Bridging the Gap between Research and Clinical Practice in Asymptomatic Alzheimer's Disease.

Due to the growing global health impact of Alzheimer's disease (AD), there is a greater need for interventions that prevent or delay the onset of clinical symptoms of this debilitating disease. Clinical trials for disease-modifying compounds in AD have shifted towards earlier stages in the spectrum of illness, including the stage prior to cognitive symptoms. A population of specific interest for clinical research includes individuals with evidence of Alzheimer's disease pathology who are asymptomatic (ADPa). The challenges and barriers regarding medical treatment of ADPa must be identified and addressed prior to the completion of a positive clinical trial in order to accelerate the translation of research findings to clinical practice. This report applies an existing public health impact model from Spencer and colleagues (2013) to evaluate the readiness of the clinical practice environment to treat ADPa individuals if a disease-modifying agent achieves approval. We contrast the current clinical practice environment with a potential future state through investigating the effectiveness, reach, feasibility, sustainability, and transferability of the practice of treating ADPa individuals.

ß-Amyloid burden in healthy aging: regional distribution and cognitive consequences.

OBJECTIVE: Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of ß-amyloid (Aß) in a healthy adult lifespan sample (aged 30-89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. METHODS: A total of 137 well-screened and cognitively normal adults underwent Aß PET imaging with radiotracer (18)F-florbetapir. Aß load was estimated from 8 cortical regions. Participants were genotyped for APOE and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability. RESULTS: Aß deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE ε4 (38%) than nonelevated adults (19%). Aß burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. CONCLUSIONS: Even in a highly selected lifespan sample of adults, Aß deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses.

Longitudinal changes of structural connectivity in traumatic axonal injury.

OBJECTIVES: To identify structural connectivity change occurring during the first 6 months after traumatic brain injury and to evaluate the utility of diffusion tensor tractography for predicting long-term outcome. METHODS: The participants were 28 patients with mild to severe traumatic axonal injury and 20 age- and sex-matched healthy control subjects. Neuroimaging was obtained 0-9 days postinjury for acute scans and 6-14 months postinjury for chronic scans. Long-term outcome was evaluated on the day of the chronic scan. Twenty-eight fiber regions of 9 major white matter structures were reconstructed, and reliable tractography measurements were determined and used. RESULTS: Although most (23 of 28) patients had severe brain injury, their long-term outcome ranged from good recovery (16 patients) to moderately (5 patients) and severely disabled (7 patients). In concordance with the diverse outcome, the white matter change in patients was heterogeneous, ranging from improved structural connectivity, through no change, to deteriorated connectivity. At the group level, all 9 fiber tracts deteriorated significantly with 7 (corpus callosum, cingulum, angular bundle, cerebral peduncular fibers, uncinate fasciculus, and inferior longitudinal and fronto-occipital fasciculi) showing structural damage acutely and 2 (fornix body and left arcuate fasciculus) chronically. Importantly, the amount of change in tractography measurements correlated with patients' long-term outcome. Acute tractography measurements were able to predict patients' learning and memory performance; chronic measurements also determined performance on processing speed and executive function. CONCLUSIONS: Diffusion tensor tractography is a valuable tool for identifying structural connectivity changes occurring between the acute and chronic stages of traumatic brain injury and for predicting patients' long-term outcome.

Treatment advances for cocaine-induced ischemic stroke: focus on dihydropyridine-class calcium channel antagonists.

