalities were not prevented by the icv pretreatment of glucose transport inhibitor 5-thio-D-glucose in the STZ-icv treated rats, suggesting different mechanism for STZ-induced central effects from those at the periphery. Similarities in the oxidative stress alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for new drugs in the treatment of sAD that have antioxidant activity.

Alterations in cholesterol homeostasis are associated with Alzheimer's disease (AD). The role played by specific fractions of serum lipoproteins in modifying the risk of AD, and the interaction with APOE genotype has not yet been investigated. We studied serum lipoprotein profiles using a gradient-density ultracentrifugation method in a cohort of late-onset sporadic AD patients without cerebrovascular lesions and in healthy elderly subjects. In the AD group the lipoprotein cholesterol distribution showed an increase in LDL cholesterol, reaching a significant difference with respect to controls in the LDL sub-fractions representing the transition between small dense-LDL (fraction 11, p = 0.04) and normal-density LDL particles (fraction 12, p = 0.03). APOE genotype and LDL cholesterol were independently associated with AD. The mean concentration of LDL in fractions 11 and 12 increased the risk of developing AD (p = 0.01 and p = 0.025, respectively). These results confirm that an alteration of cholesterol homeostasis is associated with AD and that serum concentrations of LDL cholesterol are higher in AD patients without cerebrovascular pathology than in elderly normal subjects. The presence of the APOE epsilon4+ allele is a risk factor for AD independent of increased serum cholesterol or a modification of other vascular risk factors. Increased levels of specific sub-fractions of LDL cholesterol may be associated with increased risk of AD.