Thomas Bertsch

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Recent epidemiological studies show a strong reduction in the incidence of Alzheimers disease in patients treated with cholesterol-lowering statins. Moreover, elevated Aβ42 levels and the ɛ4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimers disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Aβ42 and Aβ40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Aβ42 and Aβ40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimers disease. Lowered levels of Aβ42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.

Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.

BACKGROUND Only 2-5% of patients who have a stroke receive thrombolytic treatment, mainly because of delay in reaching the hospital. We aimed to assess the efficacy of a new approach of diagnosis and treatment starting at the emergency site, rather than after hospital arrival, in reducing delay in stroke therapy. METHODS We did a randomised single-centre controlled trial to compare the time from alarm (emergency call) to therapy decision between mobile stroke unit (MSU) and hospital intervention. For inclusion in our study patients needed to be aged 18-80 years and have one or more stroke symptoms that started within the previous 2·5 h. In accordance with our week-wise randomisation plan, patients received either prehospital stroke treatment in a specialised ambulance (equipped with a CT scanner, point-of-care laboratory, and telemedicine connection) or optimised conventional hospital-based stroke treatment (control group) with a 7 day follow-up. Allocation was not masked from patients and investigators. Our primary endpoint was time from alarm to therapy decision, which was analysed with the Mann-Whitney U test. Our secondary endpoints included times from alarm to end of CT and to end of laboratory analysis, number of patients receiving intravenous thrombolysis, time from alarm to intravenous thrombolysis, and neurological outcome. We also assessed safety endpoints. This study is registered with ClinicalTrials.gov, number NCT00153036. FINDINGS We stopped the trial after our planned interim analysis at 100 of 200 planned patients (53 in the prehospital stroke treatment group, 47 in the control group), because we had met our prespecified criteria for study termination. Prehospital stroke treatment reduced the median time from alarm to therapy decision substantially: 35 min (IQR 31-39) versus 76 min (63-94), p<0·0001; median difference 41 min (95% CI 36-48 min). We also detected similar gains regarding times from alarm to end of CT, and alarm to end of laboratory analysis, and to intravenous thrombolysis for eligible ischaemic stroke patients, although there was no substantial difference in number of patients who received intravenous thrombolysis or in neurological outcome. Safety endpoints seemed similar across the groups. INTERPRETATION For patients with suspected stroke, treatment by the MSU substantially reduced median time from alarm to therapy decision. The MSU strategy offers a potential solution to the medical problem of the arrival of most stroke patients at the hospital too late for treatment. FUNDING Ministry of Health of the Saarland, Germany, the Werner-Jackstädt Foundation, the Else-Kröner-Fresenius Foundation, and the Rettungsstiftung Saar.

The LPS receptor (CD14) links innate immunity with Alzheimer's disease

To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe‐detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimers disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimers disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimers disease.

Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries

Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH.

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

Background—Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Methods and Results—Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). Conclusions—NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Homocysteine in cerebral macroangiography and microangiopathy

