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.

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.

Hypofrontality and cognitive impairment in schizophrenia: dynamic single-photon tomography and neuropsychological assessment of schizophrenic brain function.

Regional cerebral blood flow (rCBF) was assessed in 40 chronic male schizophrenic patients (20 medicated, 20 unmedicated) and 31 matched normal controls with Dynamic Single-photon Emission Computed Tomography (D-SPECT). Blind analyses of normalized color-coded tomograms revealed significant bifrontal and bitemporal rCBF deficits in the patient group. Frontal flow deficits were most prominent in paranoid patients (n = 21) and right temporal deficits were most prominent in nonparanoid patients (n = 19). These relative regional declines were observed within the context of significantly elevated hemispheric blood flow in schizophrenics compared with controls. Reduced left frontal rCBF was associated with neuropsychological impairment on the Wisconsin Card Sorting Test and Luria-Nebraska Battery. Increased hemispheric CBF was correlated with the presence of positive schizophrenic symptoms. Medication status was unrelated to rCBF. These findings demonstrate that hypofrontality has important implications for cognitive function in some schizophrenic individuals.

Error analysis of the double-integral method for calculating brain blood perfusion from inert gas clearance data.

A single-photon dynamic computer-assisted tomograph (DSPECT) has been built and is currently being used to evaluate regional cerebral blood perfusion in patients and volunteers. A computer simulation of the system was created to analyze the effects of data collection, Poisson noise, attenuation compensation, and the reconstruction technique now employed in the DSPECT. Several methods of attenuation compensation were used to generate perfusion images from both ideal and noisy data. The results indicate that the mean perfusion is calculated to within 10.4% accuracy for all perfusion rates in a region of interest if attenuation correction is used. Without attenuation correction, perfusions are underestimated by as much as 27%. The three correctors tested have different effects on the calculated perfusion value, depending on the location of the region of interest in the picture. The algorithm introduces random noise that is proportional to both the random error in the input data and the perfusion rate. Air-curve delay errors result in inaccuracies in the final perfusion picture that are proportional to perfusion rate. Physiological values (0.8-1.5) of the partition coefficient cause overestimation of both gray (0-34%) and white (7-67%) matter perfusion values. Compton scatter and collimator effects were not addressed in this study.

Normal distribution of regional cerebral blood flow measured by dynamic single-photon emission tomography.

Regional CBF (rCBF) was measured quantitatively using the inert-gas washout technique with xenon-133 and single-photon emission computed tomography. Tomographic data were reconstructed by filtered back projection, and flow was calculated according to the double-integral method. Ninety-seven subjects ranging in age from 20 to 59 years received a single examination; eight of these received a second examination within 1 h of the first; seven others received a second examination separated from the first by 1-10 days. Transverse-section images were obtained at 2, 6, and 10 cm above and parallel to the canthomeatal line (CML). Cortical gray matter flows were obtained from 12 brain regions in the slice 6 cm above the CML, and cerebellar and inferior cerebral gray matter flows were obtained from 4 regions in the slice 2 cm above the CML. Mean gray matter flow was 72 +/- 12 ml/min/100 g, with highest flows in the parietal lobes and visual cortex. No significant differences in rCBF occurred when a second study followed the first by 30 min to 10 days. Right-sided rCBF was slightly higher than left in all regions except frontal and parietal lobes where there was no difference. Flow was higher in women than in men and declined mildly with age for both sexes (slope = -0.33 ml/min/100 g/year; p less than 0.05).

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.

Cerebral blood flow changes during sodium-lactate-induced panic attacks.

Dynamic single-photon emission computed axial tomography (CAT) with inhaled xenon-133 was used to measure regional cerebral blood flow in 10 drug-free patients with DSM-III-diagnosed panic disorder and in five normal control subjects. All subjects underwent regional cerebral blood flow studies while at rest or during normal saline infusion and during sodium lactate infusion. Six of the 10 patients and none of the control subjects experienced lactate-induced panic attacks. Lactate infusion markedly raised hemispheric blood flow levels in both control subjects and patients who did not panic. Patients who did panic experienced either a minimal increase or a decrease in hemispheric blood flow.

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.

Single-proton tomographic study of regional cerebral blood flow in epilepsy. A preliminary report.

Regional cerebral blood flow (rCBF) may be measured with a single-photon-emission computed tomograph (SPECT) after inhalation of xenon 133. Our SPECT studies of rCBF in a group of 18 patients with seizure disorders, when compared with studies in 32 normal control subjects, have shown enhanced flow to an active seizure focus and ischemia of brain areas in certain subjects between seizures. Thus, SPECT determination of rCBF has demonstrated a number of findings recently observed with positron-emission tomography and may become a useful modality in the study of patients who have epilepsy.

