Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as ...a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET.
We analyzed 18F-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal 18F-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time.
Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (−18%) and MCI (−10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0.907) or with brainstem scaling for the contrast between HC/MCI (0.658). Longitudinal increases were greatest in all diagnosis groups with application of PVEC, and inter-subject variability was lowest for the white matter reference.
Thus, discriminatory power of 18F-AV45-PET was improved by use of a VOI-based PVEC and white matter or brainstem rather than cerebellum reference region. Detection of longitudinal amyloid increases was optimized with PVEC and white matter reference tissue.
•Different reference regions were compared for 18F-AV45 PET quantification.•Effects of segmentation and partial volume effect correction (PVEC) were assessed.•White matter (WM) SUV was most stable between diagnosis groups.•WM and brainstem reference improved discriminatory power compared to cerebellum.•WM reference including PVEC distinctly improved longitudinal PET assessment.
Background
The bone marrow (BM) is a main organ at risk in Lu-177-PSMA-617 therapy of prostate cancer and Lu-177-Octreotate therapy of neuroendocrine tumours. BM dosimetry is challenging and ...time-consuming, as different sequential quantitative measurements must be combined. The BM absorbed dose from the remainder of the body (ROB) can be determined from sequential whole-body planar (WB-P) imaging, while quantitative Lu-177-SPECT allows for more robust tumour and organ absorbed doses. The aim was to investigate a time-efficient and patient-friendly hybrid protocol (HP) for the ROB absorbed dose to the BM. It combines three abdominal quantitative SPECT (QSPECT) scans with a single WB-P acquisition and was compared with a reference protocol (RP) using sequential WB-P in combination with sequential QSPECT images. We investigated five patients receiving 7.4 GBq Lu-177-Octreotate and five patients treated with 3.7 GBq Lu-177-PSMA-617. Each patient had WB-P and abdominal SPECT acquisitions 24 (+ CT), 48, and 72 h post-injection. Blood samples were drawn 30 min, 80 min, 24 h, 48 h, and 72 h post-injection. BM absorbed doses from the ROB were estimated from sequential WB-P images (RP), via a mono-exponential fit and mass-scaled organ-level
S
values. For the HP, a mono-exponential fit on the QSPECT data was scaled with the activity of one WB-P image acquired either 24, 48, or 72 h post-injection (HP24, HP48, HP72). Total BM absorbed doses were determined as a sum of ROB, blood, major organ, and tumour contributions.
Results
Compared with the RP and for Lu-177-Octreotate therapy, median differences of the total BM absorbed doses were 13% (9–17%), 8% (4–15%), and 1% (0–5%) for the HP24, HP48, and HP72, respectively. For Lu-177-PSMA-617 therapy, total BM absorbed doses deviated 10% (2–20%), 3% (0–6%), and 2% (0–6%).
Conclusion
For both Lu-177-Octreotate and Lu-177-PSMA-617 therapy, BM dosimetry via sequential QSPECT imaging and a single WB-P acquisition is feasible, if this WB-P image is acquired at a late time point (48 or 72 h post-injection). The reliability of the HP can be well accepted considering the uncertainties of quantitative Lu-177 imaging and BM dosimetry using standardised organ-level
S
values.
Magnet resonance image (MRI)-based segmentations are widely used for clinical brain research, especially in conjunction with positron-emission-tomography (PET). Although artifacts due to segmentation ...errors arise commonly, the impact of these artifacts on PET quantitation has not yet been investigated systematically. Therefore, the aim of this study was to assess the effect of segmentation errors on (18)F-AV45 and (18)F-FDG PET quantitation, with and without correction for partial volume effects (PVE).
119 subjects with both (18)F-AV45, and (18)F-FDG PET as well as T1-weighted MRI at baseline and at two-year follow-up were selected from the ADNI cohort, and their MRI brain images were segmented using PMOD 3.5. MRIs with segmentation artifacts were masked with the corresponding (18)F-FDG PET standard-uptake-value (SUV) images to elucidate and quantify the impact of artifacts on PET analyses for six defined volumes-of-interest (VOI). Artifact volumes were calculated for each VOI, together with error-% and root-mean-square-errors (RMSE) in uncorrected and PVE corrected SUV results for the two PET tracers. We also assessed the bias in longitudinal PET data.