Vascular dementia is the second most frequent cause of dementia in the elderly after Alzheimer’s disease. Subcortical vascular encephalopathy (SVE), a distinct type of vascular dementia, is characterised by stepwise progressive memory deficits and cognitive decline, typical gait disorders, and i n c o n t i n e n c e . Sclerosis of small cerebral arteries and arterioles is responsible for the diffuse periventricular whitematter abnormalities and the central lacunar lesions evidenced in computed or magnetic resonance tomography. Multiple studies have described the association between elevated homocysteine concentrations and carotid artery d i s e a s e . Here, homocysteine concentrations were differentially investigated in macroangiopathic and microangiopathic diseases of the central nervous system. History, clinical examination, extracranial and transcranial doppler, extracranial colour doppler flow imaging, and computed tomography (CT) or magnetic resonance imaging (MRI) were used in all patients and controls to classify possible cerebrovascular disease. Hypertension values over 160 mm Hg (systolic) and over 95 mm Hg (diastolic) or both, diabetes (antidiabetic therapy or pathological fasting glucose values), and smoking (during the previous year) were assessed. 82 patients (37 females, 45 males; median age 73 years) had SVE. This disease was diagnosed by combined information from standardised neurological, neuropsychological (including the Mini-Mental-State Examination [MMSE] in all patients and further scales such as the Structured Interview for the Diagnosis of Dementia [SIDAM], Brief Assessment Interview [BAI] or Nuernberg Aging Inventory [NAI] in the majority of them), and neuroradiological (CT or MRI) examination according to the ICD-10 criteria. These require the presence of disorders of memory and cognition, typical vascular risk-factor profile, and typical subcortical diffuse white-matter lesions or multiple subcortical lacunes detected on CT or MRI as opposed to a cortical lesion pattern. Further symptoms such as typical gait disorders, urinary incontinence, or emotional disturbances were used to strengthen the diagnosis. In addition, 144 patients (55 females, 89 males; median age 67 years) with cerebral large vessel disease (plaques or stenoses of the extracranial arteries and increase of cerebral blood flow velocity of 140 cm/s in the large intracranial vessels or both), and 102 people (54 females, 48 males; median age 65 years) without any cerebrovascular disease, were studied. Homocysteine and vitamin B6 were measured in plasma by HPLC after extraction with a Merck-Hitachi HPLC system (reagents from Medchrom, Heidelberg and Recipe, Munich, Germany). Folic acid and vitamin B12 were measured with a microparticle-enzyme immunoassay (Abbott, Wiesbaden, Germany). Results are expressed as mean (SD). Spearman’s correlation, the Mann-Whitney U-test with a Bonferroni correction, and logistic-regression analysis were used. Patients with SVE exhibited surprisingly high concentrations of homocysteine compared with controls and even to patients with cerebral macroangiopathy (table). Homocysteine concentrations were high irrespective of concomitant presence of large vessel disease. Concentrations in SVE with and without concomitant large-vessel disease did not significantly differ (table). Subgroups of patients with large-vessel disease (plaques in extracranial vessels only, Thessaloniki, Greece. Between December 17–19, 1997, 154 (64%) of the 242 residential students reported a severe sore throat. None of the 55 college employees had a sore throat. All residential students, but not staff, had their meals in the college restaurant. The epidemic curve showed a high attack rate and a short incubation period amongst most of the students who had obtained their meals in the college restaurant, suggesting a common food source rather than person-toperson transmission. The onset of illness was acute with fatigue and muscle weakness followed by sore throat, high fever (39–40°C), tonsillar enlargement, and cervical lymphadenopathy. Co-amoxyclav or penicillin was given in most cases. Secondary respiratory transmission was sporadically reported in a small number of students, employees, and their relatives, 3 to 6 days after the onset of the outbreak. None of the food handlers reported pharyngitis or had any cutaneous lesions during the time of the outbreak or previously. We started an epidemiological study to identify the source of the infection. 72 students (42 with symptoms and 30 without) were interviewed about their symptoms, onset of illness, and consumption of particular foods from the restaurant menu. Analysis showed that the probable transmission vector was the vegetable-salad dressing made of mayonnaise ( 2 test, Yates corrected, p<0·001), eaten 18 hours before the onset of the outbreak. The preparation of the dressing involved extensive handling and it had been prepared in advance and remained at room temperature for about 15 hours until served. Foods containing fresh eggs or dairy products have shown to be ideal culture media for the growth of GAS, and the dressing contained many raw eggs. The restaurant staff and facilities were inspected, but the suspect food or the ingredients were not available for examination. Cultures from other food specimens and the kitchen chopping board taken on subsequent days did not yield GAS or other potential pathogen. Throat swabs were obtained from 28 of 154 students and GAS were isolated, in large numbers, from 26. All isolates were serotyped by T-protein and M-protein typing. All belonged to the provisional M-type PT 4931, recently designated as Mtype 90. This report is one of the largest documented outbreaks of food-borne streptococcal pharyngitis. The observation that this serotype was involved in a severe epidemic of pharyngitis along with an unusually large number of affected people may imply the invasive potential of this organism. This particular serotype is seldomly isolated from GAS disease and it had not been previously reported in food-borne or air-borne streptococcal outbreaks. There has only been one report of sporadic isolations of this streptococcal serotype; from throat infections and skin lesions in the city of Oxford and the district of Cherwell, U K .

