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.

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.

Evaluation of the secretory pattern of plasma arginine vasopressin in stroke patients.

Arginine vasopressin (AVP) may play a role in the development of ischemic brain edema and/or cerebral vasospasm. Data available on AVP plasma levels in ischemic stroke are few and discordant. In order to ascertain whether changes in AVP plasma levels occur in ischemic stroke, plasma AVP levels, plasma osmolality and mean arterial pressure were determined in 24 patients with unprecedented ischemic cerebral infarction and in 15 controls over a 24-hour period. In stroke patients, mean 24-hour plasma AVP levels (7.2 +/- 0.8 ng/l) were higher (p < 0.05) than in control subjects (2.4 +/- 0.3 ng/l), and correlated with the severity score of the neurologic deficit and the mean size of the lesion. In patients with a more severe neurologic deficit, the mean 24-hour plasma AVP levels (8.7 +/- 1.0 ng/l) were higher than in patients with a less severe neurologic deficit (5.2 +/- 0.8 ng/l). Data indicate that in ischemic stroke an increased AVP secretion occurs independently of osmotic or baroreceptorial mechanisms. The possibility that AVP may play a role in neuronal cell damage following cerebral ischemia warrants further attention.

Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis.

BACKGROUND/AIM: Serum levels of leptin, the adipocyte-derived hormone regulating food intake and energy expenditure in mammals, have been found to be increased in cirrhotic patients. The aim of the present study was to investigate leptin serum level in relation to anthropometric features and liver function in patients with viral chronic hepatitis or liver cirrhosis. METHODS: Serum leptin levels were determined by radioimmunoassay in 30 male and 10 female patients with chronic hepatitis, in 42 male and 10 female patients with liver cirrhosis, and in four respective control groups. Liver function was evaluated by the monoethylglycinexylidide formation test. Body mass index and body fat mass were estimated by weight, height and skinfold thickness measurements. RESULTS: Compared with controls, absolute serum leptin levels were significantly (p<0.01) lower in chronic hepatitis patients and similar in cirrhotic patients. Leptin serum levels were significantly (p<0.05) higher in cirrhotic than in chronic hepatitis patients. When expressed in relation to body fat mass, the above differences persisted; however, cirrhotic females showed significantly (p<0.05) higher serum leptin values than controls. Serum leptin values correlated negatively (p<0.01) with monoethylglycinexylidide serum values in all groups of patients. CONCLUSIONS: In patients with chronic viral liver disease, serum leptin levels tend to increase as liver function worsens. This may reflect a decline in the ability to downregulate energy expenditure as an adaptation to anorexia and/or to defective substrate utilisation due to liver disease and may negatively influence body weight homeostasis in these patients.

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.

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.

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.

Inter-organ leptin exchange in humans.

To assess the individual role of splanchnic organs, kidney, and peripheral tissues on leptin metabolism, leptin exchange across the splanchnic bed, kidney, and leg has been evaluated by the arterio-venous technique in post-absorptive non-obese subjects. Leptin levels in the hepatic and renal veins were significantly lower (p < 0.001), while femoral vein levels were consistently greater (p < 0.05) than in the artery. The fractional extraction of leptin, namely the percentage of arterial leptin extracted, was greater in splanchnic organs (16%) than in the kidney (9.5%). Urinary excretion of leptin was undetectable in most subjects, indicating that leptin is degraded within the kidney. There was no correlation between fractional extraction of leptin and glomerular filtration rate, whereas leptin fractional extraction was directly related to renal plasma flow (p = 0.017). Renal leptin clearance was about 50% of the glomerular filtration rate. Our data demonstrate that both splanchnic organs and the kidney cooperate in the disposal of leptin, while peripheral tissues add significant amounts of leptin to the circulation. In non-obese subjects the contribution of the kidney to whole body clearance is no more than 50%. The removal of leptin by the kidney depends on renal plasma flow but not on glomerular filtration rate or filtered leptin.

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.

Evaluation of beta-endorphin secretion in patients suffering from episodic cluster headache.

