Hemodynamic effects of combined focal cerebral ischemia and amyloid protein toxicity in a rat model: a functional CT study

Abstract

Background/objective: Clinical evidence indicates that cerebral ischemia (CI) and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ) protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP) functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics.

Methods: A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF) and blood volume (CBV) parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology.

Results: CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results.

Conclusion: These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.

Figure 1. Cerebral blood flow maps at four time points in: control rat (1^st row); CI rat (2^nd row); Aβ alone rat (3^rd row) and Aβ+CI rat (4^th row).

Baseline imaging was done before any injection. In CI and Aβ+CI brains, ischemia (white arrow head) and hyperperfusion (white arrow) in the right striatum were observed at 30 minutes and 1 week post injection, respectively. No significant change in CBF was observed over four weeks in control and Aβ alone rats, when compared to their baselines.

Figure 2. Cerebral blood volume maps at four time points in: control, CI, Aβ alone and Aβ+CI rat.

Baseline imaging was done before any injection. In CI and Aβ+CI brains, similar to the CBF results, CBV deficit (white arrow head) and hypervolemia (white arrow) in the right striatum were observed at 30 minutes and 1 week post injection, respectively. Similar to the CBF maps, no significant CBV change was observed over four weeks in control and Aβ alone rats, when compared to their baselines.

Figure 3. Evolution of striatal CBF and CBV over four-week period post injection.

Absolute CBF and CBV in the right (ipsilateral) striatum at each time point from Aβ+CI, CI and control group were normalized by their contralateral values. (a), normalized (relative) CBF; (b), normalized CBV. In Aβ+CI group (*, n = 7), there were significant differences in CBF and CBV between baseline and those at other time points (30 min, 60 min, week 1 and week 4. p<0.05). Similar findings were shown in the CI group (&, n = 6. p<0.05), except for week 4. No significant CBF and CBV difference from baseline was found in the control group (n = 3). In addition, Aβ+CI and CI groups showed significantly lower CBF and CBV at acute phase and higher CBF and CBV at week 1 than control. However, no significant difference between Aβ+CI and CI group was seen over 4 weeks.

Figure 4. Hemodynamic effects of Aβ+CI and Aβ alone models.

For rats which had combined Aβ and ET injections (n = 7) and Aβ only injections (n = 6), absolute CBF and CBV in the right (ipsilateral) striatum were normalized with their respective baseline values. Both relative CBF (a) and CBV (b) were significantly different between the Aβ+CI and Aβ alone group at the time points post insult except for week 4 (#, p<0.01 for 30–60 min, p<0.05 for week1). At week 4, rCBF and rCBV in both Aβ+CI and Aβ alone groups dropped to the baseline level.

Figure 5. Histology of cerebral microvessels in control, CI and Aβ+CI groups.

Microphotographs showed laminin-stained microvessels in the core of ipsilateral (right) striatum at week 1 (A–C) and week 4 (D–F) post insults. Quantitative analysis of the whole striatal core showed that average density of dilated microvessels (i.e. diameter greater than 10 µm) in CI and Aβ+CI groups was significantly higher at week 1 than those at week 4. As induced injury advanced, at week 4 regular vasculature was almost absent in the Aβ+CI group. Letter “C” indicates significant differences when compared to the control group, p<0.05.