Egon Werle

Cerebrospinal fluid Aβ42 is increased early in sporadic Alzheimer's disease and declines with disease progression

All mutations known to cause familial Alzheimers disease (AD) act by increasing the levels of soluble β‐amyloid peptide (Aβ), especially the longer form, Aβ42. However, in vivo elevation of soluble Aβ in sporadic AD has so far not been shown. In the present study, we used enzyme‐linked immunosorbent assays specific for Aβ42 and Aβ40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of Aβ42 and Aβ40 during disease progression. We also evaluated three other groups—one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that Aβ42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, Aβ40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of Aβ42 than the healthy control group, implying that Aβ42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of Aβ42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics. Ann Neurol 1999;45:504–511

Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: Clinical and biochemical studies

We performed a case-control study to investigate the role of recent infection as stroke risk factor and to identify pathogenetic pathways linking infection and stroke. We examined 166 consecutive patients with acute cerebrovascular ischemia and 166 patients hospitalized for nonvascular and noninflammatory neurologic diseases. Control subjects were individually matched to patients for sex, age, and season of admission. We assessed special biochemical parameters in subgroups of stroke patients with and without recent infection (n = 21) who were similar with respect to demographic and clinical parameters. Infection within the preceding week was a risk factor for cerebrovascular ischemia in univariate (odds ratio [OR] 3.1; 95% confidence interval (CI), 1.57 to 6.1) and age-adjusted multiple logistic regression analysis (OR 2.9; 95% CI, 1.31 to 6.4). The OR of recent infection and age were inversely related. Both bacterial and viral infection contributed to increased risk. Infection elevated the risk for cardioembolism and tended to increase the risk for arterioarterial embolism. Stroke patients with and without preceding infection were not different with respect to factor VII and factor VIII activity, fibrin monomer, fibrin D-dimer, von Willebrand factor, C4b-binding protein, protein S, anticardiolipin antibodies, interleukin-1 receptor antagonist, soluble tumor necrosis factor-α receptor, interleukin-6, interleukin-8, and neopterin. In conclusion, recent infection is an independent risk factor for acute cerebrovascular ischemia. Its role appears to be more important in younger age groups. The pathogenetic linkage between infection and stroke is still insufficiently understood.

Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension.

Asymmetrical dimethyl-l-arginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. We hypothesized that plasma levels of ADMA could be increased in patients with congenital heart disease and pulmonary hypertension. Cardiac catheterization was performed in 20 children and young adults with congenital heart disease with a median age of 10 years (range, 4 months to 33 years). The patients were assigned to group I (high flow, low pressure; n = 14) when Qp/Qs was 1.5 or greater and the mean PAP was less than 25 mm Hg or to group II (high pressure, high resistance; n = 6) when the mean PAP was greater than 25 mm Hg and Rp/Rs was greater than 0.3. Blood samples were taken from pulmonary vein or left ventricle. ADMA was measured by high-performance liquid chromatography. In addition, levels of ADMA were measured in peripheral venous blood obtained from eight control patients. Levels of ADMA in control patients (median, 0.21 &mgr;M/l; range, 0.08–0.27 &mgr;M/l) did not differ from levels obtained in group I (median, 0.30 &mgr;M/l; range, 0.06–0.49) &mgr;M/l). Patients in group II showed increased plasma levels of ADMA (median, 0.55; range, 0.25–0.79) (p < 0.01). Inhibition of nitric oxide synthase by increased levels of ADMA might contribute to pulmonary hypertension in patients with congenital heart disease.

The association of leukocyte count, fibrinogen and c-reactive protein with vascular risk factors and ischemic vascular diseases

In 154 subjects (age 63 +/- 11 years; 63 women and 91 men) randomly selected from the population, we tested the hypothesis that inflammatory parameters are associated with vascular risk factors and particularly with a history of ischemic vascular diseases. The subjects were part of the control group (n = 197) in a case-control study investigating recent infection as a risk factor for acute cerebrovascular ischemia and had been matched for sex and age with patients suffering from acute ischemic stroke or transient ischemic attack. Subjects with malignant or inflammatory diseases, with recent trauma, surgery or vascular diseases (n = 43) were excluded from the present analysis. In multivariate analysis, current smoking, diabetes mellitus, age > or = 65 years, and a history of stroke independently increased the leukocyte count. Hypertriglyceridemia, peripheral arterial disease, and diabetes mellitus were positively associated with C -reactive protein (CRP). Age > or = 65 years and diabetes mellitus independently increased fibrinogen. (p < 0.05, respectively) Subjects with a history of cerebrovascular, cardiovascular or peripheral arterial disease had higher leukocyte counts, fibrinogen and CRP than subjects without vascular risk factors and higher leukocytes and fibrinogen than subjects with one or more risk factors. Subjects under the age of 65 with vascular risk factors but without ischemic diseases had higher leukocyte count, fibrinogen and CRP and subjects older than 65 with risk factors had higher CRP than subjects without risk factors or ischemic diseases in the same age group. (p < 0.05, respectively) These results support the hypotheses that low-grade inflammation is associated with vascular risk factors and that inflammatory mechanisms may contribute to the risk of organ ischemia.

