Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI).

BACKGROUND: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aß) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aß species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results. METHODS: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aß40 and Aß42 peptides. The association between Aß40 and Aß42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aß levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aß plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis. RESULTS: FBB-PET global SUVR correlated weakly but significantly with Aß42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aß measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aß FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aß measurements (p value for interaction = 0.105). CONCLUSION: Brain and plasma Aß levels are partially correlated in individuals diagnosed with SCD. Aß plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

[Therapeutic effect of Olea europea var. oleaster leaves on carbohydrate and lipid metabolism in obese and prediabetic sand rats (Psammomys obesus)]. / Effet thérapeutique des feuilles d'Olea europea var. oleaster sur le métabolisme glucido-lipidique chez le rat des sables (Psammomys obesus) obèse prédiabétique.

Sand rats develop obesity, insulin-resistance, hyperlipidemia and prediabetes, when given a standard laboratory chow diet. We have used this model to demonstrate the beneficial action of olea europea var. oleaster leaves to regulate unbalanced metabolism. 32 sand rats fed on hypercaloric diet during 7 months, were divided into 3 groups: controls (n=10), treated by plant (n=13) and treated by simvastatin (Zoco); hypocholesterolemic drug. The plant decoction prepared at 10% was given orally at the rate of 1.5 ml/100g during 3 months. Results show that the plant presents a hypocholesterolemic effect (42%) related to decreases in LDL and VLDL cholesterol. In addition, hypoglycemic (16%) and antihyperglycemic (40%) effects were observed accompanied by a 27% decrease in insulin. Chronic treatment with Zocor reduced total cholesterol (32%), LDL and VLDL cholesterol. Both of treatments produced no significantly reduction in plasma levels of triglycerides and HDL cholesterol. No noxions effect of this plant have been observed in usual doses.

New model of atherosclerosis in insulin resistant sand rats: hypercholesterolemia combined with D2 vitamin.

To overcome the sand rats' resistance to cholesterol induced atherosclerosis, animals were given D2 vitamin at 2000 IU/rat per day associated with cholesterol-enriched diet for 45 days, following 45 days of high cholesterol diet alone. At days 0, 45 and 90, plasma parameters, aortic and heart morphology were examined. Other animals receiving a high cholesterol diet alone were used as a control group. Results showed at day 45 severe hypercholesterolemia, elevated plasma LDL and VLDL-cholesterol, oxidized LDL and calcium levels, a rise of lecithin cholesterol acyl transferase activity and moderate hyperinsulinemia. Lesions were characterized by widening of the first interlamellar spaces in the aorta, fibrosis of coronary arterial wall and recent foci of myocardial fibrosis. At day 90, plasma calcium level decreased and oxidized LDL were more enhanced. Insulin resistance development was associated with glucose intolerance and hyperinsulinemia. The D2 vitamin administration induced advanced atherosclerotic lesions in arterial wall, represented by the rupture of elastic lamellae, smooth muscle cell proliferation and lipid-calcic core. The complicated plaque frequently evolved into ulcerations. The ischaemic effects were represented by acute myocardial infarction. D2 vitamin is an atherogenic agent which, when associated with hypercholesterolemia, allows the development of advanced atherosclerotic lesions in sand rat which resembles human plaque.

New model of atherosclerosis in sand rats subjected to a high cholesterol diet and vitamin D2.

In order to defeat the atheroresistance in sand rats, 25 animals were given a high cholesterol diet for 45 days, which was then associated with oral treatment with vitamin D2 2000 IU/day for a further 45 days. At days 0, 45 and 90, plasma parameters, and aortic and heart morphology were examined. Results showed at D45 hypercholesterolaemia, increased plasma LDL and VLDL cholesterol, oxidized LDL, triglycerides, free fatty acids (FFA) and calcium levels and moderate hyperinsulinaemia. At D90, plasma-oxidized LDL and FFA were more enhanced, whereas calcium level was reduced. Development of hyperglycaemia was associated with hyperinsulinaemia and insulin resistance. The vitamin D2 administration induced advanced lesions, represented by the degenerescence of elastic lamina, smooth muscle cell proliferation and lipid calcic plaque at an ulcerated stage in most cases. The ischaemic effects were represented by acute myocardial infarction. The potential of the sand rat to develop atherosclerotic lesions at different stages opens the field to therapeutic tests of new anti-atherogenic agents.

Effect of Suaeda fruticosa aqueous extract in the hypercholesterolaemic and insulin-resistant sand rat.

