Established donepezil treatment modulates task relevant regional brain activation in early Alzheimer's disease.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.

Resting metabolic rate, fat-free mass and catecholamine excretion during weight loss in female obese patients.

The reduction in resting metabolic rate (RMR) during weight loss exceeds that accounted for by changes in body composition by 15%, suggesting that factors other than fat-free mass (FFM) explain the metabolic adaptation during food restriction in obesity. Our study aimed to establish if changes in the sympathoadrenal system activity, as inferred from an integrated measure such as 24 h urinary excretion of catecholamines, may play a role in the RMR adaptation observed during dietary restriction in obese patients. Ninety-three obese female subjects consumed a low-energy diet (LED) (2930 kJ/d (700 kcal/d)) for a 3-week period. At the beginning and at the end of the study, 24 h urinary excretion of catecholamines, FFM and RMR were measured. The LED induced a significant reduction in body weight (-3.3 (SEM 0.4) kg; P < 0.01), FFM (-1.9 (SEM 0.7) kg; P < 0.01) and in the fat mass (-1.2 (SEM 0.5) kg; P < 0.01). Noradrenalin excretion (24 h) decreased during the LED from 264 (SEM 26) during a weight-maintenance period to 171 (SEM 19) nmol/24 h after consumption of the LED for 3 weeks (P < 0.001); mean 24 h adrenalin excretion did not change during the LED (22 (SEM 3) during the weight-maintenance period v. 21 (SEM 3) nmol/24 h after consumption of the LED for 3 weeks; NS). The LED induced a significant decrease in RMR (7300 (SEM 218) v. 6831 (SEM 138) kJ/24 h; P < 0.001). The only independent variable that significantly explained variations in RMR both before and after consumption of the LED for 3 weeks, was FFM (r2 0.79 and r2 0.80 respectively). Urinary noradrenalin excretion explained a further 4% of the variability in RMR, but only before the diet, so that a role of sympathoadrenal system on RMR seems to be present in obese patients in basal conditions but not at the end of the LED.

Metabolic effects of fluoxetine in obese menopausal women.

Our objective was to assess thermogenic action of fluoxetine (FL) in obese menopausal women, evaluating the effect of FL administration on resting energy expenditure (REE) and on glucose-induced thermogenesis both after acute administration (40 mg in single dose the evening before measurements) and after a 12- week period of diet treatment plus FL (60 mg per day) or placebo. It was a double-blind, placebo-controlled design both in acute and in chronic study. The subjects were 32 obese, otherwise healthy, menopausal women. The patients were assigned randomly to three groups, one performing an acute study protocol, in which resting and glucose-induced thermogenesis was measured after FL and placebo administration, performed in randomised order. The other two groups underwent dietary plus pharmacological treatment (FL or placebo, PL). Resting and glucose-induced thermogenesis was measured at baseline and after 12 weeks of treatment. The results showed that acute FL administration caused an increase in resting energy expenditure (PL: 5.35+/-0.18 vs FL: 5.53+/-0.24 KJ/min, p<0.05). A significant decrease of REE was observed in the PL group after 12 weeks (p<0.03), while a slight, but not significant, decrease was observed in the FL group (p=NS). FL did not affect thermic response to oral glucose neither after acute nor chronic administration (p=NS for all groups studied). The conclusion was that our data give support to thermogenic actions of FL after acute administration, suggesting also that chronic FL treatment may restrain to some degree the metabolic adaptation expected during weight loss in obese subjects. At variance with what observed with other drugs, such as dexfenfluramine, an increased thermic effect of oral glucose does not seem to be involved in the thermogenetic action of FL.

Adrenomedullary response to caffeine in prepubertal and pubertal obese subjects.