OBJECTIVE: The authors reviewed the pathogenesis of cocaine-related cerebral ischemia, appraised current knowledge of its sequelae, and assessed the role of putative therapeutic agents, particularly dihydropyridine-class calcium channel antagonists. METHOD: The authors performed an OVID-based literature review of all indexed journals between 1966 and 2000. RESULTS: Cocaine abuse significantly increases the risk of ischemic stroke. The principal mechanism of cocaine-induced cerebral ischemia is vasospasm of large cranial arteries or within the cortical microvasculature. Increased levels of extracellular monoamines, particularly dopamine, mediate vasospasm. Neuroanatomical and labeling studies also have shown that dopamine-innervated neurons may regulate cerebral blood flow. Indeed, dopamine-rich brain regions appear to be relatively specific targets for cocaine-induced cerebral ischemia. Neuroimaging studies show that cocaine-induced hypoperfusion can persist even after 6 months of abstinence. Hypoperfusion can result in deficits on complex and simple psychomotor tasks but perhaps not on memory or attention. Severe cerebral ischemia can directly precipitate neuronal death and degradation, a condition exacerbated by liberation of the excitatory amino acid glutamate. Dihydropyridine-class calcium channel antagonists inhibit cocaine-mediated dopamine release on neurons involved in vasospasm and the control of cortical circulation. Other causes of cerebral ischemia include thrombogenesis and vasculitis. Although antithrombotic agents have potential in alleviating cocaine's neurotoxic effects, their use may be limited by the risk of spontaneous hemorrhage. CONCLUSIONS: Cocaine abuse can result in stroke, neuroischemia, and cognitive deficits that can persist even after prolonged abstinence. Dihydropyridine-class calcium channel antagonists, such as isradipine, show promise as therapeutic agents for preventing cocaine-induced cerebral ischemia.

Occipital brain perfusion deficits in children with major depressive disorder.

UNLABELLED: Occipital lobe perfusion defects have been identified on regional cerebral blood flow (rCBF) SPECT scans of adolescent children and young adults with major depressive disorder (MDD). We reinvestigated a series of rCBF SPECT scans obtained several years ago on drug-naive children with a clinical diagnosis of MDD and on healthy children. METHODS: To test whether visually apparent abnormalities in rCBF constitute statistically significant differences between patients, given the relatively small sample sizes, we applied the technique of statistical parametric mapping (SPM). RESULTS: Two groups of patients were identified: 8 with significant posterior flow deficits in the occipital cortex (Brodmann's areas 18 and 19), usually symmetric, and best visualized on paramedian sagittal sections, and 13 without obvious occipital perfusion deficits but with anterior rCBF deficits in a pattern often described in the literature, attaining statistical significance in the right frontal region. Other localizations in the left frontal and bilateral prefrontal regions did not attain significance, but each localization contained statistically significant maxima (z scores). The scan findings of all 18 healthy children were normal. CONCLUSION: With the aid of SPM, 2 groups of children with significantly different rCBF behavior were identified. The reason for this difference is not known but should be investigated to determine its possible significance to patients with MDD.

Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers.

UNLABELLED: Functional brain imaging is a powerful tool for examining the central nervous system (CNS) response to pharmacologic challenges. Amphetamine is of interest both because of its role as a stimulant of the dopaminergic system and because of its use to alter mood in mood-disordered patients, particularly in patients suffering from depression. In this study, we report the effects of oral D-amphetamine relative to placebo on regional cerebral blood flow (rCBF) measured by SPECT in healthy volunteers to characterize the normal CNS response to this primarily dopaminergic stimulant. METHODS: SPECT was used to assess changes in rCBF induced by amphetamine in 16 healthy volunteers. Subjects received placebo and then 0.4 mg/kg oral amphetamine in a fixed-order single-blind design and were imaged on a triple-head tomograph. Another six healthy volunteers received placebo at both times to assess normal rCBF variability. rCBF changes were assessed with a three-dimensional voxel-based analysis integrated into an automated coregistration system. Data were automatically normalized to whole-brain counts and coregistered. Resultant rCBF changes were evaluated parametrically through the formation of an image whose voxel values were based on the paired t statistic. RESULTS: Amphetamine increased rCBF in two mesial prefrontal zones (Brodmann's areas 8 and 10), inferior orbital frontal lobe (area 11), brain stem (ventral tegmentum), anteromesial temporal lobe (amygdala), and anterior thalamus. Amphetamine decreased rCBF to motor cortex, visual cortex, fusiform gyrus, posterolateral temporal lobe, and right lateral temporal lobe. CONCLUSION: Our data suggest that amphetamine induces focal increases and decreases in rCBF in healthy volunteers in areas primarily innervated by dopamine pathways and in areas with secondary (primarily limbic) affiliations. These data are consistent with glucose metabolic data from autoradiographic studies in animals, in which the largest increases are seen in brain stem, followed by striatum, thalamus, and frontal and sensory cortices. Frontopolar and temporal increases observed in our study appear to be unique to humans.

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

Limbic responsiveness to procaine in cocaine-addicted subjects.