To study the effect of Suaeda fruticosa in lipid and carbohydrate metabolism in the hypercholesterolaemic and insulin resistant sand rat, 25 rats were subjected to a high cholesterol diet for 90 days. On the 45th day the animals were divided into two groups: control and treated. Aqueous extract prepared in infusion at 10 per cent was administered orally at 1.5 ml per 100 g of body weight per day. On the 90th day, the control group developed a severe hyperlipidaemia, impaired glucose tolerance test and insulin resistance. Treatment by Suaeda fruticosa extract showed hypoglycaemic (41 per cent) and antihyperglycaemic (53 per cent) effects. Furthermore, the plant led to a decrease in plasma levels of insulin (31 per cent), total cholesterol (50 per cent), LDL cholesterol (55 per cent), VLDL cholesterol (49 per cent), oxidized LDL (40 per cent), lecithin cholesterol acyl transferase (44 per cent), triglycerides (57 per cent) and free fatty acids (36 per cent). We concluded that Suaeda fruticosa aqueous extract contains at least two compounds responsible for hypoglycaemic and hypolipidaemic activities.

Effects of Olea europea var. oleaster leaves in hypercholesterolemic insulin-resistant sand rats.

Sand rats fed a hypercaloric diet manifest obesity and diabetes. We have used this model to develop hypercholesterolaemia and describe the beneficial action of Olea europea var. oleaster leaves. Twenty-eight sand rats submitted to a high cholesterol diet for four months were assigned to control and treated groups. Plant decoction at 10 per cent was given orally for two months. Results showed that the control group exhibited hyperglycaemia, glucose intolerance, hypercholesterolaemia and moderate hyperinsulinaemia. Light microscopic study showed thickening of capillary walls in skin, pancreas and kidney. The treatment produced hypoglycaemic (43 per cent, p < 0.001), antihyperglycaemic (48 per cent, p < 0.001) and hypoinsulinaemic (39 per cent, p < 0.01) activities. In addition, the plant presented a hypocholesterolaemic effect (47 per cent, p < 0.001) accompanied by lowering of oxidized LDL (30 per cent, p < 0.01). Accordingly, capillary wall thickening was reduced in skin and pancreas and completely prevented in kidney. The data demonstrate that oleaster leaves possess at least two active compounds to treat hypercholesterolaemia and diabetes.

Metabolic and anti-atherogenic effects of long-term benfluorex in dyslipidemic insulin-resistant sand rats (Psammomys obesus).

Benfluorex is a clinical lipid-lowering agent with antihyperglycemic properties. The effect of long-term oral treatment (10 mg/kg/day for 7.5 months) on carbohydrate and lipid metabolism and aortic morphology was investigated in 24 insulin-resistant sand rats receiving a standard laboratory diet supplemented with cholesterol (2%). Untreated controls (n=34) developed impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and elevated plasma LDL- and VLDL-cholesterol, positively correlated with the proportion of the thoracic aorta displaying oil red O-positive atherosclerosis; ultrastructural examination showed intimal lipid deposits, foam cells, polymorph infiltrates and fibrosis. Benfluorex-treated animals showed significant decreases in glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and plasma LDL- and VLDL-cholesterol, with no evidence of aortic atheroma. The metabolic benefits of benfluorex may protect against the long-term development of atherosclerosis in the insulin-resistant dyslipidemic syndrome.

S 15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus. Effect on pancreatic islets of insulin resistant animals.

A histological study has been conducted on pancreata from insulin resistant sand rats treated with S15261. As previously shown, standard laboratory chow induced dietary hyperinsulinaemia, insulin resistance and hyperlipaemia in sand rats (Psammomys obesus). Degranulation, vacuolization and even necrosis of beta-cells were observed in these animals. These changes were often accompanied by fibrosis and lymphocytic infiltration. Insulin and amylin immuno-reactivity of beta-cells was markedly decreased whilst glucagon secreting cells were localized now in the centre of the islets. Chronic treatment with S15261, a compound able to restore insulin sensitivity in insulin resistant animals, promoted the regranulation of the beta-cells and maintained the usual cytoarchitecture and integrity of the islets.

S15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus.

