Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone

BACKGROUND: Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT) images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM) to SPECT. METHODS: After linear spatial normalization of brain perfusion SPECT using (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD) to a Talairach space, high-dimension-warping was done using an original (99m)Tc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2) between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C) patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images. RESULTS: SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a (99m)Tc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. CONCLUSIONS: The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPEC

First clinical assessment of [ 18 F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood-brain barrier

Objective: 5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([18F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood-brain barrier (BBB) of [18F]MC225 in healthy subjects. Methods: [18F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [18F]MC225 injection. Dynamic [18F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [18F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). VT was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time-activity curves [TACs] and negative slope of calculated TACs) were compared with the VT values. Results: No serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was 0.9). AUCs of TACs were positively correlated with VT (2-TCM) values (r2: AUC0-60 min = 0.61, AUC0-30 min = 0.62, AUC30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with VT (2-TCM) values (r2 = 0.53, p < 0.0001). Conclusions: This initial evaluation indicated that [18F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB. Keywords: Blood–Brain barrier; Dosimetry; First-in-human; P-glycoprotein; Positron emission tomography

Dissociation of Tau Deposits and Brain Atrophy in Early Alzheimer’s Disease: A Combined Positron Emission Tomography/Magnetic Resonance Imaging Study

The recent advent of tau-specific positron emission tomography (PET) has enabled in vivo assessment of tau pathology in Alzheimer’s disease (AD). However, because PET scanners have limited spatial resolution, the measured signals of small brain structures or atrophied areas are underestimated by partial volume effects (PVEs). The aim of this study was to determine whether partial volume correction (PVC) improves the precision of measures of tau deposits in early AD. We investigated tau deposits in 18 patients with amyloid-positive early AD and in 36 amyloid-negative healthy controls using 18F-THK5351 PET. For PVC, we applied the SPM toolbox PETPVE12. The PET images were then spatially normalized and subjected to voxel-based group analysis using SPM12 for comparison between the early AD patients and healthy controls. We also compared these two groups in terms of brain atrophy using voxel-based morphometry of MRI. We found widespread neocortical tracer retention predominantly in the posterior cingulate and precuneus areas, but also in the inferior temporal lobes, inferior parietal lobes, frontal lobes, and occipital lobes in the AD patients compared with the controls. The pattern of tracer retention was similar between before and after PVC, suggesting that PVC had little effect on the precision of tau load measures. Gray matter atrophy was detected in the medial/lateral temporal lobes and basal frontal lobes in the AD patients. Interestingly, only a few associations were found between atrophy and tau deposits, even after PVC. In conclusion, PVC did not significantly affect 18F-THK5351 PET measures of tau deposits. This discrepancy between tau deposits and atrophy suggests that tau load precedes atrophy

Japanese multicenter database of healthy controls for [¹²³I]FP-CIT SPECT

Purpose: The aim of this multicenter trial was to generate a [¹²³I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. Methods: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30–83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. Results: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30–39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70–79 age group. Conclusions: This study provided a large-scale quantitative database of [¹²³I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database

Anserine/Carnosine Supplementation Suppresses the Expression of the Inflammatory Chemokine CCL24 in Peripheral Blood Mononuclear Cells from Elderly People

Our goal was to determine whether anserine/carnosine supplementation (ACS) suppresses chemokine levels in elderly people. In a double-blind randomized controlled trial, volunteers were assigned to the ACS or placebo group (1:1). Sixty healthy elderly volunteers (active, n = 30; placebo, n = 30) completed the study. The ACS group was administered 1.0 g of anserine/carnosine (3:1) for 3 months. A microarray analysis and subsequent quantitative real-time polymerase chain reaction (qRT-PCR) analysis of peripheral blood mononuclear cells (PBMCs) showed decreased expression of CCL24, an inflammatory chemokine (p &lt; 0.05). Verbal memory, assessed using the Wechsler memory scale–logical memory, was preserved in the ACS group. An age-restricted sub-analysis showed significant verbal memory preservation by ACS in participants who were in their 60s (active, n = 12; placebo, n = 9; p = 0.048) and 70s (active, n = 7; placebo, n = 11; p = 0.017). The suppression of CCL24 expression was greatest in people who were in their 70s (p &lt; 0.01). There was a significant correlation between the preservation of verbal memory and suppression of CCL24 expression in the group that was in the 70s (Poisson correlation, r = 0.46, p &lt; 0.05). These results suggest that ACS may preserve verbal episodic memory, probably owing to CCL24 suppression in the blood, especially in elderly participants

Automated semi-quantitative amyloid PET analysis technique without MR images for Alzheimer\u27s disease.

Objective: Although beta-amyloid (Aβ) positron emission tomography (PET) images are interpreted visually as positive or negative, approximately 10% are judged as equivocal in Alzheimer\u27s disease. Therefore, we aimed to develop an automated semi-quantitative analysis technique using 18F-flutemetamol PET images without anatomical images.Methods: Overall, 136 cases of patients administered 18F-flutemetamol were enrolled. Of 136 cases, five PET images each with the highest and lowest values of standardized uptake value ratio (SUVr) of cerebral cortex-to-pons were used to create positive and negative templates. Using these templates, PET images of the remaining 126 cases were standardized, and SUVr images were produced with the pons as a reference region. The mean of SUVr values in the volume of interest delineated on the cerebral cortex was compared to those in the CortexID Suite (GE Healthcare). Furthermore, centiloid (CL) values were calculated for the 126 cases using data from the Centiloid Project ( http://www.gaain.org/centiloid-project ) and both templates. 18F-flutemetamol-PET was interpreted visually as positive/negative based on Aβ deposition in the cortex. However, the criterion "equivocal" was added for cases with focal or mild Aβ accumulation that were difficult to categorize. Optimal cutoff values of SUVr and CL maximizing sensitivity and specificity for Aβ detection were determined by receiver operating characteristic (ROC) analysis using the visual evaluation as a standard of truth.Results: SUVr calculated by our method and CortexID were highly correlated (R2 = 0.9657). The 126 PET images comprised 84 negative and 42 positive cases of Aβ deposition by visual evaluation, of which 11 and 10 were classified as equivocal, respectively. ROC analyses determined the optimal cutoff values, sensitivity, and specificity for SUVr as 0.544, 89.3%, and 92.9%, respectively, and for CL as 12.400, 94.0%, and 92.9%, respectively. Both semi-quantitative analyses showed that 12 and 9 of the 21 equivocal cases were negative and positive, respectively, under the optimal cutoff values.Conclusions: This semi-quantitative analysis technique using 18F-flutemetamol-PET calculated SUVr and CL automatically without anatomical images. Moreover, it objectively and homogeneously interpreted positive or negative Aβ burden in the brain as a supplemental tool for the visual reading of equivocal cases in routine clinical practice