Diagnostic approach with Z-score mapping to reduce artifacts caused by cerebral atrophy in regional CBF assessment of mild cognitive impairment (MCI) and Alzheimer's disease by [99mTc]-ECD and SPECT.

PURPOSE: The aim of this study was to develop a novel approach that enhanced diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and early Alzheimer's disease (AD) using cerebral perfusion SPECT by minimizing artifacts caused by cerebral atrophy. MATERIALS AND METHODS: [99mTc]-ECD and SPECT studies were performed on 15 cognitively normal patients, 40 patients with MCI, and 16 patients with AD. SPECT images were compared using SPM. The atrophy correction method was incorporated to reduce artifacts through the MRI masking procedure. Regional Z-score, percent extent, and atrophy correction rate were obtained and compared. The Z-score mapping program was structured as a single package that ran semi-automatically. RESULTS: The method significantly reduced regional Z-score in most regions, leading to improved estimates. The mean atrophy correction rate ranged from 10.4 to 12.0%. In MCI and AD, the convexities of the frontal and parietal lobes and the posterior medial cerebrum were particularly sensitive to cerebral atrophy, and the Z-scores were overestimated, whereas the posterior cingulate cortex and the cerebellum were less sensitive. The diagnostic accuracy for MCI increased from 67 to 69% and for AD from 78 to 82%. CONCLUSION: The proposed approach provided more precise Z-scores with less over- or underestimation, artifacts, and improved diagnostic accuracy, being recommended for clinical studies.

Whole-body vibration exercise and training increase regional CBF in mild cognitive impairment with enhanced cognitive function.

OBJECTIVES: Preclinical and non-medicinal interventions are essential for preventing and treating cognitive decline in patients with mild cognitive impairment (MCI). Whole-body vibration (WBV) exercise is conducted on a platform that generates vertical sinusoidal vibrations, and WBV training may improve regional cerebral blood flow (rCBF) and cognitive function, however, the underlying mechanism remains unclear. The aim of the present study was to investigate whether WBV exercise and a 24-week WBV training protocol increased rCBF and enhanced cognitive function in patients with amnestic MCI (aMCI). METHODS: [99mTc]-ECD and SPECT studies were performed on 16 aMCI patients at baseline, during WBV exercise, and on 6 of the 16 patients after 24-week WBV training. To diagnose SPECT images and select the patients, a Z-score mapping approach was used, which revealed pathological hypoperfusion in the parietal association cortex, precuneus and/or posterior cingulate gyrus for MCI at baseline. rCBF was semi-quantitatively measured and underestimation in the high flow range was corrected. Since it is difficult to quantitatively measure rCBF during WBV exercise, the rCBFratio was obtained by standardizing with the average of individual mean SPECT counts with correcting underestimation in the high flow range. The rCBFratios at baseline and after WBV training were also obtained in a similar manner. Since the changes in rCBF were regarded as corresponding to the changes in rCBFratio, the ratios were compared. Cognitive function was also evaluated and compared. RESULTS: We found that the rCBFratio changed with an average range of 11.5% during WBV exercise, and similar changes were observed after 24-week WBV training with a 13.0% change, resulting in improved cognitive function (MoCA-J, P = 0.028). The rCBFratio increased in the parietal association cortex and occipital lobes, including the precuneus and posterior cingulate gyrus, at which hypoperfusion was detected at baseline, but decreased in the frontal lobe and anterior cingulate gyrus. The rCBFratio increased on the right side of several motion-suppressive nuclei by WBV exercise; the bilateral red nuclei and right medial globus pallidus by WBV training. CONCLUSION: WBV exercise and training increase rCBF in aMCI patients, and WBV training enhances cognitive function and may increase the cognitive reserve. Further investigation is necessary.

Simplified estimation of binding parameters based on image-derived reference tissue models for dopamine transporter bindings in non-human primates using [18F]FE-PE2I and PET.

The aim of this study on dopamine transporter binding by [18F]FE-PE2I and PET was to describe an image-derived approach using reference tissue models: the Logan DVR approach and simplified reference tissue model (SRTM), the features of which were simple to operate and precise in the measurements. Using the approach, the authors sought to obtain binding images and parameters. [18F]FE-PE2I and dynamic PET as well as an MRI was performed on three rhesus monkeys, and metabolite corrected arterial plasma inputs were obtained. After co-registering of PET to MR images, both image sets were resliced. The time-activity curve of the cerebellum was used as indirect input, and binding parametric images were computed voxel-by-voxel. Voxel-wise linear calculations were used for the Logan DVR approach, and nonlinear least squares fittings for the SRTM. To determine the best linear regression in the Logan DVR approach, the distribution volume ratio was obtained using the optimal starting frame analysis. The obtained binding parameters were compared with those obtained by the other independent ROI-based numerical approaches: two-tissue compartment model (2TCM), Logan DVR approach and SRTM using PMOD software. Binding potentials (BP) obtained by the present approach agreed well with those obtained by ROI-based numerical approaches, although reference tissue models tended to underestimate the BP value than 2TCM. Image-derived Logan approach provided a low-noise image, the computation time was short, and the error in the optimal starting frame analysis was small. The present approach provides a high-quality binding parametric image and reliable parameter value easily.