S15261 is a novel compound that has been proposed for the treatment of insulin resistance syndrome. We have studied the effects of this drug in insulin resistant sand rats (Psammomys obesus). When sand rats are transferred from their natural desert environment and placed on a laboratory chow diet, they become overweight, develop hypertriglyceridaemia, hypercholesterolaemia, become insulin resistant, and ultimately diabetic. In the present study glucose intolerant animals, with very mild if any hyperglycaemia were used. Chronic treatment for a month with S15261 normalised plasma levels of triglycerides and cholesterol. The effects on cholesterol were the result of a decrease in LDL- and VLDL-cholesterol without any modification of HDL-cholesterol. In this study only female sand rats showed elevated plasma glucose levels, which were normalised by S15261. The compound also decreased plasma insulin levels both in male and female sand rats. An oral glucose tolerance test showed a major improvement in glucose tolerance in both male and female animals treated with S15261. These data confirm in another animal model the therapeutic benefits of S15261 in insulin resistant states.

Prevention of preatheromatous lesions in sand rats by treatment with a nutritional supplement.

Sand rats fed a hypercholesterolaemic diet containing 0.01% of the anti-thyroid agent 2-mercapto-1-imidazole develop preatheromatous lesions similar to those found in humans, in addition to obesity and insulin resistance. The effects of a nutritional supplement rich in essential fatty acids and garlic extract (Arterodiet) on the appearance and evolution of the lesions were studied. Treatment with this nutritional supplement significantly decreased circulating triglycerides and low-density lipoprotein (LDL)-cholesterol levels but did not alter plasma insulin or glucose levels. Intra-arterial cholesterol levels were also decreased by the treatment which resulted in a normalisation of the atherosclerotic lesions in these animals.

Latent autoimmune diabetes mellitus in adult humans with non-insulin-dependent diabetes: is Psammomys obesus a suitable animal model?

Recent data suggest that in a proportion of NIDDM patients there is a slowly evolving insulitis which results in a latent autoimmune diabetes leading to full insulin-dependence. Many animal models exist of NIDDM but none have reported the spontaneous existence of a similar phenomenon. We have re-examined the histology of pancreata from a few Psammomys obesus who had become insulin-dependent in the late stages of NIDDM. We report here the unexpected finding of the presence of insulitis in these animals and suggest that they could be a model for the clinical observation of latent IDDM in NIDDM patients.

Islet amyloid polypeptide in Psammomys obesus: lack of correlation between insulin resistance and plasma IAPP levels.

Sand rats (Psammomys obesus) develop insulin resistance and diabetes when given a standard laboratory diet. We have examined the presence of islet amyloid polypeptide (IAPP), or amylin, in these animals. IAPP is present in the beta-cells of pancreatic islets, its localization and intensity of immuno-reactivity are, thus, similar to that of insulin. In insulin resistant Psammomys obesus, insulin and IAPP immuno-reactivity in pancreas are markedly decreased, plasma insulin levels are 20-fold higher than in controls but IAPP levels are not different from those of normal animals. Therefore, insulin resistance in Psammomys obesus does not appear to result from an elevated plasma IAPP level nor from development of amyloid deposits.

Development of macroangiopathy in sand rats (Psammomys obesus), an animal model of non-insulin-dependent diabetes mellitus: effect of gliclazide.

The risk of developing macroangiopathy associated with diabetes led us to study in sand rats the long-term consequences of non-insulin-dependent diabetes on the development of arterial lesions promoted by feeding a high-cholesterol diet. Gliclazide, an agent whose preventive effect has previously been suggested in other experimental models of atheroma, was also investigated in these diabetic and hypercholesterolemic animals. Sand rats were fed a natural diet (ND group), a standard laboratory feed (StD group), or a high-cholesterol feed (HCD group) for 15 months. Biologic parameters were monitored throughout the period of the study, and histologic and histochemical examinations were conducted when the animals were killed (month 15). One StD group and one HCD group were treated with gliclazide from month 3 to month 15. The StD group developed a syndrome of obesity, hyperglycemia, hyperinsulinemia, and triglyceridemia. The high cholesterol feed further increased hypercholesterolemia. These biologic abnormalities were accompanied by arterial lesions (thickening of the intima, deposition of glycosaminoglycans). Foam cells were seen in the intima, and microthrombi were present in the lumen of the arteries of animals in the HCD group. Long-term gliclazide medication at doses that normalized serum glucose levels also reduced the obesity, hyperinsulinemia, lipid disorders, and it prevented or retarded the appearance of arterial lesions.

Morphological characteristics of the endocrine pancreas in alloxan diabetes after cyclosporin A administration.

