Evolution and Protection of Cerebral Infarction Evaluated by PET and SPECT
Since cerebral infarction results from a reduction of cerebral blood flow (CBF) by the occlusion or stenosis of carotid or intracranial arteries, CBF is a primary parameter to predict of ischemic brain injury. Single-photon emission tomography (SPECT) and positron emission tomography (PET) contributed to evaluate loss of cerebral autoregulation, uncoupling state between CBF and brain metabolism, and ischemic penumbra. Measurement of CBF and oxygen metabolism by 15O PET revealed the process of infarct growth in hyperacute stage of cerebral infarction and areas with depressed oxygen metabolism, but normal water diffusion in magnetic resonance imaging (MRI) was termed as “metabolic penumbra.” Recently, some researchers shed light on the role of glial cells in the energy metabolism of the brain and 11C-acetate PET and demonstrated that astrocytic energy metabolism in TCA cycle was protective against ischemia. SPECT and PET studies for secondary reaction after ischemia (i.e., selective neuronal loss by 123I-iomazenil SPECT and 11C-flumazenil PET, tissue hypoxia by 18F-FMISO PET, and neuroinflammation by TSPO-PET) are expected as new biomarkers. Combining these imaging biomarkers with classical CBF measurement may contribute to develop innovative drugs for pharmacological neuroprotection in the therapy of cerebral infarction.
KeywordsCerebral infarction SPECT PET Hypoxia TSPO-PET
Cerebral infarction results from a reduction in cerebral blood flow (CBF) arising from the occlusion or stenosis of carotid or intracranial arteries, and the progression of this event typically ends with the necrosis of various brain tissue components, including neurons. Since tissue damage varies according to the severity of brain ischemia, CBF is a primary parameter for predicting the extent of ischemic brain injury.
19.2 Perfusion and Oxygen Metabolism in Brain Ischemia
CBF is a key parameter of ischemic brain damage that can be quantitatively measured using PET and SPECT. A decrease in the cerebral perfusion pressure (CPP) induces primary damage to the supply of oxygen and energy substance to the brain. Protective mechanisms against reductions in the CPP can be evaluated using PET and SPECT. The first mechanism is “cerebral autoregulation,” the origin of which is cardiac pump function. CBF is constant within a mean arterial blood pressure (MABP) range of 60–160 mmHg . To maintain a constant CBF, cerebral precapillary arterioles can dilate when the CPP decreases and can constrict when the CPP increases. Although this mechanism of dilation and constriction for cerebral autoregulation remains unclear, recent studies have indicated that CBF control is initiated in the cerebral capillaries, where pericytes can constrict capillaries in response to the effect of noradrenaline . Cerebral autoregulation is disturbed by brain ischemia , and its capacity can be estimated using the cerebral vasoreactivity (CVR) to the change in the arterial partial pressure of carbon dioxide (PaCO2). In SPECT studies, acetazolamide, which is another vasodilating agent, is used to test CVR. A reduced CVR in patients with steno-occlusive carotid artery disease is a major predictor of stroke recurrence [4, 5].
19.3 Infarct Growth in Acute Cerebral Infarction
19.4 Role of Astrocytic Function in Brain Ischemia
Recently, some researchers have shed light on the role of glial cells in energy metabolism in the brain. Glutamate is a major excitatory neurotransmitter of the brain, and glutamate in the synaptic cleft is removed by astrocytes surrounding glutaminergic synapses. The removed glutamate is converted into glutamine in astrocytes by glutamine synthetase. Glutamine is released by astrocytes and taken up by neuronal terminals, where it is enzymatically reconverted to glutamate and stored in the neurotransmitter pool for the next transmission. This process is called “glutamate-glutamine cycle” and requires ATP . Furthermore, astrocytes play an important role in glycolysis in the brain. Activation by the glutamate transporter on the astrocytic membrane stimulates glucose uptake into astrocytes. This glucose is processed glycolytically, resulting in the release of lactate as an energy substrate for neurons. Lactate produced by this process is transferred to neurons for oxidation (the astrocyte-neuron lactate shuttle: ANLS) . This lactate produces two ATP molecules, which contribute to the Na-K ion pump function and the synthesis of glutamine from glutamate. In ischemic brain where ATP synthesis is restricted, the conversion of glutamate in the synaptic cleft is disturbed. Continuous stimulation by glutamate induces an influx of Ca2+ ion, resulting in anoxic depolarization, and leads to inflammation and apoptosis. Therefore, the glutamate-glutamine cycle and ANLS are deeply related to astrocytic function and plays a critical role in the evolution from penumbra to infarction.
19.5 Selective Neuronal Loss in Ischemic Brain Injury
19.6 Detection of Tissue Hypoxia
Tissue hypoxia can be visualized using 18F-labeled nitroimidazole derivatives or 62/64Cu-labeled lipophilic chelate compounds. 18F-fluoromisonidazole (18F-FMISO) PET is a representative hypoxic marker. Under hypoxic conditions, 18F-FMISO passively diffuses into cells and is reduced by nitroreductase enzymes and trapped by intracellular molecules. The retention of 18F-FMISO is inversely proportional to the tissue partial pressure of O2. Takasawa et al. revealed that the selective accumulation of 18F-FMISO was found in permanent and temporal ischemic areas surrounding the ischemic core . They demonstrated that 18F-FMISO uptake in the ischemic brain was only elevated during the early phase of middle cerebral artery (MCA) occlusion. After early reperfusion, no demonstrable tracer retention was observed. In patients with an acute MCA territory stroke, Markus et al. reported that 18F-FMISO PET showed the temporal evolution of tissue hypoxia . A higher hypoxic volume was observed in the core of the infarct within 6 h of onset, and the location moved to the periphery or external to the infarct at later time points. They also showed that tissue without 18F-FMISO uptake within the final infarct was presumed to have infarcted by the time of the acute 18F-FMISO PET. These experimental and clinical results are very interesting because they suggested that 18F-FMISO uptake changes continuously during the course of brain infarction. Since 18F-FMISO PET is unable to discriminate between complete infarcted area and non-hypoxic viable tissue during the acute stage of infarction, the timing of the PET examination is likely to be critical for diagnosing whether the tissue is salvageable.
19.7 Imaging of Neuroinflammation
Measurements of hemodynamic and metabolic disturbances using PET and SPECT have been utilized to study the acute and chronic stages of cerebral infarction. CBF, CMRO2, CBV, OEF, and CVR are basic parameters for estimating CPP reduction. An acute metabolic penumbra (decreased CMRO2 in peri-infarct area on initial PET) and misery perfusion (areas with decreased CBF with maintained CMRO2 in ischemic brain) during the acute and chronic stages are indicators of evolving infarction. Astrocytes have a protective role against cerebral infarction by reducing the glutamate concentration during ischemia, and 11C-acetate PET may provide information regarding glial cell function. Neuron-specific imaging can only be performed using PET and SPECT, and it would be useful to collate the clinical symptoms with neuronal damage. PET tracers for tissue hypoxia and neuroinflammation have been developed and are promising biomarkers for detecting infarct growth and salvageable tissue and are expected to become useful as probes in future therapeutic interventions.
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