Age and gender differences in behavioral and morphological outcome after 6-hydroxydopamine-induced lesion of the substantia nigra in rats

It is well known that Parkinson's disease occurs more commonly in older people and men are more frequently affected than women. Animal studies in models of the disease mainly use young male animals. The effects of aging on the neurochemical changes in the dopaminergic system have been extensively studied, however, data on comparative behavioral consequences of lesions of the dopaminergic system in aging and in female animals are limited. The aim of the present study was to give a detailed comparative behavioral analysis of young and aging male and female rats following 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. Young males and females, as well as aging males and females underwent 6-OHDA-induced lesion of the substantia nigra. Behavioral analysis in an open-field was performed before the injury, and 1 and 10 days after the operation. Tyrosine-hydroxylase (TH) immunohistochemistry was done in order to assess the dopaminergic cell loss in the substantia nigra. It was found that both young and aging male animals were more susceptible to 6-OHDA than females: female rats had a significantly less dopaminergic cell loss and responded to 6-OHDA with a significantly higher degree of behavioral recovery after the injury. Although the dopaminergic cell loss was not significantly different between young and aging animals of the same sex, aging rats showed more severe behavioral deficits. In summary, our present results showed clear age- and gender differences in the behavioral and histological outcome following 6-OHDA lesion of the substantia nigra.     

Pre–clinical diagnosis of Alzheimer disease combining platelet amyloid precursor protein ratio and rCBF spect analysis

Platelet Amyloid Precursor Protein ratio of different abnormal forms and 99mTc–ECD SPECT perfusion analysis were evaluated in Mild Cognitive Impairment (MCI) subjects who progressed to Alzheimer Disease (AD) and in stable MCI. We report that their combined evaluation increases the discriminative power of the analysis in identifying presymptomatic AD. The positive predictive value of these combined markers in identifying progressive MCI was 0.87, and the negative predictive value was 0.90. This observation suggests that the interplay of different markers should be considered for enhancing diagnostic accuracy of pre–clinical AD. Drs. Di Luca and Padovani contributed equally to this work.     

The importance of maintaining effective therapy in multiple sclerosis

The INCOMIN study (INdependent COMparison of INterferons) lends further support to the growing body of evidence that both dose and frequency of interferon beta (IFNbeta) administration are important in the treatment of multiple sclerosis (MS). High-dose, high-frequency IFNbeta (IFNbeta-1b 250 microg eod sc and IFNbeta-1a 44 microg sc) treatment offers greater therapeutic benefit, in terms of clinical and magnetic resonance imaging (MRI) outcome measures, compared with low-dose, once-weekly administration of IFNbeta. The importance of maintaining the most effective treatment regimen has been shown in another study. The data from this study suggested that patients who have 'stable' disease (i. e. no evidence of clinical or MRI disease activity) during long-term treatment with IFNbeta-1b 250 microg, who are subsequently treated with low-dose, once-weekly IFNbeta-1a 30 microg, are more likely to experience relapses, disease progression or MRI activity compared with those remaining on IFNbeta-1b 250 microg. These data clearly indicate that frequently administered therapy must be maintained to achieve the optimal therapeutic benefit for patients. Those patients who had their IFNbeta-1b 250 microg therapy reduced to low-dose, once-weekly IFNbeta-1a and experienced a resumption of disease activity were returned to their previous regimen. However, after 1 year of additional follow-up, many of these patients still had clinical or MRI signs of disease activity, highlighting further the risks associated with the reduction of IFNbeta dose and frequency of administration. Taking into consideration the evidence supporting the greater efficacy of IFNbeta-1b 250 microg or IFNbeta-1a 44 microg in MS it is of considerable interest to examine whether it is useful to increase the dose of IFNbeta-1b in patients who do not respond satisfactorily to the approved standard dose. This is the rationale for the recently completed OPTIMS (OPTimization of Interferon for MS) study, in which partially responding patients were randomised to IFNbeta-1b 250 or 375 microg every other day. An interim safety analysis of OPTIMS patients has not raised any safety or tolerability concerns. In summary, there is consistent evidence to support the importance of maintaining frequently administered IFNbeta (IFNbeta-1b 250 microg or IFNbeta-1a 44 microg) for the treatment of MS.     

Human cortical responses during one-bit delayed-response tasks: an fMRI study

Neuroimaging study of cognition across aging requires simple tasks ensuring: (i) high rate of correct performances in neurophysiological settings; and (ii) significant modulation of cortical activity. As a preliminary step, the present functional magnetic resonance imaging (fMRI) study tested the hypothesis that very simple delayed-response tasks fit these requirements in normal young adults. The short-term memory (STM) variant included a sequence of cue stimulus (two vertical bars), delay period (blank screen for only 5s), go stimulus, and motor response compatible with the taller vertical bar. Noteworthy, the retention (only one bit) could be based on visuo-spatial, phonological, and somatomotor coding. In the control variant (no STM, NSTM), the cue stimulus was present during the delay period. Results showed high rate of correct performances in both tasks (about 95%). Compared to the NSTM task (delay period), the STM task enhanced cortical responses in bilateral dorsolateral prefrontal (Brodmann area 8-9 (BA 8-9)), lateral premotor (BA 6L), medial premotor (BA 6M), inferior parietal (BA 40), and superior parietal (BA 7) areas. In the STM task, cortical responses were stronger in right than left BA 8-9 and BA 6L. These results indicate that, in normal young adults, a simple STM variant of delayed-response tasks (one bit to be retained) is correctly performed and enhances bilateral fronto-parietal responses. Therefore, it may be used for future cognitive neuroimaging studies on aging.     

