of the molecules in the blood before they reach the brain. The more blood that flows through a given brain region, the more tracer it receives. Both agents are highly lipophilic and easily cross the BBB. Once in the brain, they undergo conversion to polar compounds that cannot diffuse back into the blood. The precise mechanisms involved are still disputed: in the case of 99mTc-HMPAO a significant part of the transformation is through reaction of the native molecule with reduced glutathione in astrocytes, whereas for 99mTc-ECD most of the transformation is through the action of esterases located both extra- and intra-cellularly.
Four principles must be kept in mind when interpreting SPECT studies:
• After first pass uptake, tracer trapped within brain tissue remains essentially stable over time. One can therefore consider that the SPECT images produced are a "snapshot" of the distribution of rCBF at the time of injection of the tracer.
• Although these tracers are highly lipophilic, they are diffusion limited at high flow rates. Overall, high flow regions accumulate more radioactivity than low flow ones, but the relationship is not linear: as flow increases, the relative accumulation decreases. Techniques that correct for this effect are either cumbersome or inexact. Practically speaking, underestimation of high blood flow is of limited clinical importance as precise determination of rCBF is not generally required.
• Since 99mTc-HMPAO and 99mTc-ECD do not undergo the same chemical transformations, it is not surprising that their exact distributions differ slightly. This is most important for the diagnosis of sub-acute cerebral infarctions. During the luxury perfusion phase these lesions can show significant uptake of 99mTc-HMPAO, sometimes to levels that overestimate actual perfusion, perhaps due to locally increased glutathione concentrations. In contrast, 99mTc-ECD uptake is decreased in these cases, probably because the maintenance of the esterase activity which allows trapping of the tracer is energy dependent.
• SPECT rCBF studies represent a technically simple method for assessing complex neurophysiological events. Whereas it might be "simple" to interpret the very focal cortical activation associated with a strong sensory stimulation (strobe light in the eyes, vibrating ball in the hand) or a convulsive episode, evaluation of the more elaborate operations involved in the performance of tasks of greater complexity, cognitive function or emotion is more daunting. The emerging view of "brain function" is that the completion of even simple tasks relies on the activation of large distributed networks which interact extensively, are shared by a variety of different tasks, and can be efficiently replaced by secondary centres. In that context, highly specific associations between a given clinical state and a brain perfusion pattern are the exception rather than the norm.
Decreased rCBF arises through two mechanisms:
• Decreased vascular supply: Occlusive vascular disease directly interferes with nutritive blood flow. SPECT imaging can help to determine the hemodynamic effect of a vascular lesion.
• Decreased energy demand: Under most circumstances, brain energy utilisation and blood flow are tightly coupled (probably through nitric oxide [NO] release from specialized neurons). This allows small resistive vessels of the brain to dilate or constrict as energy consumption increases or falls. Since energy consumption in the brain is mostly devoted to sustaining glutamatergic (excitatory) transmission, rCBF mapping is essentially an indirect indicator of excitatory neurotransmission. SPECT imaging can thus depict the distribution of brain activity in neurologic disorders (such as primary degenerative processes) and psychiatric diseases that directly affect neurotranmission.
Techniques to separate these two processes rely on the fact that, under normal circumstances, cerebral perfusion increases or decreases according to local energy requirements by dilating or constricting resistance vessels. If a feeding vessel is stenotic then downstream vessels will dilate and the total blood volume will increase. Flow is thus maintained at a constant value at the expense of reducing "vasodilatory reserve". Cerebrovascular vasodilators, such as carbon dioxide (CO2) and acetazolamide, will increase flow to the normally supplied brain. Because of the decreased vasodilatory reserve in the area subtended by the stenotic vessel, flow will increase less than in areas with normal circulation. If, however, energy demand is decreased then decreased perfusion is adaptive and the vessels will respond normally to direct carbon dioxide (CO2) and acetazolamide. Both agents have been frequently used in the study of cerebrovascular diseases, but the highly variable results of those studies cast serious doubts on the clinical usefulness of such techniques.
Both 99mTc-HMPAO and 99mTc-ECD are available in kits that allow easy labelling of the precursor molecule. Once labelled, 99mTc-ECD is stable for at least 6 hours. Unmodified 99mTc-HMPAO is stable for only 30 minutes, though a stabilized preparation is also available. Injection is made through a pre-installed IV catheter in a quiet environment (usual dose 750 MBq). For some applications, the injection is timed to coincide with a specific event (e.g., seizure onset).
Scan acquisition usually starts 30 to 60 minutes after injection. 99mTc-HMPAO has slower blood clearance than 99mTc-ECD and background activity usually takes longer to decrease. Some 99mTc-HMPAO defects become more obvious with time after injection (probably attributable to local ischemia with secondary vasodilatation and increased blood volume), and in this setting up to 2 hours should elapse before imaging.