OBJECTIVE: The limbic system plays a critical role in motivation, emotional expression, and memory. The authors investigated whether a state of permanent limbic neuronal hyperexcitability, or sensitization, is present in cocaine addicts as a consequence of repeated cocaine use. METHOD: Single photon emission computed tomography (SPECT) of regional cerebral blood flow (rCBF) was used to compare the central nervous system response to the limbic stimulus procaine in 10 cocaine-dependent male patients and 10 healthy comparison male subjects. RESULTS: The cocaine-addicted subjects demonstrated bilateral activation of the orbitofrontal cortex after the procaine challenge, whereas the comparison subjects showed activation of the anterior cingulate, bilateral insular, and right amygdalar regions. After receiving placebo, the cocaine-addicted subjects showed markedly lower rCBF in the bilateral orbitofrontal cortex than the comparison subjects. CONCLUSIONS: The pattern of hypoperfusion in the placebo state followed by heightened activation with procaine in the cocaine-addicted subjects is similar to the pattern of interictal hypoperfusion and ictal hyperperfusion that has been observed in subjects with epilepsy. The findings for the cocaine-addicted subjects may thus represent evidence of localized (orbitofrontal) sensitization.

Preoperative functional assessment of auditory cortex in adult cochlear implant users.

OBJECTIVES: To explore functional neuroanatomical responses to auditory stimulation before and after implantation. STUDY DESIGN: A prospective study of three cochlear implant candidates (pure-tone averages of 90 dB HL or greater bilaterally and hearing in noise test [HINT] performances of <40%) in which regional cerebral blood flow (rCBF) was assessed using single photon emission computed tomography (SPECT). METHODS: Candidates watched a 15-minute videotaped story under four conditions: audio presented monaurally in the right and left ears (aided), audio presented binaurally (aided), and visual-only presentation of the story. Five minutes into each story, 20 to 25 mCi of technetium 99m (99mTc) hexamethyl-propyleneamine-oxime (HMPAO) (Ceratec; Nycomed Amersham, Princeton, NJ, U.SA) was injected over a 30-second period to ensure that subjects were unaware of tracer administration. Subjects were scanned for 20 minutes using a PRISM 3000 gamma camera (Picker International, Cleveland, OH, U.S.A.). Data were normalized and co-registered, and subtraction images were compiled. Subtraction images contrasted activation patterns generated under the visual-only control condition to the auditory activation states acquired monaurally and binaurally. RESULTS: Right and left ear monaural stimulation in normal hearing subjects resulted in significant bilateral activation of Brodmann areas 41, 42, 21, 22, and 38. Although substantial intersubject response variability was noted, subjects generally failed to bilaterally activate these areas under monaural hearing aid presentations; however, bilateral activation of areas 41 and 22 was noted under binaural presentations. CONCLUSIONS: Despite relatively similar hearing losses in each ear, significant differences in preoperative auditory cortex activation were observed between ears. These data suggest that functional brain imaging provides a useful tool for exploring the responsiveness of the auditory cortex in cochlear implant candidates.

A SPECT HMPAO study of regional cerebral blood flow in depressed adolescents and normal controls.

1. The objective of this study was to compare the relative regional cerebral blood flow (rCBF) patterns of a group of adolescents with major depressive disorder (MDD) to a group of normal controls. 2. Seven adolescent patients with symptomatic MDD and 7 age- and gender-matched normal controls, underwent SPECT imaging with 99mTc-HMPAO while unmedicated and in a resting state. These subject's data were normalized to whole brain counts, oriented in Talairach space, and analyzed using a voxel-based, t-image approach. 3. The authors found relative rCBF increases in the depressed group as compared to normals in the right mesial temporal cortex, the right superior-anterior temporal lobe, and the left infero-lateral temporal lobe. We found rCBF decreases in the depressed group as compared to normals in the left parietal lobe, the anterior thalamus and the right caudate. 4. Adolescents with MDD show rCBF abnormalities similar to those found in adult MDD rCBF studies. Further controlled studies with larger numbers of MDD subjects and normal age- and gender-matched controls are necessary before any definitive conclusions can be made from these findings.

SPECT brain imaging in epilepsy: a meta-analysis.

