Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Evaluation of anterior pituitary function in patients with posttraumatic diabetes insipidus.

Serum LH, FSH, TSH, PRL, GH, and cortisol were measured in 10 patients with posttraumatic diabetes insipidus both basally and after a combined insulin-induced hypoglycemia, LRH and TRH test. Two patients did not show hormonal abnormalities, while 8 patients had deficiencies of 1 or more hormones. The most frequent abnormality was GH deficiency (50%), followed by TSH (40%), ACTH (30%), FSH (30%0, and LH (20%). These results indicate that anterior pituitary dysfunction frequently accompanies posttraumatic diabetes insipidus.

Evaluation of twenty-four-hour secretory patterns of growth hormone and insulin in patients with myotonic dystrophy.

Twenty-four-hour secretory patterns of GH and insulin were evaluated in seven patients with myotonic dystrophy. We found an impairment of sleep-related GH secretion and an increase of nocturnal serum insulin levels. There was no correlation between hormonal behavior and severity of disease. It is possible that the observed hormonal dysfunction is related to a multisystem disorder in myotonic dystrophy.

The effects of sumatriptan on pituitary secretion in man.

Sumatriptan, a new antimigraine drug with high affinity and selectivity for certain 5-hydroxytryptamine (5-HT1D) receptor subtypes, was administered to 12 normal subjects, in order to investigate the effects of 5-HT receptor activation on anterior pituitary secretion. Sumatriptan increased plasma growth hormone (GH) levels from 2.5 +/- 0.5 mIU/l in basal conditions to 17.3 +/- 2.6 mIU/l 30 min after administration of the drug. After pre-treatment with cyproheptadine, an anti-serotoninergic drug known to inhibit GH secretion, the mean integrated sumatriptan-induced GH response decreased from 14.8 +/- 3.9 muI/l*hr to 3.7 +/- 1.7 mIU/l*hr. Sumatriptan administration did not have any effect on the secretion of the other anterior pituitary hormones. It is concluded that sumatriptan selectively increases GH secretion in man, but the exact nature of the receptors involved is not yet known.

Plasma somatostatin response to an oral test meal in liver transplant patients.

Ten liver transplant patients were studied in basal conditions and after ingestion of a standard mixed test meal. Control groups included 10 normal subjects, 10 patients with nonalcoholic liver cirrhosis, and seven kidney transplant patients. Plasma somatostatin, blood glucose, and plasma insulin, C-peptide, and glucagon were determined before and 15, 30, 45, 60, 90, 120, and 180 minutes after the start of the meal. In liver transplant patients, basal somatostatin and insulin levels were significantly lower than in cirrhotics and were comparable to those recorded in controls and in kidney transplant patients. The time course of the somatostatin secretory response after the meal was similar in any group, but the increase, evaluated as the incremental area above baseline, was significantly higher in liver transplant patients than in controls and cirrhotics and comparable to that recorded in kidney transplant patients. Insulin incremental areas were also lower than in cirrhotics and comparable to those recorded in controls and kidney transplant patients. The data suggest that in liver transplant patients an increased somatostatin response to a meal may be related to a relative beta-cell secretory defect, which in turn seems consequent to immunosuppressive treatment.

Twenty-four-hour variation in serum leptin in the elderly.

To investigate the possibility that the aging process may affect the diurnal variation in serum leptin in humans, serum leptin levels were measured by a sensitive radioimmunoassay method in 12 elderly (aged 72 to 87 years) and 10 middle-aged (35 to 50 years) lean male subjects. Fasting blood samples (4 mL) were drawn at 8:00 AM, and then every 4 hours until 10:00 PM and every 2 hours from 12:00 midnight to 8:00 AM of the next morning. Circadian rhythmicity analysis was performed using the cosinor method. In elderly subjects, serum leptin levels showed a significant diurnal rhythm, which was similar to that observed in controls. Single cosinor analysis showed a significant rhythm in eight of 12 elderly subjects and in all middle-aged subjects but one. Compared with middle-aged subjects, similar mesor mean values (7.8 +/- 1.0 v 8.1 +/- 0.8 ng/mL) but a decreased amplitude (1.4 +/- 0.3 v 2.3 +/- 0.2 ng/mL) and an earlier acrophase (11:56 PM v 2:04 AM) were observed in the elderly. The data demonstrate that the diurnal variation in serum leptin is generally preserved in the elderly. However, the amplitude of leptin diurnal excursion undergoes a reduction with advancing age. It can be speculated that the blunted diurnal variation in serum leptin observed in the elderly may result in an alteration of the afferent signal in the adipose tissue-central nervous system homeostatic loop.