[Conflict of intentions associated with leukodystrophy: a case report].

A 50-year-old woman developed a slowly progressive inability to control her motor functions over the past 3 years. For example, she would close the refrigerator door immediately after opening it against her intension, or at intersections she would go in a direction that she did not intend. These symptoms were regarded as "conflict of intentions (COI)." Brain magnetic resonance imaging (MRI) revealed diffuse atrophy of the corpus callosum with hyperintense lesions in the rostral portion of its body and the splenium. Based on these findings, her COI could be attributable to leukodystrophy of an unknown origin.

Quantitative PET analyses of regional [11C]PE2I binding to the dopamine transporter--application to juvenile myoclonic epilepsy.

The dopamine transporter (DAT) is of central interest in research on the pathophysiology and treatment of neuro-psychiatric disorders. [(11)C]PE2I is an established radioligand that provides high-contrast delineation of brain regions that are rich in DAT. The aim of the present PET study in eight patients with juvenile myoclonic epilepsy (JME) was to evaluate the kinetics of [(11)C]PE2I in the brain and to compare binding parameters with those of age-matched control subjects (n = 6). Each patient participated in 90-minute PET measurements with [(11)C]PE2I. Data were analyzed using kinetic compartment analyses with metabolite-corrected arterial plasma input and reference tissue models using the cerebellum as a reference region. The time-activity curves were well described by the two-tissue compartment model (2TCM) for the DAT-rich regions. The 2TCM with fixed K(1)/k(2) ratio derived from the cerebellum provided robust and reliable estimates of binding potential (BP(ND)) and total distribution volume (V(T)). The reference tissue models also provided robust estimates of BP(ND), although they gave lower BP(ND) values than the kinetic analysis. Compared with those of control subjects, we found that BP(ND) values obtained by all approaches were reduced in the midbrain of the patients with JME. The finding indicates impaired dopamine uptake in the midbrain of JME patients. The three-tissue compartment model could best describe uptake in the cerebellum, indicating that two kinetically distinguishable compartments exist in cerebellar tissue, which may correspond to nonspecific binding and the blood-brain barrier passing metabolite. The reference tissue models should be applied with better understanding of the biochemical nature of the radioligand and the reliability of these approaches.

[18F]flumazenil binding to central benzodiazepine receptor studies by PET--quantitative analysis and comparisons with [11C]flumazenil.

[(11)C]flumazenil is the reference radioligand for Positron Emission Tomography (PET) studies of central benzodiazepine (BZ) receptors. Fluorine is available in the flumazenil molecule and [(18)F]flumazenil has recently been prepared. The aim of the present PET-study in 8 male subjects was to examine the binding of [(18)F]flumazenil in the human brain by direct comparison with [(11)C]flumazenil. Each subject participated in two 93-minute PET-measurements with [(11)C]flumazenil and [(18)F]flumazenil, respectively. Data were analyzed using compartment models with metabolite-corrected arterial plasma input and reference tissue models using the pons as reference region. There was no evident difference between the kinetic behaviors of the two ligands. Overall, the noise in the time activity curves for [(18)F]flumazenil was lower at late time points, and the variance of the kinetic parameters was lower than for [(11)C]flumazenil. In BZ receptor rich regions, such as the neocortex, the 3-compartment model was statistically favored, whereas the 2-compartment model was favored in the pons. Binding potential values obtained by the reference tissue models were in good agreement with those obtained by the kinetic analysis. There was no support for the presence of specific binding in the pons. In conclusion, the binding and the kinetic behavior of [(11)C]flumazenil and [(18)F]flumazenil were similar. The present analysis supports the use of pons as reference region in simplified protocols without arterial blood sampling. [(18)F]flumazenil should thus be an excellent choice for applied studies at centers not having a cyclotron.

[A new method to obtain right-to-left shunt index of the lung using 99mTc-MAA pulmonary perfusion scintigraphy and first-pass dynamic data acquisition].

Generally a right-to-left shunt index in pulmonary area was calculated from total body and pulmonary area by scintillations count using 9mTc-MAA pulmonary perfusion scintigraphy. In this study, we devised a newly calculation method for right-to-left shunt index in pulmonary area from 9mTc-MAA pulmonary perfusion scintigraphy by first-pass dynamic data. We compared the proposed method with the conventional method in 26 patients (9 men and 17 women; 3-26 years old): 23 patients with congenital biliary atresia (CBA) post operation and the other 3 patients with right-to-left shunt from hepatopulmonary syndrome. As a result, there was a positive correlation of the index values between the proposed method and the conventional method (r = 0.929). Thus, the present method should be clinically useful.