UNLABELLED: A meta-analysis of SPECT brain imaging in epilepsy was performed to derive the sensitivity and specificity of interictal, postictal or ictal rCBF patterns to identify a seizure focus in medically refractory patients. METHODS: Papers were obtained by pooling all published articles identified by two independent literature searches: (a) Dialnet (EMBASE) or Radline by CD-ROM and (b) Current Contents searched manually. Literature inclusion criteria were: (a) patients had a localization-related epileptic syndrome; (b) more than six patients were reported; and (c) patients had at least an interictal EEG-documented epileptiform abnormality. Of 46 papers meeting these criteria, 30 contained extractable data. SPECT results were compared to localization by standard diagnostic evaluation and surgical outcome. Meta-analytic sensitivities for SPECT localization in patients with temporal lobe seizures relative to diagnostic evaluation were 0.44 (interictal), 0.75 (postictal) and 0.97 (ictal). Similar results were obtained relative to surgical outcome. False-positive rates were low relative to diagnostic evaluation (7.4% for interictal and 1.5% for postictal studies) and surgical outcome (4.4% for interictal and 0.0% for postictal studies). RESULTS: The results were not dependent on tracer used (or dose), the presence of CT-identified structural abnormalities, blinding of image interpretation or camera quality (although data were more variable with low-resolution cameras). There were insufficient data for conclusions regarding extratemporal-seizure or pediatric epilepsy populations. CONCLUSION: Insights gained from reviewing this literature yielded recommendations for minimal information that should be provided in future reports. Additional recommendations regarding the nature and focus of future studies also are provided. The most important of these is that institutions using SPECT imaging in epilepsy should perform ictal, preferably, or postictal scanning in combination with interictal scanning.

Brain single-photon emission CT with HMPAO and safety of thrombolytic therapy in acute ischemic stroke. Proceedings of the meeting of the SPECT Safe Thrombolysis Study Collaborators and the members of the Brain Imaging Council of the Society of Nuclear Medicine.

BACKGROUND: To reliably identify patients at risk for symptomatic hemorrhagic transformation (SHT), future trials of thrombolysis for acute ischemic stroke might use a vascular imaging protocol applicable to a multicenter setting. The goal of this commentary is to address the safety of intravenous thrombolysis with the recombinant tissue plasminogen activator (rTPA) and potential solutions offered by single-photon emission CT (SPECT) as a noninvasive brain perfusion imaging modality. SUMMARY OF REVIEW: Even if patients with severe stroke, extensive ischemic changes on CT scan, advanced age, and high blood pressure are excluded from thrombolytic therapy, this cannot completely guarantee the safety of using rTPA. Brain SPECT scanning with hexamethylpropyleneamine-oxime (HMPAO) may help to screen out patients at risk if performed in addition to clinical and CT tests. The knowledge of pretreatment severity, extent, and location of ischemia might identify good versus poor responders to rTPA therapy. HMPAO-SPECT is widely available and feasible to perform without delaying rTPA therapy. Rigorous quality control and use of reproducible visual and semiquantitative methods of interpreting SPECT are necessary for implementation of SPECT technology in multicenter clinical trials. CONCLUSIONS: The major obstacle to general acceptance of thrombolytic therapies and rTPA in particular is the fear of symptomatic hemorrhagic transformation, and because HMPAO-SPECT might reliably identify patients at high risk of symptomatic hemorrhagic transformation, the clinical value of HMPAO-SPECT in patient selection for thrombolysis during the first hours of acute ischemic stroke should be determined through a prospective clinical trial.

Evaluation of neurologic function in Gulf War veterans. A blinded case-control study.