Technical parameters for rCBF SPECT acquisition should attempt to maximize counts and optimize resolution. Reconstruction techniques and image display play a crucial role and must be standardized: the same projection dataset can give rise to vastly different results depending on the reconstruction algorithm, choice of filter, attenuation correction, scatter correction and choice of display (film, computer screen, colour scale and contrast/background settings).
Deciding whether a study is normal or abnormal can be easy, as in cases with massive perfusion defects, but for milder abnormalities interpretation is more complicated. Most clinicians rely on a subjective visual interpretation where "normal" denotes symmetrical activity largely confined to grey matter in the cerebral cortex, cerebellum, basal ganglia and thalamus (white matter shows little uptake due to relatively low levels of blood flow).
More complex approaches for quantification are used in research and in some clinical settings. These methods often require spatial registration, resizing and warping of the images in an effort to superimpose different scans from the same patient (either of the same or different modalities obtained at different times) or from different patients (fused in order to compare groups of subjects). Most analytical tools were developed for PET or fMRI studies which have spatial resolution and temporal sampling capacities quite different from SPECT. Although the same techniques are applicable to SPECT, they have not been optimised for it and therefore have to be utilised with a good understanding of their characteristics and limitations.
To date nuclear neuroimaging has been used more for research than for clinical problem-solving. The clinical usefulness of SPECT rCBF imaging was carefully reviewed by an expert panel of the American Academy of Neurology. Based upon quality and strength of evidence they rated various clinical applications (Table 1). The indications designated as "established" are few and have not been expanded since the publication of this report in 1996. Although many other applications are "promising" and may eventually be accepted, for the moment caution is recommended before using rCBF SPECT studies on a systematic clinical basis in these conditions. Many of these conditions have not been evaluated in sufficient numbers and in adequately controlled prospective studies to allow firm, evidence-based conclusions to be drawn on the general usefulness of this application. This should not be construed to mean that it is useless to perform such studies on patients affected with these conditions, since many may benefit from the information provided. In some cases, the perfusion study will be useful in simply confirming an observable organic basis to symptoms and signs otherwise not linked to recognisable abnormalities on conventional imaging (CT or MRI). One such application is in the field of head trauma, where the very nature of some brain lesions (shearing at the microscopic level) can produce persistent memory and concentration problems despite normal CT and MRI examinations. Such lesions are expected to alter perfusion, and the demonstration of cerebral perfusion abnormalities helps to support claims for compensation or disability payments. An even more direct application is in the evaluation of vascular spasm following subarachnoid haemorrhage (SAH) where the cause of a deterioration in the neurological status of a patient with a known SAH is an alteration in blood flow (Fig 3). The results from SPECT rCBF studies seem to correlate very well with those of angiography but SPECT is a much less invasive technique for recognizing this serious complication and evaluating response to therapy. Other neurological conditions (such as AIDS dementia complex and viral encephalitis) have been reported to show altered patterns of brain perfusion, but the available evidence remains insufficient at this time to gauge the overall performance of SPECT perfusion studies in such cases.
The same remarks can be made for psychiatric illnesses, which are also associated with a variety of abnormal brain perfusion patterns. The observation of these patterns has been useful in helping to understand the pathophysiology of these afflictions, but to date they do not allow the use of SPECT rCBF studies as clinical tools for diagnosis or follow-up. For instance, the reported observations of activation in the
Table 1 Effectiveness of clinical applications of brain SPECT rCBF studies
Detection of acute ischemia Established
Determination of stroke subtypes Promising
Vasospasm following SAH Promising
Prognosis/recovery from stroke Investigational
Monitoring therapies Investigational
Diagnosis of TIA Investigational
Prognosis of TIA Investigational
Grading of gliomas Investigational Differentiating radiation necrosis from Investigational tumor recurrence
Localization of seizure focus Differential diagnosis of ictus Interictal detection of seizure focus Determination of seizure subtypes Receptor studies (not rCBF) Monitoring therapy
Alzheimer's disease To support clinical diagnosis
Huntington's chorea Persistent vegetative state Brain death
Adapted from: Assessment of brain SPECT—Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1996; 46:278-285.
auditory cortex during auditory hallucinations, or the modification of cerebral perfusion in a predictable way during the course of anti-depressant therapy (improved perfusion to the left dorsal pre-frontal cortex) shed light on the regions involved but have no impact on patient classification or management.
The three "established" clinical indications will be discussed in some detail.
Patients with medically uncontrollable epilepsy are potential candidates for surgical removal of the focus from which the attacks originate. This represents a substantial number of patients, since it is generally accepted that 15-25% of patients with epilepsy are sub-optimally to poorly controlled with medication alone. Conventional imaging
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