Effects of sarizotan on the corticostriatal glutamate pathways

The effects of sarizotan, a 5-HT(1A) agonist with additional affinity for D(3) and D(4) receptors, have been studied on the corticostriatal glutamate pathways using dual-probe microdialysis in the awake rat. Sarizotan given systemically (0.1-10 mg/kg s.c.) or perfused into the motor cortex (10 microM) produced 20-30% reduction of cortical and striatal glutamate levels. The inhibitory effects of the systemic sarizotan on cortical and striatal glutamate levels were counteracted by intracortical perfusion with the 5-HT(1A) antagonist WAY100135 (10 microM). These findings suggest that the anti-dyskinetic properties of sarizotan could be mediated via its 5-HT(1A) agonist actions in the motor cortex, leading to reduced activity in the corticostriatal glutamate pathways with reduced activation of the striatopallidal GABA pathway mediating motor inhibition.     

Depressive and negative symptoms in schizophrenia: different effects on clinical features

Objective

The primary aim of this study was to investigate whether depressive symptoms were significantly associated with functional outcome measures in a clinically stable group of outpatients with schizophrenia. We also analyzed whether depressive and negative symptoms presented different patterns of predictors.

Method

Seventy-eight consecutive outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for schizophrenia in the stable period were enrolled in this cross-sectional study. Assessment were performed using the Calgary Depression Scale for Schizophrenia, Positive and Negative Syndromes Scale (PANSS), Clinical Global Impression Scale-severity, Social and Occupational Functioning Assessment Scale, Sheehan Disability Scale, and Quality of Life Scale. A neuropsychologic battery including the vocabulary and block design subtests of the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale, Wisconsin Card Sorting Test, and Continuous Performance Test was also administered to the patients. Two multiple regressions were performed testing demographic and clinical factors, rating scales, and cognitive measures as independent variables and Calgary Depression Scale for Schizophrenia and PANSS-negative subscale scores as dependent variables.

Results

Four variables were predictors of depressive symptoms in our sample of schizophrenic patients: 2 outcome measures (Sheehan Disability Scale and Quality of Life Scale), gender, and Continuous Performance Test reaction time. Predictors of negative symptoms were the measures of severity of psychopathology (Clinical Global Impression Scale-severity and PANSS-general psychopathology subscale) and the cognitive tests Wechsler Adult Intelligence Scale-Revised block design and Wechsler Memory Scale.

Conclusion

We found that depressive symptoms in schizophrenia are mainly a function of the level of social adjustment and quality of life, whereas negative symptoms constitute an indicator of severity of schizophrenia. The 2 symptom dimensions showed also distinct cognitive correlates.     

Effects of AV3V lesion on pilocarpine-induced pressor response and salivary gland vasodilation

The cholinergic agonist pilocarpine injected intraperitoneally (ip) increases mean arterial pressure (MAP) and superior mesenteric (SM) vascular resistance and reduces submandibular/sublingual gland (SSG) vascular resistance. In the present study, we investigated the effects of electrolytic lesions of the anteroventral third ventricle (AV3V) region on the changes in MAP, SM, and SSG vascular resistances induced by ip pilocarpine. Male Holtzman rats anesthetized with urethane (1.0 g/kg) and chloralose (60 mg/kg) were submitted to sham or electrolytic AV3V lesions and had pulsed Doppler flow probes implanted around the arteries. Contrary to sham rats, in 1-h and 2-day AV3V-lesioned rats, pilocarpine (4 micromol/kg) ip decreased MAP (-41 +/- 4 and -26 +/- 4 mm Hg, respectively, vs. sham: 19 +/- 4 mm Hg) and SM (-48 +/- 11 and -45 +/- 10%, respectively, vs. sham: 41 +/- 10%) and hindlimb vascular resistances (-65 +/- 32 and -113 +/- 29%, respectively, vs. sham: 19 +/- 29%). In 7-day AV3V-lesioned rats, pilocarpine produced no changes on MAP and SM and hindlimb vascular resistances. Similar to sham rats, pilocarpine reduced SSG vascular resistance 1 h after AV3V lesions (-46 +/- 6%, vs. sham: -40 +/- 6%), but it produced no effect 2 days after AV3V lesions and increased SSG vascular resistance (37 +/- 6%) in 7-day AV3V-lesioned rats. The responses to ip pilocarpine were similar in 15-day sham and AV3V-lesioned rats. The cholinergic antagonist atropine methyl bromide (10 nmol) iv slightly increased the pressor response to ip pilocarpine in sham rats and abolished for 40 min the fall in MAP induced by ip pilocarpine in 1-h AV3V-lesioned rats. The results suggest that central mechanisms dependent on the AV3V region are involved in the pressor responses to ip pilocarpine. Although it was impaired 2 and 7 days after AV3V lesions, pilocarpine-induced salivary gland vasodilation was not altered 1 h after AV3V lesions which suggests that this vasodilation is not directly dependent on the AV3V region.