OBJECTIVE: To determine whether Gulf War-related illnesses are associated with central or peripheral nervous system dysfunction. DESIGN: Nested case-control study. PARTICIPANTS: Twenty-three veterans with factor analysis-derived syndromes (the cases), 10 well veterans deployed to the Gulf War (the deployed controls), and 10 well veterans not deployed to the Gulf War (the nondeployed controls). METHOD: With investigators blinded to group identities, participants underwent objective neurophysiological, audiovestibular, neuroradiological, neuropsychological, and blood tests. MAIN OUTCOME MEASURES: Evidence of neurologic dysfunction. RESULTS: Compared with the 20 controls, the 23 cases had significantly more neuropsychological evidence of brain dysfunction on the Halstead Impairment Index (P=.01), greater interside asymmetry of the wave I to wave III interpeak latency of brain stem auditory evoked potentials (P=.02), greater interocular asymmetry of nystagmic velocity on rotational testing, increased asymmetry of saccadic velocity (P=.04), more prolonged interpeak latency of the lumbar-to-cerebral peaks on posterior tibial somatosensory evoked potentials (on right side, P=.03, and on the left side, P=.005), and diminished nystagmic velocity after caloric stimulation bilaterally (P values range from .02 to .04). Cases (n=5) with syndrome 1 ("impaired cognition") were the most impaired on brain stem auditory evoked potentials (P=.005); those (n=13) with syndrome 2 ("confusion-ataxia") were the most impaired on the Halstead Impairment Index (P=.006), rotational testing (P=.01), asymmetry of saccadic velocity (P=.03), and somatosensory evoked potentials (P< or =.01); and those (n=5) with syndrome 3 ("arthro-myo-neuropathy") were the most impaired on caloric stimulation (P< or =.01). CONCLUSIONS: The 3 factor-derived syndromes identified among Gulf War veterans appear to represent variants of a generalized injury to the nervous system.

Effects of four normalizing methods on data analytic results in functional brain imaging.

Functional brain imaging data may contain large individual differences in information about whole brain and regional levels of activity, and it is common to remove these differences using arithmetic transformation (normalization) prior to statistical analysis. As no single transformation is widely accepted, we examine the effects of four normalizing methods (ratioing, residuals from regressions on global cerebral blood flow, Z scores, and subject residual profiles) on 1) profile shape, 2) correlations between regions, 3) correlations between subjects, and 4) analysis of variance results. These effects are evaluated using an empirical data set consisting of regional cerebral blood flow values from 22 regions of interest in 46 depressed adults and 48 age-matched normal controls obtained by 133Xe single photon emission computed tomography. Results show that normalization method has substantial but different effects on characteristics of the data and statistical results. The rationing method appears to be an optimal choice for most analyses.

Comparison of technetium-99m-HMPAO and xenon-133 measurements of regional cerebral blood flow by SPECT.

UNLABELLED: This study compares 99mTc-HMPAO count ratios and derived regional cerebral blood flow (rCBF) to 133Xe rCBF ratios and true rCBF (ml/min/100 g), respectively. METHODS: Technetium-99m-HMPAO distribution was evaluated in 14 patients and 5 normal control subjects. Immediately after 133Xe SPECT, subjects received 22 +/- 4mCi 99mTc-HMPAO, and images were acquired 15 min after injection. rCBF (ml/min/100 g, 133Xe) or regional count density (99mTc-HMPAO) were extracted from 24 ROI located 6 cm above the cantho-meatal line. These data were also normalized to global cerebral blood flow (gCBF) for 133Xe or to global count density (gCD) for 99mTc-HMPAO. Technetium-99m-HMPAO ROI data also were expressed in units of ml/min/100 g by relating gCD to gCBF. Comparisons between 133Xe and 99mTc-HMPAO were evaluated using a Bonferroni-corrected paired t-test and by linear regression analysis. RESULTS: Profile plots demonstrated agreement in the pattern of relative distribution between rCBF ratios (133Xe) and count density ratios (99mTc-HMPAO). Regression analysis indicated a significant correlation (r = 0.78), with a modest slope (0.52) and a large intercept (0.48). A closer correlation (r = 0.92) was found for the comparison between rCBF (133Xe) and derived 99mTc-HMPAO rCBF. The slope was closer to one (0.82) and the intercept closer to zero. This relationship was also examined during high rCBF after a subset of these subjects (n = 7) was injected intravenously with 1 g acetazolamide. Again, profile plots and regression analysis demonstrated agreement in the pattern of distribution (ratios) between 133Xe and 99mTc-HMPAO (r = 0.66). However, the slope was reduced and the intercept increased relative to resting data. Absolute flow correlations showed some improvement relative to the ratio data (r = 0.77). CONCLUSION: The distribution of 99mTc-HMPAO is linearly related to rCBF measured by 133Xe SPECT, although our data suggest that 99mTc-HMPAO mildly underestimates rCBF above 80 ml/min/100 g. These results are similar to our previous comparison of 99mTc-ECD and 133Xe.