Histological, immunocytochemical, morphometric and electron microscope studies were carried out on the pancreas of alloxan diabetic rats pretreated with cyclosporin A. High mortality, severe destruction of pancreatic B-cells and presence of sporadic mononuclear infiltrations in islets and around excretory ducts were observed. The results obtained show that cyclosporin A potentiates the toxic effect of alloxan on the pancreatic B-cells.

Diabetes mellitus in sand rats (Psammomys obesus): microangiopathy during development of the diabetic syndrome.

The purpose of the study was to investigate the development of microangiopathic complications in North African sand rats with diabetes induced by a long-term standard laboratory diet. Hyperinsulinaemic rats, whether non-diabetic obese or diabetic, developed capillary basement membrane (CBM) thickening in the skin; in insulin-dependent animals, this change was diffuse. Many PAS positive areas were demonstrated in skeletal muscle and myocardium, together with evidence of microangiopathy; the primary myocardial lesion in insulin-dependent disease was ischaemic fibrosis. The kidney was also affected with marked basement membrane thickening in Bowman's capsule and glomerular capillaries; glomerulosclerosis and tubular changes were found in insulin-dependent disease. No evidence of diabetic retinopathy was found, and there was a high incidence of cataract.

Immunohistochemical investigations of the endocrine pancreas in normoglycemic sand rats (Psammomys obesus).

A morphological analysis of the endocrine pancreas in the normoglycemic sand rat (Psammomys obesus) has been carried out and the immunoreactivity for insulin, glucagon, somatostatin and pancreatic polypeptide (PP) studied. The islets of both parts of the pancreas (pancreatic head and tail) investigated were of the 'mantle' type: centrally located B-cells and A-, D- and PP-cells at the periphery. In the 'glucagon islets' (tail of pancreas) predominated the A-cells, while the PP-cells were more abundant in the "PP-islets' (head of the pancreas).

Diabetes mellitus in sand rats (Psammomys obesus). Metabolic pattern during development of the diabetic syndrome.

It has been reported that sand rats, naturally feeding on low-caloric-value plants containing a high concentration of salt, become obese and develop hyperglycemia when fed on a standard laboratory diet. The aim of this study was to examine the long-term effects of a synthetic-chow diet on the metabolic pattern of the diabetic syndrome in a large group of sand rats. While a few animals had a fulminant reaction with markedly decreased glucose tolerance, low plasma insulin levels, and death within 3-4 wk, most sand rats developed obesity and elevated plasma insulin levels. From the third month and forward, 40% of sand rats presented with a diabetic syndrome with hyperinsulinemia, hyperglycemia, markedly decreased glucose tolerance, and insulin resistance. This diabetic syndrome can be compared with maturity-onset (type II) diabetes. When this synthetic-chow diet was given for more than 6 mo, the majority of animals lost considerable weight and showed a major depletion of fat stores. Serum immunoreactive insulin levels fell, while blood glucose rose to above 500 mg/dl with glycosuria and ketonuria. The elevated triglyceride content of plasma and the lipid deposits in the liver were greatly augmented, and no glycogen was present. Animals developed frank insulin-dependent diabetes, and diabetic animals not treated with insulin died in diabetic coma with presumed ketoacidosis. The disease was essentially confined to sand rats showing abnormal glucose tolerance, even before eating laboratory chow. This observation suggests a genetic factor. Thus, the sand rat appears to be a potentially interesting model for investigation of both maturity-onset and insulin-dependent diabetes.

[Effects of insulin, somatomedin--a multiplication stimulating activity (MSA)--and transferrin, on the lipolysis of rat adipocytes in vitro]. / Effects de l'insuline, d'une somatomédine--facteur de multiplication cellulaire (MSA)--et de la transferrine, sur la lipolyse de l'adipocyte de rat in vitro.

Antilipolytic effect was researched when insulin (0.1 and 1 mIU/ml), MSA (200 and 500 ng/ml) and transferrin (2 and 5 micrograms/ml) were added to a suspension of freshly isolated rat adipocytes in vitro. Lipolysis was measured as glycerol secretion in the medium: micromoles/90 minutes/100 mg total lipids. Insulin (1 mIU/ml) reduced adrenalinic stimulation of lipolysis: A 1 microgram/ml (P less than 0.05). MSA 200 ng/ml had no effect. MSA 500 ng/ml reduced basal lipolysis and adrenalinic stimulation (P less than 0.05), and increased insulin-induced antilipolysis (P less than 0.05). Transferrin was active, only when insulin is present: antilipolysis increased (P less than 0.05).