Metabolic downregulation

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There are other possible mechanisms for the phenomenon of normal CBV in patients with increased OEF discussed above. One potential cause for normal or reduced CBV values is reduced metabolic demand. CBV falls when the metabolic activity of the tissue falls, due to either local or remote neuronal injury (diaschisis) [80], [6], [90]. In the study presented above, however, we found no significant difference in CMRO2 between patients with increased OEF and increased CBV and those with normal or reduced CBV.

Sette and colleagues noted the phenomenon of increased OEF associated with normal CBV and pro posed a metabolically-mediated vasconstriction, associated with the vascular collapse that may occur with severe reductions in perfusion pressure, to account for their observations [80]. Based on CBF/CBV ratios, they considered these patients to have greater reductions in perfusion pressure than those with increased OEF and increased CBV. They studied 4 patients with carotid occlusion and found regions with reduced absolute ipsilateral values of CBF, increased OEF, and normal CBV. CMRO2 was slightly reduced in these areas as well. Importantly, the outcome data from our study suggests that patients with increased OEF and normal CBV have less severe hemodynam-ic impairment than those with increased OEF and increased CBV. If the normal CBV values in patients with increased OEF were caused by reductions in the diameter of previously dilated vessels, secondary to severe reductions in intraluminal pressure, one would expect a higher risk of stroke in the patients with increased OEF and normal CBV than those with increased OEF and increased CBV. In our data, patients with increased OEF and increased CBV had a higher risk of stroke, suggesting the degree of hemo-dynamic impairment is more, not less, severe in these patients.

Bilateral hemispheric reductions in absolute CMRO2 have been found in patients with unilateral carotid occlusion [33], [76]. Gibbs et al., reported hemodynamic and metabolic data for 32 patients with unilateral and bilateral carotid occlusions [33]. They grouped their data by anatomy - contralateral hemisphere and ipsilateral hemisphere for unilateral occlusions, and both hemispheres for bilateral occlusions. Absolute hemispheric values of CMRO2 were significantly lower than normal control values in all three groups. No difference between the three groups was seen, however. Additionally, improvement in CBF and CMRO2 in both hemispheres has been reported after EC/IC bypass or with increased mean arterial pressure in selected patients [76], [77]. The nature of this phenomenon remains unclear.

The phenomenon of reversible metabolic down-regulation due to long-standing hemodynam-ic impairment and a clinical correlate to improved cognitive function after revascularization are two unproven but attractive hypotheses [80], [78].

CMRO2 is frequently reduced patients with severe hemodynamic impairment. Whether this is a reversible compensation to reduced CBF or reflects underlying ischemic injury is unknown. Prospective randomized studies before and after revasculariza-tion will be required.

Molecular imaging studies of carotid atherosclerosis

As discussed above, there is more to carotid atherosclerosis than just vessel narrowing and limitation of flow. Growing evidence points to synergistic effects of embolic and hemodynamic factors [37], [67]. Patients with recent transient ischemic attack, stroke, or silent emboli in the middle cerebral artery by transcranial Doppler are at much higher risk for subsequent stroke than asymptomatic patients with identical degrees of carotid stenosis [57]. Molecular imaging techniques have great promise in the investigation of the biology of atherosclerosis and in identifying factors associated with the formation of thrombo-emboli [13].

The pathology of atherosclerosis is well described. Lipids and macrophages accumulate on the endothelium, initially as a fatty streak. Over time, a plaque develops with a central lipid core and a fibrous cap. The fibrous cap has an endothelial covering and contains vascular smooth muscle cells and collagen. In carotid disease, this plaque may expand to cause severe stenosis or occlusion. As discussed above, this limits flow only if collateral sources are not adequate. In addition, as there is no global increase in flow with neuronal activation, there is no angina-equivalent in the brain: you don't get a headache from thinking.

Thrombo-embolic phenomenon occurs when the fibrous cap ruptures. This exposes subendothelial structures that are very thrombogenic [32]. Circulating clotting factors VII and XI are activated through extrinsic and intrinsic pathways. Thrombin, fibrinogen and fibrin are generated. Platelet activation occurs via upregulation of glycoprotein IIb/IIIa receptors. The ultimate product of these events is thrombus formation.

Plaque formation and rupture is a consequence of multiple complex and inter-related factors. These factors include endothelial cell function (impaired in atherosclerotic disease, even in the absence of plaque) and inflammation. Atherosclerotic risk factors, smoking, elevated low-density lipoprotein (LDL) levels, and hypertension, are associated with impaired endothelial responses to hypoxia. This endothelial dysfunction likely predisposes to the accumulation of foam cells in the subendothelial layer. The vascular smooth muscle cells that migrate from the media create the collagen that forms the fibrous cap. The foam cells often die and leave behind the lipid that forms the core of the plaque. Lesions with a thin fibrous cap have a higher risk for future rupture [12]. Inflammation likely plays a role in this process [12], [52].

Much of the molecular imaging studies to date have utilized single-photon emission computed tomography (SPECT) tracers in animal models of atherosclerosis and will not be reviewed here. These labels have been aimed at the plaque itself, including LDL, endothelial peptides, and receptor site antibodies for macrophages, and at adherent thrombus, using labeled platelets, fibrin and other related molecules.

The only studies to date using PET radiotracers have employed 18F-Fluouro deoxyglucose (FDG). FDG is taken up by metabolically active cells as a glucose analog, but cannot be metabolized. Uptake is particularly high in anaerobic cells, such as most tumors and macrophages [49]. Yun and colleagues observed vascular FDG uptake in approximately 50% of 137 consecutive cancer patients undergoing PET [95]. This uptake was associated with risk factors for atherosclerosis [94]. Age and hypercholesterolemia had the strongest associations. Rudd et al., studied 8 patients with symptomatic carotid atherosclerosis with CT/PET image fusion [75]. They found uptake of FDG within the plaque in all patients. They also performed autoradiography of the removed plaques from 3 patients that underwent end-arterectomy. Tritiated deoxyglucose (an analogue of FDG) accumulation was localized to macrophage-rich areas of the plaque.

Molecular imaging studies of stroke

The potential utility of this application of PET imaging is to confirm or exclude a cerebral ischemic event in a patient with a clinical history that is not definitive. The presence or absence of ischemic symptoms is a critical distinction in determining therapy for many patients with atherosclerotic disease, particularly women [74]. In some patients, it may not be clear from history or structural brain imaging if an ischemic event occurred in association with carotid disease.

DeReuck and colleagues have extensively investigated the use of Cobalt-55 as a label for recent (within two months) irreversible brain ischemia [15], [14] Cobalt-55 is a calcium analogue and may reflect calcium influx in ischemic tissue [82]. The degree of uptake appears to correlate with the severity of the ischemic damage within the first 2 months after stroke and then returns to normal levels [15].

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