Calcium 45 autoradiography and dual-isotope single-photon emission CT in a canine model of cerebral ischemia and middle cerebral artery occlusion.

PURPOSE: To determine whether transient ischemia can be separated from permanent ischemia via calcium 45 autoradiography and to assess the applicability of dual isotope single-photon emission CT (SPECT) in the evaluation of cerebral blood flow. METHODS: We examined calcium influx in 12 dogs (group A) by using whole-brain calcium 45 autoradiography: Animals received 250 microCi/kg 24 hours after 30-minute (n = 6) or permanent (n = 6) middle cerebral artery (MCA) occlusion. Forty-eight hours after MCA occlusion, 5-mm coronal brain sections were fixed for either autoradiography or pathologic examination. In a separate study, 9 mongrel dogs (group B) were given 250 microCi/kg calcium 45 and a mean dose of 700 microCi/kg technetium Tc 99m hexamethylpropyleneamine oxime intravenously. A silicone plug was then injected into the internal carotid artery and angiography was performed to verify MCA occlusion. A 10th (control) animal did not undergo occlusion. In an 11th animal, placement of the plug could not be achieved and a slurry of microfibrillar collagen was injected into the carotid artery. No angiography was performed in animals 10 and 11. After occlusion, each animal was injected with a mean dose of 126 microCi/kg simultaneous acquisition for technetium 99m and 123I-iodoamphetamine. RESULTS: In group A, all animals who had permanent MCA occlusion showed infarction and increased calcium 45 uptake in infarcted territories. None of the animals who had 30-minute occlusion had either increased calcium 45 uptake or infarction at 48 hours. In group B, 7 or 10 dogs had SPECT findings that were consistent with the calcium autoradiographic marker for ischemia. One animal died during the procedure and 1 dog served as a control. CONCLUSION: Calcium 45 autoradiography allowed distinction between areas of temporary and permanent occlusion. Iodoamphetamine imaging was not consistently sensitive to that level of ischemia. Timing of calcium influx may lead to insight that could impact timing of pharmacologic or endovascular intervention.

Wisconsin card sorting activated regional cerebral blood flow in first break and chronic schizophrenic patients and normal controls.

Dynamic 133Xe single photon emission computed tomography (SPECT) was used to measure regional cerebral blood flow (rCBF) during the Wisconsin Card Sorting test (WCS) and the Number Matching task (NM) in six never-medicated first break schizophrenic and schizophreniform patients, seven chronic schizophrenic patients, and seven normal controls. Because of a difference in mean age between first break patients and normals, we adjusted rCBF data for age effects using ANCOVA. For age-adjusted absolute superior and middle frontal rCBF bilaterally, we found significantly less activation from NM to WCS in first break patients compared to normals. Similarly, for age-adjusted absolute and relative left middle frontal rCBF, we found significantly less activation in chronics compared to normals. Changes in age-adjusted global cerebral blood flow (gCBF) were not statistically significant among the three groups, but were in the same direction as activated absolute frontal rCBF. Because of the small number of subjects in each group, the results of this study should be regarded as preliminary and interpreted cautiously.

SPECT functional brain imaging. Technical considerations.

The technical aspects of functional brain single-photon emission computed tomography (SPECT) imaging, referring primarily to the most common SPECT brain function measure--regional cerebral blood flow--are reviewed. SPECT images of regional cerebral blood flow are influenced by a number of factors unrelated to pathology, including tomographic quality, radiopharmaceuticals, environmental conditions at the time of radiotracer administration, characteristics of the subject (e.g., age, sex), image presentation, and image processing techniques. Modern SPECT scans yield excellent image quality, and instrumentation continues to improve. The armamentarium of regional cerebral blood flow and receptor radiopharmaceuticals is rapidly expanding. Standards regarding the environment for patient imaging and image presentation are emerging. However, there is still much to learn about the circumstances for performances and evaluation of SPECT functional brain imaging. Challenge tests, primarily established in cerebrovascular disease (i.e., the acetazolamide test), offer great promise in defining the extent and nature of disease, as well as predicting therapeutic responses. Clearly, SPECT brain imaging is a powerful clinical and research tool. However, SPECT will only achieve its full potential in the management of patients with cerebral pathology through close cooperation among members of the nuclear medicine, neurology, psychiatry, neurosurgery, and internal medicine specialties.