OBJECTIVE: To investigate whether blunted adrenomedullary responsiveness to stimuli is a primary feature of human obesity in childhood and adolescence DESIGN: Comparison of plasma catecholamine response to caffeine in obese and lean subjects before and after puberty onset. SUBJECTS: Twelve lean prepubertal subjects (six males and six females), 15 prepubertal obese subjects (seven males and eight females), 12 pubertal lean subjects (six males and six females) and 24 pubertal obese subjects (12 males and 12 females) MEASUREMENTS: Plasma levels of Luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17beta-estradiol and testosterone were used to validate Tanner score. Systolic and diastolic blood pressure, pulse rate and plasma catecholamines before and after caffeine administration (4 mg/kg of ideal body weight). RESULTS: Caffeine administration significantly stimulated adrenaline release in all subjects studied. The incremental area of adrenaline response to caffeine, analysed by multiple comparison test, was lower in pubertal obese subjects with respect to other groups. CONCLUSIONS: At variance with what is observed in adulthood obesity, prepubertal obese subjects show an intact adrenomedullary response to caffeine.

Acute estradiol and progesterone administration reduced cardiovascular and catecholamine responses to mental stress in menopausal women.

Steroid hormones are involved in the regulation of sympathoadrenal activity. Since the effect of sex steroids on the cardiovascular system and catecholamine secretion could also be exerted through an acute, nongenomic mechanism, we have studied the response to mental stress (color word test, CWT) in a group of 15 menopausal women during estrogen (100 microg of estradiol by patch), progesterone (100 mg i.m.) or placebo administration. Systolic blood pressure (SBP) increased during CWT in the three sessions (F = 11.0, p < 0.001) but the area under the curve of SBP was higher during placebo (2,855 +/- 131 mm Hg x min) than during estradiol (2,585 +/- 139 mm Hg x min) and progesterone (2,553 +/- 179 mm Hg x min, p < 0.05 for both). Plasma epinephrine increased during CWT in the three sessions (F = 31.1, p < 0.001) and the plasma epinephrine response to mental stress was higher during placebo than during estradiol administration (F = 4.3, p < 0.01). The area under the curve of epinephrine was 10,342 +/- 1,348 pmol/min x 1 during placebo and 7,280 +/- 818 pmol/min x 1 during estradiol (p < 0.03). The plasma glycerol levels at the end of CWT were higher during placebo (0.26 +/- 0.04 nmol/l) than during estradiol (0.19 +/- 0.03 mmol/l) and progesterone (0.17 +/- 0.04 mmol/l) administration (p < 0.05 for both). No significant differences were found in the responses of diastolic blood pressure, heart rate, norepinephrine and cortisol to mental stress during placebo and estradiol or progesterone administration. This study demonstrates that acute steroid administration is able to modify the cardiovascular and catecholamine response to mental stress in menopausal women.

Alpha-2 adrenergic activity in perimenopausal women.

Lipid alterations and increased blood pressure may occur during perimenopause. No data are available in perimenopausal women on the alpha-2 adrenergic activity which affects norepinephrine secretion. We studied cardiovascular and catecholamine responses to clonidine (300 mg per os) in a group of 15 perimenopausal women (PeriMW) and in a control group of 13 premenopausal women (PreMW). Nine of the perimenopausal women were also studied after 4-month percutaneous estrogen replacement therapy (PeriMWE). Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), plasma norepinephrine (NE) and epinephrine (E) were evaluated before and at 120 min, 130 min, 140 min after clonidine administration. Basal values of SBP, DBP and HR were not different (F = 0.7, p = NS; F = 0.2, p = NS and F = 0.1, p = NS respectively) between PeriMW both before and after therapy and PreMW. Resting levels of E were similar in PreMW and in PeriMW before and during estrogen therapy (F = 0.8, p = NS); PeriMW showed higher basal NE levels both before and during estrogen therapy than PreMW (F = 12; p < 0.001). Clonidine administration decreased SBP, DBP and NE levels in PreMW, in PeriMW and in PeriMWE without any difference between the groups (F = 1.2, p = NS; F = 0.5, p = NS and F = 1.3, P = NS respectively). HR decreased significantly after clonidine in PreMW (F = 5.4, p < 0.03) but not in PeriMW before (F = 1.0, p = NS) and during estrogen therapy (F = 0.5, p = NS). Clonidine did not affect plasma E in the three groups studied (F = 2.8, p = NS; F = 2.2, P = NS and F = 0.1, p = NS). The present study demonstrates that increased basal plasma NE levels are present in PeriMW. The cardiovascular and catecholamine response to clonidine in PeriMW both before and during estrogen therapy are similar to those observed in PreMW, suggesting a normal inhibitory alpha-2 receptor pathway.