Endothelin-1 in Subarachnoid Hemorrhage An Acute-Phase Reactant Produced by Cerebrospinal Fluid Leukocytes

Background and Purpose The most potent vasoconstrictor known, endothelin-1, is currently considered to mediate cerebral vasospasm in subarachnoid hemorrhage (SAH), which can cause delayed cerebral ischemia. In our study, we performed clinical and in vitro experiments to investigate the origin and the mechanisms of the secretion of endothelin-1 in SAH. Methods Endothelin-1 and markers of inflammatory host response (interleukin [IL]-1&bgr;, IL-6, and tumor necrosis factor-&agr;) were comparatively quantified in the cerebrospinal fluid (CSF) of SAH patients and control subjects, and concentrations were related to clinical characteristics. Furthermore, mononuclear leukocytes isolated from the CSF of SAH patients and control subjects were analyzed regarding their mRNA expression of endothelin-1 and inflammatory cytokines. Finally, complementary in vitro experiments were performed to investigate whether coincubation of blood and CSF can trigger leukocytic mRNA expression and release of these factors. Results Activated mononuclear leukocytes in the CSF of SAH patients synthesize and release endothelin-1 in parallel with known acute-phase reactants (IL-1&bgr;, IL-6, and tumor necrosis factor-&agr;). Complementary in vitro experiments not only further confirmed this leukocytic origin of endothelin-1 but also showed that aging and subsequent hemolysis of blood is sufficient to induce such endothelin-1 production. Conclusions The demonstration that endothelin-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and delayed cerebral ischemia after SAH.

High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs.

Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reductase, so-called statins, are effective in lowering the prevalence of Alzheimers disease. Whether the effect of statins is due to a local inhibition of cholesterol synthesis in the brain or whether it is mediated by the reduced levels of cholesterol in the circulation is not known. In the present work, we tested the possibility that high doses of lipophilic and hydrophilic statins, simvastatin and pravastatin, respectively, or a diet high in cholesterol could affect cholesterol homeostasis in the brain of guinea pigs. The total brain cholesterol levels were not affected by high-dose simvastatin or pravastatin treatment. Significantly lower levels of the cholesterol precursor lathosterol and its ratio to cholesterol were found in the brains of simvastatin and pravastatin-treated animals. 24S-Hydroxycholesterol, the transportable form of cholesterol across the blood-brain barrier, was significantly lower in the brain of pravastatin-treated animals. Excessive cholesterol feeding resulted in higher serum cholesterol levels but did not affect total brain cholesterol level. However, de novo cholesterol synthesis in the brain seemed to be down-regulated, as indicated by lower absolute levels and cholesterol-related ratios of lathosterol compared with controls. The passage of deuterium-labeled cholesterol across the blood-brain barrier in one animal was found to be approximately 1%. Our results suggest that brain cholesterol synthesis in guinea pigs can be slightly, but significantly, influenced by high doses of lipophilic and hydrophilic statins as well as by high dietary cholesterol intake, while total brain cholesterol content and thus, cholesterol homeostasis is maintained.

Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (A&bgr;) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer A&bgr;.

Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurobiochemical and electrophysiological investigations may provide high prognostic certainty in patients after cardiac arrest.

A reliable and reproducible method for precisely predicting the neurological outcome of patients with hypoxic-ischemic encephalopathy after cardiac arrest is urgently needed in neurological intensive care units. We prospectively investigated the predictive power of serum concentrations of neuron-specific enolase (NSE) and protein S-100B (S-100B) measured on days 1, 2, 3 and 7 as well as somatosensory-evoked potentials (SEPs) recorded within 48 h and on day 7 after cardiopulmonary resuscitation (CPR) in 27 patients (14 females, 13 males; mean age 61.3 ± 17.3 years) with hypoxic-ischemic encephalopathy. During the first 7 days after CPR, median values of NSE and S-100B were increased in patients who remained unconscious after CPR compared to those patients who regained consciousness (significance up to ≤0.001). The best predictor of negative outcome was an NSE cutoff point ≧43 µg/l on day 2; this had a sensitivity of 90.9% and a specificity of 100%. Additional use of S-100B on day 2 did not increase sensitivity, but this could be markedly increased by combining NSE and S-100B on days 1, 3 and 7. SEPs showing bilateral loss of cortical responses identified patients who did not regain consciousness with a specificity of 100%.