K. Fassbender

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.

Proinflammatory cytokines in serum of patients with acute cerebral ischemia : kinetics of secretion and relation to the extent of brain damage and outcome of disease

The release of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha and soluble TNF-receptors p55 and p75 in peripheral blood was serially determined in 19 patients with acute cerebral ischemia. Only patients admitted within 4 h following onset of symptoms were studied. In contrast to serum levels of IL-1 beta, TNF-alpha and TNF-receptors, which did not exhibit a significant response, IL-6 showed a significant increase of serum levels already within the first hours following onset of disease and reached a plateau at 10 h until day 3 and returned to baseline by day 7. The increase of levels of this cytokine was significantly (P < 0.05) correlated with increasing volumes of brain lesion and was also significantly (P < 0.005) associated with poor functional and neurological outcome. The increase of levels of IL-6 despite a considerable dilution in peripheral blood shown in this preliminary study suggests an early inflammatory response in ischemic brain lesion.

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.

Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome.

Background and Purpose The aim of this study was to characterize the response of the hypothalamic-pituitary-adre-nal system in the first hours of ischemic stroke and to relate its extent to the occurrence of acute confusional state, volume of brain damage, and clinical outcome. Methods The secretion of corticotropin (adrenocorticotropic hormone [ACTH]) and cortisol was studied in 23 patients by determinations at hours 4, 6, 8, 10, and 14 and days 1, 3, 5, and 7 after onset of symptoms. Acute confusional state (DSM-III-R criteria), extent of lesion (volumetry of computed tomographic scans), and neurological and functional outcome (Scandinavian Stroke Scale, Barthel Index scores) were assessed. Results The massive neuroendocrine response observed consisted of an initial phase with concomitantly increased levels of ACTH and cortisol and a second phase with decreased levels of ACTH while high concentrations of cortisol persisted. Initial levels of ACTH but not cortisol were significantly increased in patients with acute confusional state and significantly correlated with volume of brain lesion and neurological and functional outcome. Conclusions An early and persisting activation of the hypothalamic-pituitary-adrenal axis was observed in relation to severity of disease. Its characteristic biphasic pattern suggests an initial central stimulation of release of ACTH followed by feedback suppression concomitant with an increased susceptibility of the adrenal gland. Because these hormones are known to exacerbate hypoxic injury to neurons, their massive release in hyperacute stroke may increase the extent of brain damage.

Circulating Selectin- and Immunoglobulin-Type Adhesion Molecules in Acute Ischemic Stroke

BACKGROUND AND PURPOSE Cellular adhesion molecules mediate adhesion between endothelial cells and leukocytes as a precondition for extravasation of leukocytes at sites of tissue injury. The pattern of release of circulating adhesion molecules has been characterized in patients with acute ischemic stroke. METHODS Serum concentrations of soluble selectin-type adhesion molecules (solube endothelial leukocyte adhesion molecule-1 [sELAM-1], soluble lymph node homing receptor [sL-selectin]) and immunoglobulin-type adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1]) were serially determined (at hours 4, 8, and 10 and at days 1, 3, and 5) in 22 patients with acute ischemic stroke. As control subjects, age- and sex-matched individuals with (n = 40) and without (n = 22) vascular risk factors were studied. RESULTS We observed increased concentrations of sICAM-1 and decreased levels of sL-selectin in patients with risk factors even in the absence of stroke. Patients with acute stroke had, in addition, an initial transient increase of sELAM-1 and a persistent increase of sVCAM-1. CONCLUSIONS The results suggest a chronic alteration of expression of adhesion molecules sICAM-1 and sL-selectin in subjects with risk factors for atherosclerosis; they also indicate acute changes of levels of sELAM-1 and sVCAM-1 in response to acute ischemic stroke. Determination of soluble adhesion molecules could allow in vivo monitoring of the initial steps of leukocyte-mediated brain damage in acute ischemic stroke.

Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke

The clinical value of determination of CNS-specific proteins in peripheral blood at the acute phase of ischemic stroke is unclear. S-100 protein and neurone specific enolase were serially quantified in peripheral blood at the acute and subacute phase of ischemic stroke (hours 4, 8, 10, 24 and 72 after onset of symptoms). Whereas S-100 protein was detected in none of the matched control subjects. this protein was observed in 17/24 of the stroke patients. Patients with detectable S-100 protein had significantly larger infarctions. Cortical infarctions had already significantly increased S-100 concentrations at days 1 and 3 compared to subcortical or brainstem infarctions. Patients with volumes of brain lesion of >5 ccm exhibited significantly increased serum levels of S-100 at hours 10, 24 and 72 compared to those with lesion volumes of <5 ccm. At hours 10, 24 and 72, concentrations of S-100 correlated with scores of neurological outcome. Although kinetics of release of neurone specific enolase showed a similar pattern of release in blood, no significant association to outcome or extent of brain damage was observed. These results suggest that S-100 protein and not NSE may represent a useful serum marker of brain damage in acute stroke.

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;.

Temporal profile of release of interleukin-1β in neurotrauma

Timing and extent of trauma-induced release of interleukin-1beta (IL-1beta) in extracellular fluid of the CNS were analyzed. In brain tissue perfusates obtained by in vivo microdialysis a marked release of IL-1beta was unexpectedly detected within less than 60 min. At such an early stage of neurotrauma, mRNA expression of IL-1beta was detected whereas immunoreactivity for the IL-1beta protein was negative. Concentrations of extracellularly secreted IL-1beta protein gradually increased, peaked at day 2 and decreased thereafter. Drugs acting on mononuclear phagocytes significantly modulated IL-1beta secretion. This so far unrecognized acuity of IL-1beta release demonstrated here, may represent a precondition for the orchestrating role of this mediator in the cascade of inflammatory host response.

Adhesion Molecules in Cerebrovascular Diseases Evidence for an Inflammatory Endothelial Activation in Cerebral Large- and Small-Vessel Disease

BACKGROUND AND PURPOSE Adhesion molecules mediate attachment and transendothelial migration of leukocytes as a critical step in pathogenesis of atherosclerosis. Their expression and release were comparatively investigated in patients with large- and small-vessel disease of the central nervous system. METHODS With immunological methods, serum concentrations of endothelial-derived adhesion molecules (soluble endothelial-leukocyte adhesion molecule [sE-selectin], soluble vascular-leukocyte adhesion molecule-1, and soluble intercellular adhesion molecule-1 [sICAM-1]) were quantified in patients with obstructive disease of extracranial (n=89) and intracranial (n=20) large-vessel disease and patients with subcortical vascular encephalopathy (n=64), a cerebral small-vessel disease. As controls, age- and sex-matched subjects without obstructive cerebrovascular disease (n=67) were studied. RESULTS We observed significantly increased serum concentrations of sE-selectin and sICAM-1 in patients with both obstructive disease of the large brain-supplying arteries and subcortical vascular encephalopathy. Interestingly, the highest levels were observed in intracranial macroangiopathy. Furthermore, concentrations of sICAM-1 and sE-selectin were significantly increased in current smokers but not in diabetic or hypertensive patients. CONCLUSIONS The observation of elevated release of endothelial-derived adhesion molecules in both patients with stenoses of the large brain-supplying arteries and patients with subcortical vascular encephalopathy indicates that inflammatory endothelial activation and adhesion of leukocytes play similarly important roles in cerebral large- and small-vessel disease.

Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients

Experimental and clinical studies give evidence for breakdown of membrane phospholipids during neurodegeneration. In the present study, we measured the levels of glycerophosphocholine (GPCh), phosphocholine (PCh), and choline, that is, water-soluble metabolites of phosphatidylcholine (PtdCho), in human cerebrospinal fluid (CSF). Among 30 cognitively normal patients the average CSF levels of GPCh, phosphocholine and choline were 3.64, 1.28, and 1.93 microM, respectively; metabolite levels did not change with increasing age. When compared with age-matched controls, patients with Alzheimers disease had elevated levels of all choline metabolites: GPCh was significantly increased by 76% (P<0.01), phosphocholine by 52% (P<0.05), and free choline (Ch) by 39%. Six patients with vascular dementia had lower choline and elevated phosphocholine levels, when compared to controls, but normal levels of GPCh. These data demonstrate that Alzheimers disease is accompanied by an increased PtdCho hydrolysis in the brain. PtdCho breakdown seems to be mediated by phospholipase A2 and leads to significantly elevated levels of GPCh in CSF.