Plasma catecholamines after thyrotropin-releasing hormone administration in hypothyroid patients before and during therapy.

In order to investigate sympathoadrenal activity in hypothyroidism we studied the cardiovascular and catecholamine responses to thyrotropin-releasing hormone (TRH) infusion in nine hypothyroid patients before and during adequate therapy and in seven healthy subjects. We evaluated mean arterial pressure, heart rate, plasma epinephrine and norepinephrine levels after TRH administration (200 micrograms iv) in the three groups. Mean arterial pressure, heart rate and plasma epinephrine levels were not different in the three groups and did not change after TRH administration. Hypothyroid subjects showed increased plasma norepinephrine levels (1.48 +/- 0.15 nmol/l), which were reduced after euthyroidism was reached (0.84 +/- 0.11 nmol/l) (p < 0.01). An exaggerated response of norepinephrine to TRH was observed in hypothyroid patients before therapy (incremental peak (IP) = 0.59 +/- 0.13 nmol/l) but not in hypothyroid patients during therapy (IP = 0.19 +/- 0.02 nmol/l p < 0.02) or in the control group (IP = 0.15 +/- 0.04 nmol/l; p < 0.05). This study indicated that TRH administration is able to influence the sympathetic activity during hypothyroidism in humans.

Alpha 2-adrenergic activity is normal in patients with thyroid disease.

OBJECTIVE: Several studies indicate an inverse relationship between the sympathetic nervous system activity and thyroid function. Altered adrenoceptor sensitivity, particularly alpha 1 and beta, have been described in hypothyroid and hyperthyroid patients. No information in patients with thyroid disease is available on the main mechanism regulating sympathetic nervous system outflow, i.e. the alpha 2-adrenoceptor pathway. In our study we evaluated alpha 2-adrenergic activity in patients with thyroid disease by the assessment of cardiovascular and catecholamine response to clonidine, a central alpha 2 adrenergic agonist. PATIENTS: Ten patients with hypothyroidism, six patients with hyperthyroidism before and during adequate therapy, and ten healthy subjects. MEASUREMENTS: After three blood samples for the basal determination of noradrenaline and adrenaline, the subjects swallowed 4 micrograms/kg body weight of clonidine. Blood pressure and pulse rate were measured 30, 60, 90, 120, 130 and 140 minutes after clonidine administration; blood samples for determination of catecholamines were drawn at 120, 130 and 140 minutes. RESULTS: At presentation the decrease in plasma noradrenaline after clonidine in the patients was similar to that of the control group (hypothyroids: 1.07 +/- 0.23 nmol/l mean +/- SEM; hyperthyroids: 0.54 +/- 0.06 nmol/l; controls; 0.36 +/- 0.10 nmol/l; F = 1.2, P = NS). No differences were detected in the fall in adrenaline and mean arterial pressure (MAP) after clonidine. The adequate therapy induced in hypothyroid patients a decrease in the basal levels of noradrenaline (1.88 +/- 0.28 vs 0.67 +/- 0.10 nmol/l; P < 0.05) and a lesser fall in mean arterial pressure after clonidine (delta MAP 20.4 +/- 2.0 vs 9.7 +/- 2.8 mmHg; P < 0.05). No variations were detected in hyperthyroid patients after therapy either in basal hormones levels or in the magnitude of decrement in MAP and noradrenaline induced by clonidine. CONCLUSIONS: We conclude that in spite of the previously reported abnormalities in alpha 1 and beta-adrenergic receptor activity, the inhibitory alpha 2-receptor pathway is normal in patients with altered thyroid function.