These voids corresponded directly to histologically identified small extracellular clusters of A-positive plaques that were iron-loaded

These voids corresponded directly to histologically identified small extracellular clusters of A-positive plaques that were iron-loaded. Evidence for endothelial dysfunction has been reported as loss of vascular relaxation in hypercholesterolemic rabbits (53). different. == Conclusion == Reduction in vessel diameter of mediumsized vessels but not large vessels was measured in these hypercholesterolemic rabbits. The vessel diameter narrowing and cortical A deposition occurred before measurable ventricular enlargement. Keywords:cerebrovascular, amyloid-peptide, A, TOF-MRA, Hyodeoxycholic acid MRI, angiography, cholesterol, rabbit, copper, Alzheimer’s disease, stroke ALZHEIMER’s DISEASE (AD) IS a degenerative neurological disorder that affects more than 5 million Americans and their families. Epidemiological studies indicate a strong link between AD and cardiovascular risk factors such as high blood pressure, heart disease, stroke, diabetes, and high cholesterol (14). The cardiovascular factors suggest a possible neurovascular component to AD and evidence has been accumulating recently to support this idea (58). Since 1975 (9), amyloid -peptide (A) accumulation in cortical tissue and vessels has also been linked to cerebral amyloid angiopathy (CAA). A comprehensive review of studies of the neurovascular pathway in Alzheimer’s Disease has recently been published (8). A link has been established between A and elevated cholesterol levels in the blood of AD patients (2,1013) and clinical studies suggest a link between elevated cholesterol and increased risk of AD (10,14,15). Further evidence supports this idea. First, in the three-city study in France based on 9294 individuals, the authors identified a significant increase in the risk of Mouse monoclonal to FCER2 dementia with hyperlipidemia (11). Second, the Nun study of 678 nuns (16) demonstrated a connection between cerebrovascular disease and AD. Participants with one or more lacunar infarcts had significantly more advanced disease than those without lacunae. This result was independent of the number of neurofibrillary tangles. Third, the Rotterdam study (14) of 1730 participants found that reduced cortical perfusion appeared before clinical dementia and reduced relative cerebral blood volume preceded brain atrophy seen on MRI. Thus, neurovascular dysfunction and neurodegenerative processes are both causal mechanisms in AD although neither has yet been established as the instigating insult (1720). A dominant contributor to both processes is the deposition of neurotoxic A in vessels and brain parenchyma. The link between AD, arteriosclerosis, and hyper-cholesteremia is also being studied in an animal model of AD, the cholesterol-fed rabbit. The cholesterol-fed rabbit has a long history of being used as a model of atherosclerosis because a cholesterol diet can induce vascular lesions (21,22). The peripheral effects of feeding cholesterol to rabbits are atherosclerosis, inflammation, and liver pathology. As a result of elevated cholesterol, the liver produces increased lipo-proteins rich in cholesterol esters that stay in the bloodstream and lead to atherosclerotic lesions. High levels of low-density lipoprotein (LDL) induce the endothelial cell expression of adherence Hyodeoxycholic acid molecules that mediate attachment of monocytes and lymphocytes to the rabbit artery wall that then migrate into the wall and result in fatty streaks (23). Oxidized LDL in the artery wall accumulates in macrophages that have differentiated from monocytes and develop into foam cells. Based on Sparks’ observation that rabbits fed cholesterol also have A staining in the brain (4,24), the cholesterol-fed rabbit has also been studied as an animal model of the cortical and vascular damage present in AD (13,2426). The A accumulation seen in cholesterol-fed rabbits can include senile plaque-like structures in the hippo-campus and temporal lobe. Trace amounts of copper in drinking water may influence clearance of A from the brain at the level of the interface between the blood and cerebrovasculature and combined with high cholesterol may be a key component to the accumulation of A in the brain vessels and parenchyma, having a significant impact on learning and memory (26,27) The cholesterol-fed rabbit exhibits an AD-like decline of performance in classic conditioning of the nictating membrane when A plaques form in the cortex (27). The goal of this study was to find out if the cholesterol-fed rabbits exhibit changes in the cranial vessel diameters that are measurable by Hyodeoxycholic acid time-of-flight MR angiography (TOF-MRA). Also the data were tested to see if any observed vessel changes were correlated with differences in A accumulation between the groups. The MRI images were also used to screen for hyperintensities on T2-weighted images indicative of stroke and hyperintensities on cerebrospinal fluid (CSF) -suppressed spoiled gradient-echo indicative of lacunae. To determine if neuronal loss was observable in these animals, ventricular volumes of the third and lateral ventricles were measured in two groups: the normal diet and 12-week cholesterol-fed rabbits as an index of cortical atrophy (28,29). == MATERIALS AND METHODS == == Animals == A total of 25 male.