Comparison of mezlocillin and carbenicillin as therapy for various infectious diseases.

The efficacy and safety of mezlocillin, a new broad-spectrum semisynthetic penicillin, were compared with those of carbenicillin in a nonblind, controlled clinical study in 89 adult patients. The infections treated were primarily those of the urinary tract, skin, and gastrointestinal or hepatobiliary tract. Escherichia coli, Proteus mirabilis, Proteus morganii, and Pseudomonas aeruginosa were the causative organisms isolated most frequently. A complete resolution of signs and symptoms was achieved in 78% of the mezlocillin patients and in 71% of the carbenicillin patients. In the mezlocillin group, causative organisms were eliminated in 80% of the courses, and in the carbenicillin group the elimination rate was 86%. Two adverse reactions, rash and diarrhea, were reported in mezlocillin-treated patients; none were reported for the carbenicillin group.

Oxidative stress in subjects affected by celiac disease.

In order to study the role of oxidative stress in celiac disease, protein carbonyl groups, thiobarbituric acid-reactive substance and pentosidine were evaluated in the plasma of nine patients with asymptomatic celiac disease and in a control group (n = 25). Plasma alpha-tocopherol, retinol and lipids were determined in the same samples. The levels of markers of oxidative stress derived from both protein (carbonyl groups) and lipids (thiobarbituric acid-reactive substances) were significantly higher in celiac disease patients, whereas lipoproteins and alpha-tocopherol were significantly lower. These data indicate that in celiac disease, even when asymptomatic, a redox imbalance persists; this is probably caused by an absorption deficiency, even if slight. Dietary supplementation with antioxidant molecules may offer some benefit and deserves further investigation.

Diurnal beta-endorphin changes in human cerebrospinal fluid.

Plasma and cerebrospinal fluid (CSF) beta-endorphin levels were determined by a RIA method in seven hydrocephalic male patients. The samples were simultaneously collected every two hours from 8 AM to 12 midnight and every hour from 1 AM to 7 AM. In both plasma and CSF beta-endorphin levels showed significant time-related variations during the 24 hour period. These results suggest the existence of diurnal CSF beta-endorphin variations analogous to those observed in plasma.

Variations of prolactin content in human cerebrospinal fluid after metoclopramide and morphine.

Serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations were determined in fourteen patients of both sexes suffering from hydrocephalus, in basal conditions and after i.m. administration of 10 mg metoclopramide or 10 mg morphine. A significant increase in both serum and CSF hormone values was found after administration of both drugs. Serum and CSF PRL values after metoclopramide administration increased earlier and to a greater extent than after morphine. Furthermore, the metoclopramide induced CSF PRL increase immediately followed the serum peak, whereas after morphine administration an evident delay in the CSF hormone peak with respect to the serum increase was found. These data suggest that PRL entry in the CSF compartment is subject to a controlling mechanism which acts at the blood/brain barrier.

Lichen planus induced by interferon-alpha-2a therapy for chronic active hepatitis C.

OBJECTIVE: To report the development of hepatitis C virus (HCV)-positive chronic active hepatitis with lichen planus in a patient during interferon treatment. DESIGN: Case report and literature review. PATIENT: A 64-year-old anti-HCV and HCV-RNA-positive woman. INTERVENTIONS: The patient received interferon-alpha-2a treatment for histologically proven chronic active hepatitis. RESULTS: Four months after the start of treatment the patient developed multiple cutaneous lesions on her hands, feet and back. A skin biopsy led to the diagnosis of lichen planus. The withdrawal of interferon was followed by a marked improvement in the cutaneous lesions, but not complete regression. CONCLUSION: This case shows that HCV-positive patients with chronic active hepatitis may develop lichen planus during interferon therapy.

