Positron Imaging in Ischemic Stroke Disease Using Compounds Labeled With Oxygen 15

Weber

2016

J Nucl Med

The concept of the ischemic penumbra was formulated on the basis of animal experiments showing functional impairment and electrophysiologic disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed the "penumbra," and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. In further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and the duration of critically reduced blood flow was established, proving that the lower the flow, the shorter the time for efficient reperfusion. As a consequence, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The translation of this experimental concept as the basis for the efficient treatment of stroke requires noninvasive methods with which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. PET allows the quantification of regional cerebral blood flow, the regional oxygen extraction fraction, and the regional metabolic rate for oxygen. With these variables, clear definitions of irreversible tissue damage and of critically hypoperfused but potentially salvageable tissue (i.e., the penumbra) in stroke patients can be achieved. However, PET is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted MRI is a widely applicable clinical tool, and the "mismatch" between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. However, comparative studies of perfusion-weighted or diffusionweighted MRI and PET have indicated overestimation of the core of irreversible infarction as well as of the penumbra by the MRI modalities. Some of these discrepancies can be explained by the nonselective application of relative perfusion thresholds, which might be improved by more complex analytic procedures. The heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of perfusion-weighted or diffusion-weighted MRI to the selection of patients for clinical trials. As long as validation of the mismatch selection paradigm is lacking, the use of this paradigm as a surrogate marker of outcome is limited. ENERGY REQUIREMENTS OF BRAIN TISSUEBecause the energy demand of nervous tissue is very high, sufficient blood supply to the brain must be maintained consistently. The oxygen consumption of the brain is involved almost entirely in the oxidative metabolism of glucose which, in normal physiologic conditions, is the almost exclusive substrate for the energy metabolism of the brain (1). The glucose metabolized in neuronal cell bodies is used mainly to support cellular vegetative and hou...

Section: Identification Of Penumbra By Imagingmentioning

confidence: 99%

Validation of MRI Determination of the Penumbra by PET Measurements in Ischemic Stroke

Weber

2016

J Nucl Med

“…In humans, the brain tissue with rCBF < 12 mL/100 g per min and rCMRO 2 < 65 mmol/100 g per min (often measured several hours after stroke) usually displays eventual evidence of infarction on late computerized tomographic scans (Ackerman et al, 1981;Baron et al, 1981a;Lenzi et al, 1982;Powers et al, 1985). Relatively preserved CMRO 2 in regions of severely reduced CBF has been taken as an indicator of maintained neuronal function in regions with severely reduced CBF.…”

Section: Positron Emission Tomography Imagingmentioning

confidence: 99%

Heterogeneity in the penumbra

Zoppo

Sharp

J Cereb Blood Flow Metab

et al. 2011

142

124

Original experimental studies in nonhuman primate models of focal ischemia showed flow-related changes in evoked potentials that suggested a circumferential zone of low regional cerebral blood flow with normal K + homeostasis, around a core of permanent injury in the striatum or the cortex. This became the basis for the definition of the ischemic penumbra. Imaging techniques of the time suggested a homogeneous core of injury, while positing a surrounding 'penumbral' region that could be salvaged. However, both molecular studies and observations of vascular integrity indicate a more complex and dynamic situation in the ischemic core that also changes with time. The microvascular, cellular, and molecular events in the acute setting are compatible with heterogeneity of the injury within the injury center, which at early time points can be described as multiple 'minicores' associated with multiple 'mini-penumbras'. These observations suggest the progression of injury from many small foci to a homogeneous defect over time after the onset of ischemia. Recent observations with updated imaging techniques and data processing support these dynamic changes within the core and the penumbra in humans following focal ischemia.

“…Early PET studies on stroke have identified various tissue compartments within a brain territory compromised by ischemia (40)(41)(42)(43). Tissue with rCBF lower than 12 mL/100 g/min or regional CMRO 2 lower than 65 mmol/100 g/min at the time of measurement (usually several hours after stroke) was found to be infarcted on late CT scans.…”

Section: Identification Of the Ischemic Penumbramentioning

confidence: 99%

Radionuclide Imaging in Ischemic Stroke

2014

J Nucl Med

Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the physiologic and metabolic variables relevant for brain function and the radionuclides and methods to measure these variables in cerebrovascular disease, especially ischemic stroke; (2) the radionuclide methods to determine the thresholds of flow and metabolism relevant for preservation of function and morphology and the obtained values in their relevance to prognosis and potential treatment; and (3) the applications of radionuclide imaging for identifying pathophysiologic changes responsible for extension of ischemic lesions, for defining the hemodynamic reserve in vascular disease, for detecting remote effects outside the primary lesions, and for locating compensatory activation in disturbed functional networks.Financial Disclosure: Dr. Heiss is supported by the Wolf-Dieter Heiss Foundation within the Max Planck Society. The author of this article has indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through November 2017.Ischemic stroke is caused by interruption or significant impairment of blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphologic damage. The changes in regional cerebral blood flow and regional metabolism can be assessed by radionuclide imaging, especially SPECT and PET. SPECT and PET have broadened our understanding of flow and metabolic thresholds critical for maintenance of brain function and morphology: PET was essential in the transfer of the concept of the penumbra to clinical stroke and thereby had a great impact on developing treatment strategies. Receptor ligands can be applied as early markers of irreversible neuronal damage and can predict the size of the final infarcts, which is important for decisions on invasive therapy in large ("malignant") infarction. With SPECT and PET, the reserve capacity of the blood supply can be tested in obstructive arteriosclerosis, which is essential for planning interventions. The effect of a stroke on surrounding and contralateral primarily unaffected tissue can be investigated, helping to understand symptoms caused by disturbance in functional networks. Activation studies are useful to demonstrate alternative pathways to compensate for lesions and to test the effect of rehabilitative therapy. Radioisotope studies help to detect neuroinflammation and its effect on extension of tissue damage. Despite the...