Quantification of intracerebral steal in patients with arteriovenous malformation.

Eleven patients with angiographically and/or pathologically proved arteriovenous malformations (AVMs) were studied using dynamic, single-photon-emission computed tomography (DSPECT). Quantification of regional cerebral blood flow in structurally normal areas remote from the AVM disclosed areas of decreased flow compared with normal controls in eight of 11 patients examined. Areas of hypoperfusion correlated with altered function as manifested by epileptogenic foci and impaired cognitive function. Dynamic, single-photon-emission computed tomography provides a noninvasive technique to monitor quantitatively hemodynamic changes associated with AVMs. Our findings suggest that such changes are present in the majority of patients with AVMs and that they may be clinically significant. The potential application of regional cerebral blood flow imaging by DSPECT in the management of patients with AVMs is discussed.

Regional cerebral blood flow in developmental stutterers.

Stuttering is a poorly understood communication disorder with a 1% global prevalence. Recently, there has been a resurgence of interest in a neurogenic origin for the disorder, although no research has established clear neurological differences between "developmental" (stuttering onset in childhood) stutterers and nonstutterers. We have used xenon 133 single-photon emission computed tomography to study regional cerebral blood flow (rCBF) in 20 stutterers. Analysis revealed global, absolute flow reductions. Relative flow asymmetries (left less than right) were identified in three hemispheric regions: anterior cingulate and superior and middle temporal gyri. Milder changes were found in the left inferior frontal gyrus. Stutterers had rCBF values below median for either anterior cingulate or middle temporal gyri. With one exception, severe stutterers had rCBF values below median for the anterior cingulate gyrus. All stutterers with rCBF values above median in the cingulate gyrus had rCBF values below median in the middle temporal gyrus, and severity of their disorder was either mild or moderate. Our findings suggest that stuttering is a neurogenic disorder involving recognized cortical regions of speech-motor control.

Cognitive function and regional cerebral blood flow in partial seizures.

Patients with partial seizures have cognitive function impairments that have been attributed to the toxic side effects of anticonvulsants and structural cerebral damage. However, even when these factors are absent, neuropsychological (NP) deficits have been demonstrated, although of milder degree than in structurally brain-damaged patients. Assessment of cerebral metabolism using positron emission tomography and cerebral blood flow with single photon emission computed tomography (SPECT) reveals focal physiologic deficits in structurally normal areas. Using both SPECT and NP assessment with the Halstead-Reitan Battery, we evaluated 50 patients with partial seizures. Comparison of the location of visually identified regional cerebral blood flow (rCBF) deficits in these patients with the location of the NP deficits revealed a significant correlation. Additional analyses indicated that rCBF quantification in visually identified areas of hypoperfusion was significantly lower than in "normal" areas and that quantified NP variables significantly discriminated patients with and without visual rCBF deficits in temporal and frontal brain regions.

Heterogeneity in spasmodic dysphonia. Neurologic and voice findings.

Spasmodic dysphonia is a disturbance of phonation with laryngeal spasms. We report voice and neurologic examination findings in 45 subjects. Neurologic abnormalities were found in 32 subjects (71.1%). Rapid alternating movement abnormalities, weakness, and tremor were common. Incoordination and spasticity were rare. Lower extremity findings were frequent. Abnormalities were bilateral. Spasmodic dysphonia severity was related to age. Type, severity, and duration of vocal symptoms were not different for subjects with or without neurologic abnormalities. Vocal tremor was more frequent in neurologically abnormal subjects. Involvement of a pallidothalamic-supplementary motor area system could account for neurologic findings, brain imaging findings, and clinical heterogeneity. The view emerging is that spasmodic dysphonia is a manifestation of disordered motor control involving systems of neurons rather than single anatomical sites.

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.

Antihypertensive therapy in the elderly. Effects on blood pressure and cerebral blood flow.

Antihypertensive therapy significantly reduces cardiovascular morbidity and mortality in the rapidly growing population of elderly patients. However, the desire to treat more of these patients is dampened by the concern that a reduction in blood pressure may compromise cerebral blood flow, causing untoward consequences. This study evaluated the therapeutic effect of titrated doses of prazosin, an alpha-adrenergic blocking agent, on systemic blood pressure and cerebral blood flow in elderly patients with chronic stable hypertension. Prazosin alone or co-administered with hydrochlorothiazide significantly lowered mean systolic and diastolic blood pressures in 31 elderly hypertensive patients. At the same time, however, there was no significant change in cerebral blood flow, which was measured in eight patients. Neither harmful biochemical changes nor treatment-related adverse effects were observed in any patients. Prazosin therapy alone or in combination with low-dose diuretic therapy was effective in the treatment of hypertension in this elderly population. Furthermore, blood pressure reduction with prazosin therapy was accomplished without compromising cerebral blood flow and without unfavorably altering lipid profiles.

