Selective neurodegeneration of the hippocampus caused by chronic cerebral hypoperfusion: F-18 FDG PET study in rats

Abstract

Background Chronic cerebral hypoperfusion (CCH) is known to induce Alzheimer’s disease (AD) pathology, but its mechanism remains unclear. The purpose of this study was to identify the cerebral regions that are affected by CCH, and to evaluate the development of AD pathology in a rat model of CCH. Methods A rat model of CCH was established by bilaterally ligating the common carotid arteries in adult male rats (CCH group). The identical operations were performed on sham rats without arteries ligation (control group). Regional cerebral glucose metabolism was evaluated at 1 and 3 months after bilateral CCA ligation using positron emission tomography with F-18 fluorodeoxyglucose. The expression levels of amyloid β40 (Aβ40), amyloid β42 (Aβ42), and hyperphosphorylated tau were evaluated using western blots at 3 months after the ligation. Cognitive function was evaluated using the Y-maze test at 3 months after the ligation. Results At 1 month after the ligation, cerebral glucose metabolism in the entorhinal, frontal association, motor, and somatosensory cortices were significantly decreased in the CCH group compared with those in the control group. At 3 months after the ligation, cerebral glucose metabolism was normalized in all regions except for the anterodorsal hippocampus, which was significantly decreased compared with that of the control group. The expression of Aβ42 and the Aβ42/40 ratio were significantly higher in the CCH group than those in the control group. The phosphorylated-tau levels of the hippocampus in the CCH group were significantly lower than those in the control group. Cognitive function was more impaired in the CCH group than that in the control group. Conclusion Our findings suggest that CCH causes selective neurodegeneration of the anterodorsal hippocampus, which may be a trigger point for the development of AD pathology.

Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance

“…In addition, CCH resulting from the permanent BCCAL is linked with the development of neurodegenerative changes, including impaired BBB permeability, synaptic dysfunction, altered brain-carbohydrate metabolism, neuronal loss, and oxidative stress [25][26][27]. Meanwhile, some studies reported the limitation of utilising BCCAL to model for CCH, including the variability of the outcome associated with the duration of cerebral hypoperfusion and the compensatory vascular mechanism that could not prevent neuronal death [28,29]. In support of vascular contributions to delirium, considerable evidence has reported the co-existence of CCH in delirium [30][31][32].…”

In Vivo Preclinical Assessment of β-Amyloid–Affine [11C]C-PIB Accumulation in Aluminium-Induced Alzheimer’s Disease-Resembling Hypercholesterinaemic Rat Model

“…Positron emission tomography (PET) applying [ 18 F]-2-fluoro-deoxy-D-glucose ([ 18 F]F-FDG) is supposed to be of significant potential to decipher subtle brain metabolic alterations that precede the appearance of morphological cerebral changes. Based on research data [ 18 F]F-FDG brain hypometabolism is a promising biomarker of AD [16]. According to prior studies reporting decreased [ 18 F]F-FDG accumulation of the amygdala, the entorhinal cortex, and the hippocampus, [ 18 F]F-FDG PET appeared to be feasible in the identification of AD-associated brain metabolic patterns in a Wistar male rat model of chronic cerebral hypoperfusion (CCH) [17].…”

“…Based on research data [ 18 F]F-FDG brain hypometabolism is a promising biomarker of AD [16]. According to prior studies reporting decreased [ 18 F]F-FDG accumulation of the amygdala, the entorhinal cortex, and the hippocampus, [ 18 F]F-FDG PET appeared to be feasible in the identification of AD-associated brain metabolic patterns in a Wistar male rat model of chronic cerebral hypoperfusion (CCH) [17]. In another study, the development of neurodegeneration was strengthened by-amongst others-the serial registration of [ 18 F]F-FDG hypometabolism of the anterodorsal hippocampus in rats with bilateral common carotid artery ligation-based CCH [18].…”

“…According to prior studies reporting decreased [ 18 F]F-FDG accumulation of the amygdala, the entorhinal cortex, and the hippocampus, [ 18 F]F-FDG PET appeared to be feasible in the identification of AD-associated brain metabolic patterns in a Wistar male rat model of chronic cerebral hypoperfusion (CCH) [17]. In another study, the development of neurodegeneration was strengthened by-amongst others-the serial registration of [ 18 F]F-FDG hypometabolism of the anterodorsal hippocampus in rats with bilateral common carotid artery ligation-based CCH [18]. Although [ 18 F]F-FDG is valued as the gold-standard PET radiopharmaceutical in the evaluation of AD-linked brain glucose consumption and glucose metabolic changes, its application in neurodegenerative imaging has been hampered by its low specificity in terms of differentiating AD from other forms of dementias [19,20].…”

Elevated Cortical Tau Positron Emission Tomography Binding in Misery Perfusion: Novel, Puzzling, and Heuristic

“…4 Finally, rodent studies report that chronic cerebral hypoperfusion may trigger Alzheimer pathology, that is, Aβ and, though less consistently, p-tau. 5 However, no study in man so far has addressed the hypothesis that chronic hypoperfusion may cause p-tau accumulation. In the current issue of Stroke , Yamauchi et al 6 report an exploratory cross-sectional positron emission tomography (PET) study that used both a specific fibrillary tau PET radioligand and the standard oxygen-15 PET method to quantitatively map cerebral blood flow, oxygen consumption, and the oxygen extraction fraction (OEF) in 8 patients with symptomatic (transient ischemic attack or minor stroke) chronic unilateral occlusion or severe stenosis of the internal carotid or middle cerebral artery.…”