3-[18F]Fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Context: Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment. Objective: This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL. Methods: 3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions. Results: 3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions. Conclusion: We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [177Lu]Lu-DOTATATE.

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.

GABAA Receptor Benzodiazepine Binding Sites and Motor Impairments in Parkinson's Disease.

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABAAR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson's disease (PD). Little is known about how regional GABAAR availability affects motor symptoms. We investigated the relationship between regional availability of GABAAR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2-3) underwent [11C]flumazenil GABAAR benzodiazepine binding site and [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABAAR availability was selectively associated with axial motor scores (R2 = 0.55, F = 11.0, ß = -6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABAAR availability (R2 = 0.47, ß = -5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R2 = 0.30, ß = -3.9, F = 9.1, p = 0.019; total model: R2 = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [11C]methyl-4-piperidinyl propionate cholinesterase PET and K1 flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABAAR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD.

177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers.

PURPOSE: Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression. PATIENTS AND METHODS: Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD). RESULTS: The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models. CONCLUSIONS: Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

Diagnostic yield of whole-body 18F-FDG PET/CT in patients with suspected cardiac sarcoidosis.

BACKGROUND: Whole-body F-18 FDG PET has been included in the 2014 Heart Rhythm Society guidelines for cardiac sarcoidosis evaluation to identify alternate sites of biopsy prior to endomyocardial biopsy. The purpose of this study was to evaluate the diagnostic yield of whole-body F-18 FDG PET/CT. METHODS: All adult patients with suspected cardiac sarcoidosis undergoing same-day cardiac F-18 FDG PET/CT and whole-body F-18 FDG PET/CT between 10/1/2016 and 6/14/2021 to assess potential biopsy sites were retrospectively identified. Clinical indications, findings, recommendations, and outcomes were assessed. RESULTS: Eighty-eight patients were included. Extracardiac PET findings suggestive of sarcoidosis were present in 30 patients (34%), 27 of which had thoracic findings (90%). Sarcoidosis was diagnosed in 11% of patients. Only 1% (1/88) was diagnosed by extrathoracic biopsy of a whole-body PET finding. Incidental findings were common (31%), resulting in 11 additional tests or interventions. Recommendations from extrathoracic findings affected treatment in one case: a drainage catheter placement into an unsuspected pelvic abscess. CONCLUSION: Addition of whole-body F-18 FDG PET/CT to cardiac F-18 FDG PET/CT for the identification of extrathoracic sites of biopsy in patients with suspected cardiac sarcoidosis has marginal diagnostic yield but commonly results in incidental findings that rarely affect patient outcome.

Progression of regional cortical cholinergic denervation in Parkinson's disease.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4-8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k 3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k 3 and the k 1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k 3 deficits in Parkinson's disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k 3 changes exhibited regionally specific disconnection from k 1 changes. Interval-change analysis based on k 3/k 1 ratio images (k 3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k 3 reductions in the posterior cortices, especially Brodmann areas 17-19, were largely proportional to k 1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson's disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.

Differential cholinergic systems' changes in progressive supranuclear palsy versus Parkinson's disease: an exploratory analysis.

Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [18F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ2 = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.

Differences in tumor-to-normal organ SUV ratios measured with 68 Ga-DOTATATE PET compared with 177 Lu-DOTATATE SPECT in patients with neuroendocrine tumors.

BACKGROUND: Our goal is to quantitatively compare radiotracer biodistributions within tumors and major normal organs on pretherapy 68 Ga-DOTATATE PET to post-therapy 177 Lu-DOTATATE single-photon emission computed tomography (SPECT) in patients receiving peptide receptor radionuclide therapy (PRRT). METHODS: PET/CT at ~ 60 min postinjection of Ga-68 DOTATATE and research 177 Lu-SPECT/CT imaging ~ at 4 h (SPECT1) and ~ 24 h (SPECT2) post-cycle#1 were available. Manual contours of lesions on baseline CT or MRI were applied to co-registered SPECT/CT and PET/CT followed by deep learning-based CT auto-segmentation of organs. Tumor-to-normal organ ratios (TNR) were calculated from standardized uptake values (SUV) mean and SUV peak for tumor, and SUV mean for non-tumoral liver (nliver), spleen and kidney. RESULTS: There were 90 lesons in 24 patients with progressive metastatic neuroendocrine tumor. The correlation between PET and SPECT SUV TNRs were poor/moderate: PET versus SPECT1 R 2 = 0.19, 0.21, 0.29; PET versus SPECT2 R 2 = 0.06, 0.16, 0.33 for TNR nliver ,TNR spleen ,TNR kidney , respectively. Across all patients, the average value of the TNR measured on PET was significantly lower than on SPECT at both time points ( P < 0.001). Using SUV mean for tumor, average TNR values and 95% confidence intervals (CI) were PET: TNR nliver = 3.5 [CI: 3.0-3.9], TNR spleen = 1.3 [CI, 1.2-1.5], TNR kidney = 1.7 [CI: 1.6-1.9]; SPECT1: TNR nliver = 10 [CI: 8.2-11.7], TNR spleen = 2.9 [CI: 2.5-3.4], TNR kidney = 2.8 [CI: 2.3-3.3]; SPECT2: TNR nliver = 16.9 [CI: 14-19.9], TNR spleen = 3.6 [CI: 3-4.2], TNR kidney = 3.6 [CI: 3.0-4.2]. Comparison of PET and SPECT results in a sphere phantom study demonstrated that these differences are not attributed to imaging modality. CONCLUSIONS: Differences in TNR exist for the theranostic pair, with significantly higher SUV TNR on 177 Lu SPECT compared with 68 Ga PET. We postulate this phenomenon is due to temporal differences in DOTATATE uptake and internalization in tumor as compared to normal organs.