Radio-guided sentinel node mapping in patients with superficial esophageal carcinoma: feasibility study.

The aim of this study was to assess whether the sentinel node concept could be applicable to clinically early carcinoma of the esophagus. We studied ten consecutive cT1N0 patients who underwent radical esophagectomy with regional lymph node dissection. On the day before surgery, 99m-Tc tin colloid was injected endoscopically around the primary tumor. Lymphoscintigraphy was also performed about three hours after injection. Immediately after surgery, the radioactivity of all dissected lymph nodes was measured with a hand-held gamma probe. The radioactivity and the metastatic status assessed by routine histopathologic examination were compared. A total of six patients had hot spots detected by lymphoscintigraphy, of which the detection rate was 60% (6 of 10). The ex vivo hot node detection rate was 90% (9 of 10). Three patients were found to have metastatic nodes. In one patient, sentinel node mapping failed to identify any hot spot or hot node. In the other two patients, the metastatic nodes did not correspond to hot nodes. The accuracy of hot node status was 77.8% (7 of 9), and the false-negative rate was 100% (2 of 2). The present study showed that radio-guided sentinel node detection is insufficiently reliable at present due to the high false-negative rate and low accuracy.

Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study.

PURPOSE: The dopamine transporter (DAT) is a plasma membrane protein of central interest in the pathophysiology of neuropsychiatric disorders and is known to be a target for psychostimulant drugs. [(11)C]PE2I is a new radioligand which binds selectively and with moderate affinity to central DAT, as has been demonstrated in vitro by autoradiography and in vivo by positron emission tomography (PET). The aims of the present PET study were to quantify regional [(11)C]PE2I binding to DAT in the human brain and to compare quantitative methods with regard to suitability for applied clinical studies. METHODS: One PET measurement was performed in each of eight healthy male subjects. The binding potential (BP) values were obtained by applying kinetic compartment analysis, which uses the metabolite-corrected arterial plasma curve as an input function. They were compared with the BP values quantified by two reference tissue approaches, using cerebellum as a reference region representing free and non-specific radioligand binding. RESULTS: The radioactivity concentration was highest in the striatum, lower in the midbrain and very low in the cerebellum. The regional [(11)C]PE2I binding could be interpreted by kinetic compartment models. However, the BP values in the striatum obtained by the compartment analyses were about 30% higher than the BP values obtained using reference tissue methods. We suggest that the difference may be explained by the inaccurate metabolite correction, small amounts of radioactive metabolites that could account for the presence of non-specific binding in the cerebellum and insufficient data acquisition time. CONCLUSION: The reference methods may be used to quantify [(11)C]PE2I binding in clinical studies, assuming that non-specific binding in the cerebellum does not vary between subjects and that an extended data acquisition time is employed. Moreover, the study corroborates the previous observation that [(11)C]PE2I is advantageous for PET examination of DAT binding in the midbrain, a region from which dopaminergic innervation originates and which is of central interest for the pathophysiology of several neuropsychiatric disorders.

Quantification of 11C-MADAM binding to the serotonin transporter in the human brain.

UNLABELLED: (11)C-N,N-Dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ((11)C-MADAM) is a newly synthesized radioligand with high selectivity and specificity for the serotonin transporter (5-HTT) in a monkey model. The purpose of this study in humans was to examine the suitability and potential of (11)C-MADAM for quantitative PET studies of 5-HTT in applied clinical studies on the pathophysiology and treatment of neuropsychiatric disorders. METHODS: PET examination was performed on each of 9 male subjects after intravenous injection of (11)C-MADAM with high specific radioactivity. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. A metabolite-corrected arterial input function was used in kinetic 2- and 3-compartment analyses. Cerebellum was used as the reference region in a cross-validation of 6 reference tissue approaches. RESULTS: The highest radioactivity concentration was detected in the raphe nuclei, followed consecutively by the striatum, hippocampal complex, cingulate cortex, neocortex, and cerebellum. The time-activity curve for the fraction of unchanged (11)C-MADAM in plasma was best described by a sigmoid function. After 50 min, the fraction was 40%. The labeled metabolites were more polar than the mother compound. The compartment model approaches converged, and could describe the time-activity curves in all regions. The total volume of distribution (V(t)) was similar to the regional distribution volumes obtained by the linear graphic analysis. The binding potentials (BPs) for 6 different approaches yielded similar values in all regions but the raphe nuclei, where the 2 equilibrium methods provided lower values. CONCLUSION: The regional binding distribution of (11)C-MADAM is consistent with postmortem data acquired with (3)H-MADAM as well as with that of other reference ligands in vitro. The time-activity curves were well described by current major quantitative approaches. The suitability of the cerebellum as a reference region for nonspecific (11)C-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model, for applied clinical studies.