Dual-isotope brain SPECT imaging with technetium-99m and iodine-123: clinical validation using xenon-133 SPECT.

Our phantom studies indicate that the energy resolution (9.7% FWHM) of a new three-headed single-photon tomograph (PRISM-3000) separates the distribution of 99mTc from 123I for 10% asymmetric or 15% or 10% centered 99mTc windows when combined with a 10% asymmetric 123I window. This technique is now applied to the simultaneous measurement of resting rCBF and changes induced by vasodilation (1 g acetazolamide) in 10 subjects with cerebrovascular disease. Resting and vasodilated 133Xe SPECT images were obtained first. Within 48 hr, 99mTc HMPAO was given at rest, acetazolamide injected, and after 20 min either [123I] IMP or [123I] HIPDM was administered. Subjects were scanned for 99mTc and 123I simultaneously using 10% asymmetric windows. Regression analyses demonstrated a linear relationship between 133Xe SPECT and dual-isotope SPECT measurements of lesion-to-cerebellum ratios in baseline (r = 0.92), vasodilated (r = 0.86) and rest-minus-vasodilated data (r = 0.85). Technetium-99m and 123I images obtained through dual-isotope imaging are by definition in perfect anatomic registration.

Dual-isotope brain SPECT imaging with technetium-99m and iodine-123: validation by phantom studies.

Phantom studies were employed to determine whether the enhanced energy resolution (9.7% FWHM) of a new high-resolution, three-headed single-photon emission computed tomograph might permit the simultaneous acquisition of 99mTc and (123)I. Various window widths (15% and 10%) and positions (centered and asymmetric to the photopeak) were used to examine cross-contamination between these two isotopes. Brain phantom experiments using a 15% centered 99mTc window in conjunction with a 10% asymmetric (123)I window (upper half of the (123)I photopeak) demonstrated that approximately 95% of observed counts were derived from the isotope of interest. Shifting the (123)I window from asymmetric to centered resulted in a significant increase in contamination of the (123)I window. Shifting the 99mTc window from centered to asymmetric did not significantly alter image quality for 99mTc. Separate experiments employing vials with varying isotope concentrations demonstrated that quantitative recovery from mixed 99mTc and (123)I sources was equivalent to that from matched single-isotope sources (r2 > or = to 0.90).

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.

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.

Comparison of technetium-99m-ECD to Xenon-133 SPECT in normal controls and in patients with mild to moderate regional cerebral blood flow abnormalities.

Technetium-99m-1,1-ethyl cysteinate dimer (ECD) has been proposed as a "chemical microsphere" for SPECT measurement of regional cerebral blood flow (rCBF). However, its distribution has not yet been compared in humans to an established rCBF measure. Therefore, we compared the uptake and distribution of ECD with rCBF measured by 133Xe SPECT in subjects with mild to moderate flow abnormalities and in normal volunteers. Blood and urine chemistries and vital signs were unchanged from pre-ECD values up to seven days postinjection. Profile plots demonstrated pattern agreement between rCBF ratios (133Xe) and ECD count density ratios. A significant correlation of rCBF ratios to ECD count density ratios was observed (r = 0.77), with a slope of 0.64 and intercept of 0.36. To explore whether or not the relationship between rCBF and ECD was dependent on absolute flow, ECD region of interest data were expressed in units of ml/min/100 g by equating global CBF (133Xe) and ECD global count density. A closer correlation (r = 0.88) was found for these data than for the count ratio data. The slope was closer to one (m = 0.83) and the intercept was closer to zero (b = 8.2). Also, a significant correlation was observed between ECD-derived rCBF and 133Xe rCBF in the lesion area (r = 0.92) for patients with well-demarcated rCBF lesions. The slope (0.80) suggested a slight underestimation of lesion flow by ECD. Finally, ECD clearance from cortical gray matter ROIs derived from high-resolution scans from 1 to 4 hr postinjection was slow (2.4%/hr). In summary, ECD is a safe and effective marker of regional cerebral perfusion. The distribution of ECD is linearly related to rCBF measured by 133Xe SPECT, although our data suggest a mild underestimation of flow at the high end of the normal range.