In order to obtain data regarding peripheral levels of beta-endorphin in head pain syndromes, we evaluated the plasma beta-endorphin secretory pattern in 12 adult male patients suffering from cluster headache. Blood samples were drawn every 2 hours for a 24-hour period, and in addition at 30-minute intervals for 120 minutes during cluster attacks. The same sampling was repeated during an asymptomatic period. Cluster headache patients showed no significant beta-endorphin circadian rhythm and a delayed acrophase during cluster periods compared with that recorded in the remission period and in normal subjects. Eighteen cluster headache attacks were recorded during the study day, 13 (72%) of which were followed by a significant increase in beta-endorphin levels. No correlation was found between beta-endorphin maximum net increase and intensity and/or duration of pain. These data suggest the hypothesis of a temporary alteration of beta-endorphin circadian secretion, probably related to involvement of neural structures controlling biorhythm pacemakers.

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.

Raised plasma arginine vasopressin concentrations during cluster headache attacks.

To obtain data about peripheral concentrations of arginine vasopressin in head pain syndromes, the plasma arginine vasopressin secretory pattern in 12 adult male patients with cluster headache was evaluated. Blood samples for plasma arginine vasopressin and osmolality determinations were collected before, and at 15, 30, 45, 60, 90, and 120 minutes during a cluster attack. Blood pressure was also monitored. The same sampling was repeated during an asymptomatic period. During cluster attacks, the mean values of plasma arginine vasopressin before an attack (2.3 (0.1) ng/l) significantly increased, reaching their peak at 45 minutes (4.8 (0.5) ng/l; P < 0.01 v baseline). No significant variations were found in mean arterial pressure and plasma osmolality. These data suggested involvement of neurotransmitter mechanisms regulating arginine vasopressin secretion and a possible role of arginine vasopressin in vasomotor phenomena accompanying cluster attacks.

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.

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.

Twenty-four-hour beta-endorphin secretory pattern in stroke patients.

BACKGROUND AND PURPOSE: Abnormalities of hypothalamo-pituitary-adrenocortical axis function have been observed frequently in stroke patients. The aim of this study was to investigate plasma beta-endorphin and cortisol 24-hour secretory patterns in patients early after stroke and in the convalescent period to evaluate a possible influence of brain damage on hormonal circadian pattern. METHODS: Patients (n = 15; age, 46 to 75 years) were evaluated in the first 24 hours and 10 days after hospital admission for ischemic cerebral stroke and compared with 15 age- and sex-matched normal subjects. Blood samples for beta-endorphin and cortisol determination were drawn every 4 hours from 8 AM to 8 PM and every 2 hours from midnight to 6 AM. RESULTS: Mean 24-hour beta-endorphin and cortisol levels, recorded in the acute phase, were significantly (P < .05) higher than those recorded in normal subjects; circadian rhythm was not demonstrable for either hormone. In the convalescent period, plasma cortisol 24-hour mean values and circadian rhythm returned to the normal range, whereas the plasma beta-endorphin 24-hour mean values and circadian rhythm did not. CONCLUSIONS: Cerebral stroke induces abnormalities of beta-endorphin and cortisol circadian secretion. Whereas cortisol abnormalities are transient, those of beta-endorphin last longer. The dissociation between beta-endorphin and cortisol 24-hour secretory patterns might potentially serve as a marker of psychoneurological abnormalities occurring after stroke.

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.

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.

Sex hormones and sex hormone-binding globulin in males with chronic viral hepatitis during recombinant interferon-alpha 2b therapy.

The effect of long-term treatment with recombinant interferon-alpha 2b (IFN-alpha 2b) on luteinizing hormone (LH), testosterone, free testosterone, and sex hormone-binding globulin (SHBG) was evaluated in 7 male patients suffering from chronic viral hepatitis. The drug was given three times a week for 6 months in a single standard dose of 3 x 10(6) units. Hormone evaluations were performed in basal conditions and every 2 months for 12 months. Serum testosterone values decreased after IFN treatment, reaching the lowest levels at the 6th month. However, testosterone values did not fall below the normal range. Serum SHBG concentrations, which were above the normal range in basal conditions, also decreased after IFN. Serum-free testosterone and LH concentrations did not change during IFN therapy. IFN-alpha 2b at the dose and schedule employed was not responsible for any measurable imbalance in male sex hormones.

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.

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.