Artifacts occurred most frequently in the parietal cortex VOI. For (18)F-AV45 and (18)F-FDG PET, the percentage-errors were dependent on artifact volumes. PVEC SUVs were consequently more distorted than were their uncorrected counterparts. In static and longitudinal assessment, a small subgroup of subjects with large artifacts (≥1500 voxels; ≙5.06 cm³) accounted for much of the PET quantitation bias.
Large segmentation artifacts need to be detected and resolved as they considerably bias PET quantitation, especially when PVEC is applied to PET data.
Late life depression (LLD) even in subsyndromal stages shows high conversion rates from cognitively normal (CN) to mild cognitive impairment (MCI). Results of (18)F-fluorodesoxyglucose ...positron-emission-tomography (FDG-PET) were inconsistent in LLD patients, whereas atrophy was repeatedly described. Therefore, we set out to investigate FDG metabolism and the effect of atrophy correction (PVEC) in geriatric CN patients with depressive symptoms. 21 CN subjects with positive item for the depression category (DEP) in the Neuropsychiatric-Inventory-Questionnaire and 29 CN subjects with an absent depression item (NON-DEP) were selected from the ADNI cohort. FDG-PETs were analyzed in individual PET space using volumes-of-interest (VOI) and statistical-parametric-mapping (SPM) approaches. VOI- and MRI-based PVEC were applied to PET data. DEP subjects showed significant hypometabolism in fronto-temporal cortices and the posterior cingulate cortex (PCC) when contrasted against NON-DEP in uncorrected data. Both in VOI- and SPM-based approaches PVEC eliminated significance in PCC, while fronto-temporal regions remained significant or even attained significance such as in case of the left amygdala. Subsyndromally depressed CN subjects had decreased FDG metabolism in mood-related brain regions, which may be relevant to their elevated risk for conversion from CN to MCI. Methodological advances in PET analyses should be considered in future studies as PVEC relevantly changed results of FDG-PET for detecting apparent metabolic differences between DEP and NON-DEP subjects. Furthermore, VOI-based analyses in individual PET space will allow a more accurate consideration of variability in anatomy, especially in subcortical regions.
Purpose
Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the ...new PSMA ligand
177
Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer.
Methods
Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq)
177
Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines.
Results
The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 – 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle.
Conclusion
The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with
177
Lu-DKFZ-PSMA-617. We suggest that
177
Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour-to-kidney ratios comparable to those with RLT agents currently available for the treatment of neuroendocrine tumours. Our dosimetry results suggest that
177
Lu-DKFZ-PSMA-617 treatment with higher activities and more cycles is possible without the risk of damaging the kidneys.
Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the new PSMA ...ligand (177)Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer.
Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq) (177)Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines.
The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 - 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle.
The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with (177)Lu-DKFZ-PSMA-617. We suggest that (177)Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour-to-kidney ratios comparable to those with RLT agents currently available for the treatment of neuroendocrine tumours. Our dosimetry results suggest that (177)Lu-DKFZ-PSMA-617 treatment with higher activities and more cycles is possible without the risk of damaging the kidneys.
Purpose
Late-life depression even in subsyndromal stages is strongly associated with Alzheimer’s disease (AD). Furthermore, brain amyloidosis is an early biomarker in subjects who subsequently suffer ...from AD and can be sensitively detected by amyloid PET. Therefore, we aimed to compare amyloid load and glucose metabolism in subsyndromally depressed subjects with mild cognitive impairment (MCI).
Methods
18
FAV45 PET,
18
FFDG PET and MRI were performed in 371 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative Subjects were judged β-amyloid-positive (Aβ+; 206 patients) or β-amyloid-negative (Aβ−; 165 patients) according to
18
FAV45 PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire depression item 4. Subjects with depressive symptoms (65 Aβ+, 41 Aβ−) were compared with their nondepressed counterparts. Conversion rates to AD were analysed (mean follow-up time 21.5 ± 9.1 months) with regard to coexisting depressive symptoms and brain amyloid load.
Results
Aβ+ depressed subjects showed large clusters with a higher amyloid load in the frontotemporal and insular cortices (
p
< 0.001) with coincident hypermetabolism (
p
< 0.001) in the frontal cortices than nondepressed subjects. Faster progression to AD was observed in subjects with depressive symptoms (
p
< 0.005) and in Aβ+ subjects (
p
< 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aβ+ subjects (
p
< 0.005) and to a greater extent in those with a high amyloid load (
p
< 0.001).
