Changes in Ang1-positive vessels due to focal cerebral ischemia.

<p>(A) Immunohistochemical staining with an anti-Ang1 antibody. Representative findings are shown of the peri-infarct and infarct areas of the control, tPA-1h, tPA-4h, and PMCAO groups. High magnification (1,000×) is shown in the upper right of the low magnification (200×) photograph. Ang1-positive vessels were shown by asterisk. tPA, tissue plasminogen activator; PMCAO, permanent middle cerebral artery occlusion; Ang1, angiopoietin-1. The black scale bar is 10 µm, and the red scale bar is 100 µm. (B) Mean number of Ang1-positive vessels. Three locations were chosen randomly in the control cerebral cortex and in each infarct area and peri-infarct area. The figures are the mean number of Ang1-positive vessels from 3 random fields of view of an optical microscope at 200× magnification. Each group N = 5.</p

COMP-Ang1 protein localization in the tPA-4h group visualized with a confocal laser microscope.

<p>From left to right: markers of cells that make up the blood brain barrier (a, e, i; red), neuronal cell (m; red), COMP-Ang1 protein (b, f, j, n; green), DAPI stain (c, g, k, o; blue), and a merged image (d, h, l, p). Immunostaining with an anti-FLAG antibody was performed on COMP-Ang1 proteins in order to differentiate them from endogenous Ang1. RECA1 is an endothelial cell marker protein; PDGFRβ is a pericyte marker; GFAP is an astrocyte marker; and MAP2 is a neuronal cell marker. RECA1, rat endothelial cell antigen; PDGFRβ, platelet-derived growth factor receptor; GFAP, glial fibrillary acidic protein; Ang1, angiopoietin-1. The scale bars are 10 µm.</p

Effects of COMP-Ang1 protein administration on the tPA-4h group.

<p>These panels show the amount of cerebral hemorrhage (A), cerebral edema volume (B), cerebral infarct volume (C), and the prognosis with a 6-point neurological scale score (D) 24 h after ischemia. A-C were performed on the COMP-Ang1 group (N = 5) and the COMP group (N = 5). D was performed on the COMP-Ang1 group (N = 11) and the COMP group (N = 9). Cerebral edema and infarct volumes are expressed as proportions on the ischemic side of the cerebral hemisphere. The amount of cerebral hemorrhage is expressed as hemoglobin concentration in a whole cerebral homogenate. COMP; cartilage oligomeric protein, COMP-Ang1; cartilage oligomeric protein-angiopoietin-1.</p

Reduced CSF Water Influx in Alzheimer’s Disease Supporting the β-Amyloid Clearance Hypothesis

<div><p>Objective</p><p>To investigate whether water influx into cerebrospinal fluid (CSF) space is reduced in Alzheimer’s patients as previously shown in the transgenic mouse model for Alzheimer’s disease.</p><p>Methods</p><p>Ten normal young volunteers (young control, 21-30 years old), ten normal senior volunteers (senior control, 60-78 years old, MMSE ≥ 29), and ten Alzheimer’s disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) participated in this study. All AD patients were diagnosed by neurologists specializing in dementia based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq [¹⁵O]H₂O synthesized on-line.</p><p>Results</p><p>Water influx into CSF space in AD patients, expressed as influx ratio, (0.755 ± 0.089) was significantly reduced compared to young controls (1.357 ± 0.185; p < 0.001) and also compared to normal senior controls (0.981 ± 0.253, p < 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p < 0.01).</p><p>Conclusion</p><p>Water influx into the CSF is significantly reduced in AD patients. β-amyloid clearance has been shown to be dependent on interstitial flow and CSF production. The current study indicates that reduction in water influx into the CSF may disturb the clearance rate of β-amyloid, and therefore be linked to the pathogenesis of AD.</p><p>Trial Registration</p><p>UMIN Clinical Trials Registry <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000013940&type=summary&language=E" target="_blank">UMIN000011939</a></p></div

Schematic presentation of the results with mean (circle) and standard deviation (bar).

<p>Water influx into CSF space is expressed as influx ratio (IR): the ratio between the standardized uptake value (SUV, g/ml) of the ventricle to that of cortex. IR in Alzheimer’s disease patients (AD) is significantly reduced compared to both young controls (p < 0.001) and senior controls (p < 0.05), Mann-Whitney-Wilcoxon rank sum test. Note that there is no overlap in data points between AD and young controls. Reduction of influx ratio in senior controls compared to that in young control is found to be significant (p < 0.01) as well. A large range of influx ratio in senior controls suggests that the observed reduction likely represents one of the aging processes.</p

Consort Flow Diagram providing details of participant enrolment.

<p>Consort Flow Diagram providing details of participant enrolment.</p