Sumatriptan does not affect vasopressin secretion in humans.

The aim of the study was to investigate the effects of a new serotoninergic drug, sumatriptan, on arginine vasopressin secretion in humans. Plasma vasopressin concentrations were determined in eight healthy volunteers, before and after administration of 6 mg of sumatriptan, or placebo. No changes in hormone levels were found after sumatriptan or placebo administration. The results suggest that in humans serotoninergic mechanisms, which modulate vasopressin secretion, do not involve the serotonin receptor activated by sumatriptan.

Plasma beta-endorphin levels and glucose tolerance in patients with chronic renal failure.

In order to examine the role of endogenous opioid peptides on glucose metabolism in uraemic patients, plasma concentrations of beta-endorphin, glucose, insulin and C-peptide were determined before and during an oral glucose tolerance test (OGTT) in nine non-dialysed patients with chronic renal failure (CRF). The results are compared with those obtained in a group of age-matched normal subjects. In CRF patients, plasma beta-endorphin fasting values (16.0 +/- 1.9 pmol/l) were significantly higher than those of the controls (6.6 +/- 0.6 pmol/l) and significantly correlated with the degree of renal function impairment. After glucose load, plasma beta-endorphin in CRF patients tended to decline, whereas in normal subjects increased. The fasting and the mean OGTT plasma beta-endorphin values negatively correlated with insulin initial response to glucose, insulin and C-peptide mean OGTT values, but not with glucose OGTT mean values. Data indicate that chronic uraemia induces a significant increase in circulating plasma beta-endorphin levels, with a loss of opioid system responsiveness to glucose. The possibility that this hyper-endorphinism may have a biological importance at least as a contributory factor of impaired glucose tolerance in uraemia may be suggested.

Effect of the 5-HT3 receptor antagonist ondansetron on plasma AVP secretion: a study in cancer patients.

The aim of the present study was to investigate the effects of a serotonin subtype 3 receptor antagonist, ondansetron, on arginine vasopressin secretion in humans. Plasma vasopressin concentrations were determined in 24 breast cancer patients undergoing adjuvant chemotherapy, before and after ondansetron intravenous (i.v.) administration. Ondansetron (8 mg i.v. at time 0 and 8 mg po at time 240 min) was administered alone in 12 patients and afterwards in combination with chemotherapy in all patients. No changes in hormone levels were found after ondansetron alone and in 17 patients who did not claim nausea and/or emesis after chemotherapy. In seven patients who experienced nausea and /or emesis, vasopressin levels significantly (P < 0.01) increased (from 6.3 +/- 0.9 ng/L in basal conditions to 15.1 +/- 3.3 ng/L at 10 h; P < 0.05 vs baseline). The results suggest the possibility that in humans, serotoninergic mechanisms, which modulate vasopressin secretion, may involve the activation of the serotonin receptors recognised by ondansetron.

Somatostatin release in response to glucose is impaired in chronic renal failure.

In order to evaluate somatostatin (SRIH) secretion in uremia, plasma SRIH concentrations were determined in basal conditions and after an oral glucose tolerance test (OGTT) in 14 non-dialysed patients with chronic renal failure (CRF), seven of whom had normal glucose tolerance (NGT) and seven impaired glucose tolerance (IGT). Plasma insulin, C-peptide and glucagon and blood glucose concentrations were also evaluated. The results were compared with those obtained in a group of age- and sex-matched normal subjects. In CRF patients, plasma SRIH fasting values (8.6 +/- 0.6 and 7.8 +/- 0.6 pmol/L in NGT and IGT patients, respectively) were comparable to those recorded in controls (7.7 +/- 0.5 pmol/L). SRIH response to OGTT, evaluated as area under curves (AUC) above basal, was similar in both groups of CRF patients (412.9 +/- 84.5 and 415.6 +/- 51.9 pmol/L per min), and significantly lower than in controls (660.1 +/- 58.5 pmol/L per min). Data indicate that chronic uremia induces a loss of SRIH secretory cell responsiveness to glucose. A possible effect of impaired SRIH secretion on glucose metabolism in CRF is discussed.