Conclusion
Our results clearly indicate that Aβ+ MCI subjects with depressive symptoms have an elevated amyloid load together with relative hypermetabolism of connected brain areas compared with cognitively matched nondepressed individuals. MCI subjects with high amyloid load and coexistent depressive symptoms are at high risk of faster conversion to AD.
Purpose
Multiple measurements have been required to estimate the radiation dose to the kidneys resulting from
177
LuDOTATATE therapy for neuroendocrine tumors. The aim of this study was to ...investigate the influence of early time-point measurement in the renal dose calculation.
Procedures
Anterior/posterior whole-body planar scintigraphy images were acquired at approx. 1, 24, 48, and 72 h after administration of
177
LuDOTATATE. Furthermore, we acquired planar 1-bed dynamic recordings in 12 frames (5 min each) during the first hour. We assessed kidney exposure with a three-phase model consisting of a linear increase to the maximum within the initial minutes p.i., followed a bi-exponential decline. This three-phase-model served as reference for evaluating accuracy of dose estimates in 105 kidneys calculated by conventional mono-exponential fitting of the final three and four whole-body images.
Results
Mean effective half-life times for the reference model were 25.8 ± 12.0 min and 63.9 ± 17.6 h, predicting a mean renal dose of 5.7 ± 2.1 Gy. The effective half-life time was 46.3 ± 15.4 h for the last four and 63.3 ± 17.0 h for the last three data points. The mean start of the first whole-body measurement was 1.2 ± 0.1 h p.i. The ratio of fast to slow phases was 28.1 ± 23.9 % at this time point, which caused a mean absolute percentage dose deviation of 12.4 % for four data points, compared to 3.1 % for three data points. At a mean time of 2.4 h p.i. (max 5.1 h), the ratio of fast to slow phase declined below 5 %.
Conclusions
Kinetic analysis of renal uptake using dynamic planar scans from the first hour after injection revealed a fast and a slow washout phase. Although the fast phase did not contribute substantially to the estimated renal dose, it could influence planar measurements performed within the first hours. We found that the presence of two clearance phases can hamper accurate dose estimation based on a single-phase model, resulting in approximately 12.4 % dose underestimation, thus potentially resulting in overtreatment. In the absence of dynamic initial recordings, the first dosimetry measurements should therefore be obtained later than 3–5 h after
177
LuDOTATATE injection. Omitting the early whole-body image reduced the dose estimation error to 3.1 %.
Preclinical PET studies of β-amyloid (Aβ) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we ...aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Aβ-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Aβ burden (N = 40) were investigated by (18)F-florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (κ). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX∕REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all κ≥0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX∕REF. All SUVRCTX∕REF methods performed better than SUVCTX both with regard to longitudinal stability (d≥1.21 vs. d = 0.23) and histological gold standard agreement (R≥0.66 vs. R≥0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R mean = 0.75) was slightly superior to the brainstem (R mean = 0.74) and the cerebellum (R mean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Aβ-PET scans. Intracerebral reference regions lacking Aβ pathology serve for precise longitudinal in vivo quantification of (18)F-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria.
Abstract Gray matter (GM) atrophy and brain glucose hypometabolism are already detected in the predementia stages of Alzheimer's disease (AD), but the regional and longitudinal associations between ...the two are not well understood. Here, we analyzed the patterns of longitudinal atrophy (magnetic resonance imaging MRI) and18 F-Fluorodeoxyglucose–positron emission tomography (18FFDG-PET) metabolism decline in 40 cognitively healthy control (HC) and 52 mildly impaired (mild cognitive impairment MCI) subjects during 3 years. Based on cerebrospinal fluid and brain amyloid-PET, the subjects were divided into amyloid-beta (Aβ)− and Aβ+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Aβ-subgroups, within each diagnostic group. In joint–independent component analyses, we assessed the patterns of covariation between longitudinal change in GM volume and glucose metabolism. MCI-Aβ+ showed faster atrophy than MCI-Aβ− within the temporal, medial temporal, and medial parietal lobes. HC-Aβ+ showed faster atrophy within the precuneus than HC-Aβ−. For FDG-PET metabolism, MCI-Aβ+ exhibited faster decline than MCI-Aβ− in temporoparietal regions, whereas no differences between HC subgroups were observed. Joint–independent component analysis showed that accelerated atrophy and metabolism decline correlated across distant brain regions for MCI-Aβ+. In conclusion, abnormally increased levels of Aβ in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns.
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