Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID).

Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID). Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock

Effects of long-term moderate ethanol and cholesterol on cognition, cholinergic neurons, inflammation, and vascular impairment in rats

AbstractThere is strong evidence that vascular risk factors play a role in the development of Alzheimer's disease (AD) or vascular dementia (vaD). Ethanol (EtOH) and cholesterol are such vascular risk factors, and we recently showed that hypercholesterolemia causes pathologies similar to AD [Ullrich et al. (2010) Mol Cell Neurosci 45, 408–417]. The aim of this study was to investigate the effects of long-term (12 months) EtOH treatment (20% v/v in drinking water) alone or long-term 5% cholesterol diet alone or a combination (mix) in adult Sprague–Dawley rats. Long-term EtOH treatment (plasma EtOH levels 58±23 mg/dl) caused significant impairment of spatial memory, reduced the number of choline acetyltransferase- and p75 neurotrophin receptor-positive nucleus basalis of Meynert neurons, decreased cortical acetylcholine, elevated cortical monocyte chemoattractant protein-1 and tissue-type plasminogen activator, enhanced microglia, and markedly induced anti-rat immunoglobulin G-positive blood–brain barrier leakage. The effect of long-term hypercholesterolemia was similar. Combined long-term treatment of rats with 20% EtOH and 5% cholesterol (mix) did not potentiate treatment with EtOH alone, but instead counteracted some of the EtOH-associated effects. In conclusion, our data show that vascular risk factors EtOH and cholesterol play a role in cognitive impairment and possibly vaD

Integration von hochauflösenden Fernerkundungs- und Geländemodelldaten für die Landschaftsvisualisierung

This paper presents experiments for realistic landscape visualization using high resolution digital aerial photographs and elevation modeis. The natural environment of a river in northern Switzerland is visualized. Photogrammetrically measured digital elevation data and ortho-rectified remote sensing imagery (Landsat Thematic Mapper/TM and aerial photographs) are combined to compute realistic 3D views of the landscape. To renderthe landscape more realistically, the digital elevation model (DEM) is transformed to a digital surface model (DSM), representing the surface and including objects like forests or bushes. For this transformation land cover information and GIS tools were used. Unnaturally looking vertical borders between different land cover classes were suppressed by interpolating transition zones. Additionally, 3D objects (trees) are used in the foreground to increase the realism of the views

Intravenous Infusion of Monocytes Isolated from 2-Week-Old Mice Enhances Clearance of Beta-Amyloid Plaques in an Alzheimer Mouse Model

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ) senile plaques and tau-associated neurofibrillary tangles. Other disease features include neuroinflammation and cholinergic neurodegeneration, indicating their possible importance in disease propagation. Recent studies have shown that monocytic cells can migrate into the AD brain toward Aβ plaques and reduce plaque burden. The purpose of this study was to evaluate whether the administration of intravenous infusions of 'young' CD11b-positive (+) monocytes into an AD mouse model can enhance Aβ plaque clearance and attenuate cognitive deficits. Peripheral monocytes were isolated from two-week-old wildtype mice using the Pluriselect CD11b+ isolation method and characterized by FACS analysis for surface marker expression and effective phagocytosis of 1 μm fluorescent microspheres, FITC-Dextran or FITC-Aβ1-42. The isolated monocytes were infused via the tail vein into a transgenic AD mouse model, which expresses the Swedish, Dutch/Iowa APP mutations (APPSwDI). The infusions began when animals reached 5 months of age, when little plaque deposition is apparent and were repeated again at 6 and 7 months of age. At 8 months of age, brains were analyzed for Aβ+ plaques, inflammatory processes and microglial (Iba1) activation. Our data show that infusions of two-week-old CD11b+ monocytes into adult APPSwDI mice results in a transient improvement of memory function, a reduction (30%) in Aβ plaque load and significantly in small (40 μm) plaques. In addition, we observe a reduction in Iba1+ cells, as well as no marked elevations in cytokine levels or other indicators of inflammation. Taken together, our findings indicate that young CD11b+ monocytes may serve as therapeutic candidates for improved Aβ clearance in AD