Clinical and Biochemical Analysis in Infection-Associated Stroke

BACKGROUND AND PURPOSE Currently, recent infection (primarily bacterial infection) is discussed as a risk factor for cerebrovascular ischemia. The aim of this study was to investigate whether the association of ischemic stroke with recent infection is restricted to stroke subtypes and whether recent infection influences the severity of the postischemic deficit; we also aimed to define biochemical pathways linking infection and ischemic stroke. METHODS Analyzing the data of a prospective case-control study, we classified the etiology of cerebrovascular ischemia on the basis of clinical, neuroradiological, sonographical, cardiological, and biochemical data in 159 patients without and in 38 patients with infection within 1 week before ischemia. We assessed the severity of neurological deficits using the Scandinavian Stroke Scale. RESULTS In patients with recent infection compared with patients without infection, the neurological deficit on admission was more severe (median of scores, 41 versus 30.5; P < .005), cortical infarcts in the middle cerebral artery territory were more frequent (60% versus 26%; P < .001), the prevalence of extracranial artery stenoses was lower (9% versus 26%; P < .05), and definite or presumed cardioembolic stroke was more frequent (34% versus 19%; P < .05), as was stroke from cervical artery dissection (8% versus 1.3%; P = .05). Serum levels of C-reactive protein were higher in patients with (20.7 +/- 26.8 mg/L) than in those without infection (9.2 +/- 23.7 mg/L; P < .01). CONCLUSIONS Recent infection may be associated with a more severe postischemic deficit and with an increased risk of stroke from cardioembolic origin and from cervical arterial dissection.

Apolipoprotein E polymorphism and renal function in German type 1 and type 2 diabetic patients.

OBJECTIVE To examine the association of renal function in diabetic patients with apolipoprotein (apo) E polymorphism. RESEARCH DESIGN AND METHODS Apo E genotypes, lipid and lipoprotein serum levels, creatinine clearance (CCr), and excretion of marker proteins were determined in German type 1 (IDDM; n = 162) and type 2 (NIDDM; n = 124) diabetic patients. Albumin and immunoglobulin (Ig) G are considered to reflect charge-size permselectivity of the glomerular capillary basement membrane, and increased alpha 1-microglobulin (MG) excretion indicates compromised reabsorptive capacity of the renal tubules. RESULTS Patients with NIDDM had higher lipid levels and lower CCrs than patients with IDDM. In patients with IDDM, age- and sex-adjusted analysis of variance showed an association between apo E genotypes and CCr, and the Jonckheere-Terpstra test demonstrated a decreasing glomerular filtration rate in the following order of genotypes: ε4ε4/ε4ε3 > ε3ε3 > ε2ε2/ε2ε3. Multiple linear regression analyses revealed that in patients with IDDM, the ε2 allele was a negative predictor of CCr and a positive predictor of urinary excretion of albumin, IgG and α 1-MG independent from HDL and LDL cholesterol, TG concentration, age, and sex. CONCLUSIONS Apo E polymorphism influences serum lipoprotein levels in patients with IDDM and NIDDM. Apo E polymorphism may be a renal risk factor of clinical relevance in normolipidemic patients with IDDM.

Cerebrospinal fluid tau levels in Alzheimer's disease are elevated when compared with vascular dementia but do not correlate with measures of cerebral atrophy

Increased tau levels are a well-established finding in Alzheimers disease (AD). In contrast, the potential value of tau levels in the differential diagnosis of AD, vascular dementia (VD) and major depression warrants further investigation. The potential impact of psychotropic medication also needs to be established. We investigated cerebrospinal fluid (CSF) tau protein concentrations in 88 patients with AD, 23 patients with VD, 25 patients with major depression and 17 age-paralleled controls without cognitive impairment with respect to important clinical variables, type and dosage of psychotropic medication and cerebral changes as assessed by magnetic resonance imaging (MRI). The AD patients showed significantly elevated tau levels compared with patients with VD or major depression and controls. Tau levels obtained in the VD group were intermediate, with significant differences from both AD patients and patients with major depression and controls. Within the AD group, no significant correlation between tau levels, severity of dementia, age, duration of disease, type and dosage of psychotropic medication or MRI volumetric changes arose. A subgroup of AD patients without increased tau levels was characterized by a significantly larger percentage of patients with presenile onset.

Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients

Abstract Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for vascular diseases. There are no data on Lp(a) levels in patients on long-term medication with carbamazepine, phenytoin, phenobarbital, or valproate. To investigate the effects of such treatment on Lp(a) levels and common carotid artery intima media thickness we studied 51 epileptic outpatients on long-term antiepileptic medication and 51 age- and sex-matched controls. Lp(a) levels above 45 mg/dl were found in 11 of 50 patients, but in only 4 of 51 controls (P<0.05). The mean serum concentration of Lp(a) was 33.0±7.0 mg/dl in patients and 16.9±2.7 mg/dl in controls (P<0.05). Epileptic patients also had a thicker intima media of the common carotid artery (0.79±0.04 mm) than controls (0.69±0.02 mm, P<0.05) as measured by B-mode ultrasonography. Our results suggest an untoward effect of long-term antiepileptic medication on Lp(a) serum concentrations. Elevated Lp(a) levels might be a risk factor for arteriosclerosis in epileptic patients.

Monocyte function and plasma levels of interleukin-8 in acute ischemic stroke.

Activated monocytes may contribute to the pathogenesis of ischemic stroke. We tested the hypothesis that release products and procoagulant activity of monocytes are increased in acute ischemic stroke. In patients on days 1, 3 and 7 after ischemic stroke and in age- and sex-matched healthy control subjects, we assessed plasma levels of interleukin 8 (IL-8) and neopterin (enzyme linked immunosorbent assay, ELISA) and investigated superoxidanion release (ferricytochrome C reduction), procoagulant activity (one-stage clotting assay) and tissue factor (TF) gene transcription (reverse transcriptase polymerase chain reaction) by monocytes. As compared to control subjects (n=23), IL-8 levels were increased on day 1 after stroke (n=22; p=0.005) and remained elevated on days 3 and 7. Neopterin levels were elevated on days 3 and 7 (p<0.05, respectively) but not on day 1. Neopterin and IL-8 were not correlated with monocyte counts. Superoxid anion production by stimulated and unstimulated monocytes was not different between groups. TF mRNA could neither be detected in monocytes from patients investigated within 12 h after ischemia (n=12) nor in control subjects (n=10) and procoagulant activity of cells was similar in both groups. Our results indicate increased monocyte activation after ischemic stroke although not all activation parameters were elevated. We found no support for the hypothesis that circulating monocytes express TF and possess increased procoagulant activity. Elevated IL-8 may contribute to stroke pathophysiology by activating polymorphonuclear leukocyte (PMNL) activation early after ischemia.

Decrease in rat cardiac beta1- and beta2-adrenoceptors by training and endurance exercise

The cardiac beta-adrenoceptor adaptation to physical activity was investigated in rats which were subjected to a six-week endurance swimming training (ET; n = 7) and a training of high intensity (MT; n = 7). In addition, the effect of a single bout of endurance exercise without preceding training (EE; n = 7) was evaluated. These groups were compared with a sedentary control group (C; n = 9). Beta-adrenergic receptors in rat myocardial membranes were labelled using the high affinity antagonist radioligand (-)125iodocyanopindolol (ICYP). Computer modelling techniques provided estimates of the maximal binding capacity (Bmax) and the dissociation constants (KD). Tissue was constantly kept at temperatures of less than or equal to 4 degrees C and incubated at 4 degrees C for 18 h in buffer containing 100 microM GTP so as to prevent masking of beta-adrenoceptors by endogenous norepinephrine. In comparison with the C group (Bmax = 43.2 +/- 1.6 fmol/mg protein, KD = 11.7 +/- 1.5 pM) computerized coanalyses of saturation binding data of ET, MT, and EE revealed a 13.0%, 25.5%, and 16.6% decrease in Bmax (P less than 0.01), respectively, without significantly differing KD values (10.6 pM, 9.0 pM, 10.5 pM, respectively). We provide the first evidence that acute exercise lowers the sarcolemmal beta-adrenoceptor number in the rat heart. In the competition radioligand binding, CGP20712A and ICI118.551 were employed as subtype-selective antagonists of beta 1- and beta 2-adrenoceptors, respectively, to determine the relative proportions of the receptor subtypes. The ratio of beta 1-/beta 2-adrenoceptors in C was 67.5:32.5 and no statistically significant variation occurred in animals subjected to physical activity. On the basis of published data we assume that acute exercise induces a sequestration of beta-adrenoceptors from the cell surface to some intracellular compartment, whereas the molecular basis of the chronic beta-adrenoceptor down-regulation may involve a training-induced reduction in receptor synthesis. Our findings on cardiac beta-adrenoceptor adaptation to physical activity may represent one of the mechanisms underlying the relative bradycardia in trained subjects.