Induction of Hyperhomocysteinemia Models Vascular Dementia by Induction of Cerebral Microhemorrhages and Neuroinflammation

Abstract

Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders.

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

“…Increased levels of plasma homocysteine have been associated with dementia in many epidemiological studies [9,17,52]. A number of possible mechanisms of detrimental homocysteine action have been proposed, however, most of these studies been done in nondamaged animals, or under in vitro conditions.…”

“…Several animal models with induced elevated levels of plasma homocysteine also exhibit impairments in short-term, spatial, and long term memory [15][16][17][18]. These impairments may be a result of the negative effects of elevated levels of homocysteine on vascular function [17,18].…”

“…These impairments may be a result of the negative effects of elevated levels of homocysteine on vascular function [17,18].…”

Increased homocysteine levels impair reference memory and reduce cortical levels of acetylcholine in a mouse model of vascular cognitive impairment

“…Furthermore, increasing levels of plasma Hcy through dietary folic acid deficiencies have been proposed as an animal model of vascular dementia 34,35 .…”

Intracerebral Hematomas Disappear on T2*-Weighted Images During Normobaric Oxygen Therapy

“…Similarly, anesthesia during MRI in experimental studies should avoid the use of 100% oxygen as a delivery gas for anesthetic agents, especially if T2*-weighted imaging is performed to detect hemorrhages. 13 In addition, NBO preparation could dramatically increase the sensitivity and specificity of molecular imaging in the presence of extravasated blood. Thus, NBO preparation could be used for high-resolution molecular imaging of the perihematoma area in ICH models.…”