Calcitonin and beta-endorphin secretion.

Calcitonin is a peptide hormone secreted by the C-cells of the thyroid gland. This hormone mainly acts in preventing bone resorption. Furthermore, calcitonin is involved in other biological actions, and in particular it is able to relieve pain independently of its peripheral effects on bone. Here, we examine the possible mechanisms of calcitonin-induced analgesia, with particular regard to the opioid system involvement. Several studies in animals and in humans demonstrate that calcitonin increases plasma beta-endorphin levels, acting at the hypothalamic and/or at the pituitary level, either directly or indirectly, through monoaminergic neurotransmitters. However, this calcitonin-induced beta-endorphin release has not always been observed. These different results are discussed, and a possible implication of sex and/or calcitonin dose employed has been examined. We conclude that the analgesic effects of calcitonin are multifactorial, and beta-endorphin plays its own specific role.

Twenty-four-hour endothelin-1 secretory pattern in stroke patients.

Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictor peptide, which may play a role in the pathophysiology of a number of diseases. Controversial data exist on its role in human ischemic stroke. In order to ascertain whether changes in ET-1 plasma levels occur in ischemic stroke, plasma ET-1 levels and mean arterial pressure were determined in 15 patients at their first ischemic cerebral infarction and in 15 control subjects, over a 24-hour period. In stroke patients, mean 24-hour plasma ET-1 levels (4.9+/-0.5 ng/L) were higher (P< 0.05) than in control subjects (3.2+/-0.3 ng/L), and correlated with the mean size of the lesion, but not with the severity score of the neurological deficit. These results support the hypothesis that ET-1 levels reflect an indicator function for the amount of damaged cerebral tissue rather than a pathophysiological role.

Long term therapy with recombinant interferon alpha 2 b in patients with chronic hepatitis C: effects on thyroid function and autoantibodies.

Twelve anti HCV-positive patients (8 males and 4 females; 37-62 yrs) suffering from chronic active viral hepatitis have been evaluated in order to determine serum thyroid hormones and autoantibody pattern during recombinant interferon alpha 2b (IFN-alpha 2b) therapy. The interferon was given subcutaneously three times per week for six months in a single standard dose of 3 MU. For a further six months 5 patients (Group A) received the same interferon at 1MU dose three times per week and 7 (Group B) had no treatment. Serum T3, T4, FT4, TBG, TSH, TGAb and TMAb were determined on serum collected before the start of the treatment and every month for 12 months thereafter. Except for one case, in which a transient reduction in thyroid hormone values and an increase in TSH levels was recorded, none of the patients studied showed a significant variation of serum hormonal parameters or appearance of pathological TGAb and/or TMAb levels. The data indicate that the administration of recombinant IFN-alpha 2b to HCV positive chronic active hepatitis patients at the dose and schedule employed in the present study may result in a reduction in the incidence of thyroid dysfunction related to the IFN therapy.

Pituitary hormone concentrations in cerebrospinal fluid in patients with prolactin and growth hormone-secreting tumors.

GH, PRL, LH, FSH and TSH were measured in serum and in cerebrospinal fluid (CSF) in 16 patients with chromophobe adenomas, in 8 with acromegaly and in 18 subjects with neurological diseases without endocrine troubles. Elevated mean GH and PRL levels in serum and in CSF were found in patients with chromophobe adenomas and with acromegaly. No constant correlation was observed between serum and CSF values. The highest hormonal levels in CSF were usually observed in adenomas with suprasellar extension, but this finding was inconstant. The determination of hormonal levels in CSF does not seem to supply any reliable information about the characteristics of pituitary tumors.

Changes of CSF prolactin induced by metoclopramide in man.

A sharp increase in serum and CSF prolactin (PRL) values after acute metoclopramide (10 mg i.m.) administration was found in six male patients without endocrine diseases. Peak values occurred simultaneously in serum and in CSF. This finding suggests the possibility that CSF PRL content depends also on the retrograde transport from pituitary gland.