A Pipeline for Automated Voxel Dosimetry: Application in Patients with Multi-SPECT/CT Imaging After 177Lu-Peptide Receptor Radionuclide Therapy.

Patient-specific dosimetry in radiopharmaceutical therapy (RPT) is impeded by the lack of tools that are accurate and practical for the clinic. Our aims were to construct and test an integrated voxel-level pipeline that automates key components (organ segmentation, registration, dose-rate estimation, and curve fitting) of the RPT dosimetry process and then to use it to report patient-specific dosimetry in 177Lu-DOTATATE therapy. Methods: An integrated workflow that automates the entire dosimetry process, except tumor segmentation, was constructed. First, convolutional neural networks (CNNs) are used to automatically segment organs on the CT portion of one post-therapy SPECT/CT scan. Second, local contour intensity-based SPECT--SPECT alignment results in volume-of-interest propagation to other time points. Third, dose rate is estimated by explicit Monte Carlo (MC) radiation transport using the fast, Dose Planning Method code. Fourth, the optimal function for dose-rate fitting is automatically selected for each voxel. When reporting mean dose, we apply partial-volume correction, and uncertainty is estimated by an empiric approach of perturbing segmentations. Results: The workflow was used with 4-time-point 177Lu SPECT/CT imaging data from 20 patients with 77 neuroendocrine tumors, segmented by a radiologist. CNN-defined kidneys resulted in high Dice values (0.91-0.94) and only small differences (2%-5%) in mean dose when compared with manual segmentation. Contour intensity-based registration led to visually enhanced alignment, and the voxel-level fitting had high R 2 values. Across patients, dosimetry results were highly variable; for example, the average of the mean absorbed dose (Gy/GBq) was 3.2 (range, 0.2-10.4) for lesions, 0.49 (range, 0.24-1.02) for left kidney, 0.54 (range, 0.31-1.07) for right kidney, and 0.51 (range, 0.27-1.04) for healthy liver. Patient results further demonstrated the high variability in the number of cycles needed to deliver hypothetical threshold absorbed doses of 23 Gy to kidney and 100 Gy to tumor. The uncertainty in mean dose, attributable to variability in segmentation, averaged 6% (range, 3%-17%) for organs and 10% (range, 3%-37%) for lesions. For a typical patient, the time for the entire process was about 25 min (∼2 min manual time) on a desktop computer, including time for CNN organ segmentation, coregistration, MC dosimetry, and voxel curve fitting. Conclusion: A pipeline integrating novel tools that are fast and automated provides the capacity for clinical translation of dosimetry-guided RPT.

Quantifying cardiac sympathetic denervation: first studies of 18F-fluorohydroxyphenethylguanidines in cardiomyopathy patients.

PURPOSE: 4-18F-Fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis. The aim of this study was to evaluate their performance in cardiomyopathy patients. METHODS: Eight cardiomyopathy patients were scanned with 18F-4F-MHPG and 18F-3F-PHPG. Also, regional resting perfusion was assessed with 13N-ammonia. 18F-4F-MHPG and 18F-3F-PHPG kinetics were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as measures of regional nerve density. Patlak slope polar maps were used to evaluate the pattern and extent of cardiac denervation. For comparison, "retention index" (RI) values (mL blood/min/mL tissue) were also calculated and used to assess denervation. Perfusion polar maps were used to estimate the extent of hypoperfusion. RESULTS: Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all subjects, ranging from 25 to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion. The two tracers provided comparable metrics of regional nerve density and the extent of left ventricular denervation. 18F-4F-MHPG exhibited faster liver clearance than 18F-3F-PHPG, reducing spillover from the liver into the inferior wall. 18F-4F-MHPG was also metabolized more consistently in plasma, which may allow application of population-averaged metabolite corrections. CONCLUSION: The advantages of 18F-4F-MHPG (more rapid liver clearance, more consistent metabolism in plasma) make it the better imaging agent to carry forward into future clinical studies in patients with cardiomyopathy. TRIAL REGISTRATION: Registered at the ClinicalTrials.gov website (NCT02669563). URL: https://clinicaltrials.gov/ct2/show/NCT02669563.

Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson's disease.

Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions associating with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose were performed. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized ß = -0.34, t = -3.78, P = 0.0003), lateral geniculate nucleus (ß = -0.32, t = -3.4, P = 0.001) and entorhinal cortex (ß = -0.23, t = -2.6, P = 0.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (ß = -0.22, t = -2.4, P = 0.021) and the putamen (ß = -0.23, t = -2.3, P = 0.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (ß = 0.36, t = 3.9, P = 0.0097) and the paracentral lobule (ß = 0.26, t = 2.5, P = 0.013). Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson's disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signalling mechanisms with smaller contributions from cholinergic pathways.

Molecular Imaging of Neurodegenerative Parkinsonism.

Advances in molecular PET imaging of neurodegenerative parkinsonism are reviewed with focus on neuropharmacologic radiotracers depicting terminals of selectively vulnerable neurons in these conditions. Degeneration and losses of dopamine, norepinephrine, serotonin, and acetylcholine imaging markers thus far do not differentiate among the parkinsonian conditions. Recent studies performed with [18F]fluorodeoxyglucose PET are limited by the need for automated image analysis tools and by lack of routine coverage for this imaging indication in the United States. Ongoing research engages use of novel molecular modeling and in silico methods for design of imaging ligands targeting these specific proteinopathies.

A Novel Time-Activity Information-Sharing Approach Using Nonlinear Mixed Models for Patient-Specific Dosimetry with Reduced Imaging Time Points: Application in SPECT/CT After 177Lu-DOTATATE.

Multiple-time-point SPECT/CT imaging for dosimetry is burdensome for patients and lacks statistical efficiency. A novel method for joint kidney time-activity estimation based on a statistical mixed model, a prior cohort of patients with complete time-activity data, and only 1 or 2 imaging points for new patients was compared with previously proposed single-time-point methods in virtual and clinical patient data. Methods: Data were available for 10 patients with neuroendocrine tumors treated with 177Lu-DOTATATE and imaged up to 4 times between days 0 and 7 using SPECT/CT. Mixed models using 1 or 2 time points were evaluated retrospectively in the clinical cohort, using the multiple-time-point fit as the reference. Time-activity data for 250 virtual patients were generated using parameter values from the clinical cohort. Mixed models were fit using 1 (∼96 h) and 2 (4 h, ∼96 h) time points for each virtual patient combined with complete data for the other patients in each dataset. Time-integrated activities (TIAs) calculated from mixed model fits and other reduced-time-point methods were compared with known values. Results: All mixed models and single-time-point methods performed well overall, achieving mean bias < 7% in the virtual cohort. Mixed models exhibited lower bias, greater precision, and substantially fewer outliers than did single-time-point methods. For clinical patients, 1- and 2-time-point mixed models resulted in more accurate TIA estimates for 94% (17/18) and 72% (13/18) of kidneys, respectively. In virtual patients, mixed models resulted in more than a 2-fold reduction in the proportion of kidneys with |bias| > 10% (6% vs. 15%). Conclusion: Mixed models based on a historical cohort of patients with complete time-activity data and new patients with only 1 or 2 SPECT/CT scans demonstrate less bias on average and significantly fewer outliers when estimating kidney TIA, compared with popular reduced-time-point methods. Use of mixed models allows for reduction of the imaging burden while maintaining accuracy, which is crucial for clinical implementation of dosimetry-based treatment.

Molecular Imaging of Extrapyramidal Movement Disorders With Dementia: The 4R Tauopathies.

Two pathologically distinct neurodegenerative conditions, progressive supranuclear palsy and corticobasal degeneration, share in common deposits of tau proteins that differ both molecularly and ultrastructurally from the common tau deposits diagnostic of Alzheimer disease. The proteinopathy in these disorders is characterized by fibrillary aggregates of 4R tau proteins. The clinical presentations of progressive supranuclear palsy and of corticobasal degeneration are often confused with more common disorders such as Parkinson disease or subtypes of frontotemporal lobar degeneration. Neither of these 4R tau disorders has effective therapy, and while there are emerging molecular imaging approaches to identify patients earlier in the course of disease, there are as yet no reliably sensitive and specific approaches to diagnoses in life. In this review, aspects of the clinical syndromes, neuropathology, and molecular biomarker imaging studies applicable to progressive supranuclear palsy and to corticobasal degeneration will be presented. Future development of more accurate molecular imaging approaches is proposed.

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC).

BACKGROUND: In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing. RESULTS: The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees. CONCLUSIONS: The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.

Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs.

OBJECTIVES: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [18F]-fluoroethoxybenzovesamicol ([18F]-FEOBV) radioligand. METHODS: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [18F]-FEOBV PET. RESULTS: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices. CONCLUSIONS: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

Evaluation of [18F]-N-Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/µmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 µg (range, 0.16-8.27 µg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.