Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.

INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.

Longitudinal Tau Positron Emission Tomography in Dementia with Lewy Bodies.

BACKGROUND AND OBJECTIVE: Patients with dementia with Lewy bodies (DLB) may have overlapping Alzheimer's disease pathology. We investigated the longitudinal rate of tau accumulation and its association with neurodegeneration and clinical disease progression in DLB. METHODS: Consecutive patients with probable DLB (n = 22) from the Mayo Clinic Alzheimer's Disease Research Center and age-matched and sex-matched cognitively unimpaired controls (CU; n = 22) with serial magnetic resonance imaging and flortaucipir positron emission tomography scans within an average of 1.6 years were included. Regional annualized rates of flortaucipir uptake standardized uptake value ratios (SUVr) were calculated. Regional annualized rates of cortical volume change were measured with the Tensor Based Morphometry-Syn algorithm. RESULTS: The annual increase of flortaucipir SUVr was greater in the middle and superior occipital, fusiform, and inferior parietal cortices in DLB (mean: 0.017, 0.019, 0.019, and 0.015, respectively) compared with the CU (mean: -0.006, -0.009, -0.003, and - 0.005, respectively; P < 0.05). In patients with DLB (but not the CU), a longitudinal increase in flortaucipir SUVr was associated with longitudinal cortical atrophy rates in the lateral occipital and inferior temporoparietal cortices, hippocampus, and the temporal pole as well as a concurrent decline on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes in the lateral occipital and the fusiform cortices. CONCLUSIONS: Tau accumulation was faster in DLB compared with the CU, with increased accumulation rates in the lateral occipital and temporoparietal cortices. These increased rates of tau accumulation were associated with neurodegeneration and faster disease progression in DLB. Tau may be a potential treatment target in a subset of patients with DLB. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Large Cohort Study of 18F Fluoro-Deoxy-Glucose Uptake in Normal Spinal Cord: Quantitative Assessment of the Contamination From Adjacent Vertebral Marrow Uptake and Validity of Normalizing the Cord Uptake Against the Lumbar Thecal Sac.

PURPOSE: This study aimed (1) to assess the influence of age, sex, blood glucose, and body mass index on the F fluoro-deoxy-glucose (F-FDG) uptake in normal spinal cord; (2) to quantitatively evaluate contamination of the spinal cord SUVmax by the adjacent vertebral marrow activity; and (3) to investigate the validity of normalizing spinal cord SUVmax against lumbar thecal sac SUVmax. METHODS: Two hundred positron emission tomography-computed tomography examinations of subjects with normal spinal cord were retrospectively reviewed. SUVmax of spinal cord and vertebral body was obtained at C2, C5, T6, T12, and L3 levels. Pearson correlation coefficients (r) were obtained at each level between spinal cord SUVmax and vertebral marrow SUVmax, age, body mass index, and blood glucose. Cord to background ratio (CTB) was calculated as the ratio between SUVmax of spinal cord and SUVmax of L3 thecal sac. The coefficient of variation (CV) of spinal cord SUVmax was compared with the CV of CTB. RESULTS: Spinal cord SUVmax was highest at C2 (mean, 1.76) and lowest at T6 (mean, 1.37) with SD of 0.32 to 0.36 SUV. Sex (P > 0.45), age (r: -0.25 to -0.06), body mass index (r: 0.19 to 0.27), and blood glucose (r: -0.17 to 0.22) had no impact on the spinal cord SUVmax. A moderate to strong positive correlation (r: 0.66-0.80) was found between spinal cord SUVmax and the corresponding vertebral marrow SUVmax. The CV of CTB was greater (0.28-0.32) than the CV of spinal cord SUVmax (0.19-0.25) across all levels. CONCLUSIONS: Of the variables studied, only contamination from adjacent vertebral marrow activity significantly affected the SUVmax of spinal cord. This contamination should be corrected for when reporting spinal cord FDG uptake. Lumbar thecal sac is not a valid reference for normalizing spinal cord FDG uptake.

Influences of amyloid-ß and tau on white matter neurite alterations in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-ß with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-ß, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-ß exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Technologist-Based Implementation of Total Metabolic Tumor Volume into Clinical Practice.

Metabolic tumor volume (MTV) is defined as the total metabolically active tumor volume seen on 18F-FDG PET/CT examinations. Calculating MTV is often time-consuming, requiring a high degree of manual input. In this study, the MTV calculations of a board-certified nuclear radiologist were compared with those of 2 nuclear medicine technologists. As part of the technologists' educational program, after their classroom time they were trained by the radiologist for 30 min. The technologists calculated MTV within 7.5% of the radiologist's calculations in a set of patients who had diffuse large B-cell lymphoma and were undergoing initial staging 18F-FDG PET/CT. These findings suggest that nuclear medicine technologists may help accelerate implementation of MTV into clinical practice with favorable accuracy, possibly as an initial step followed by validation by the interpreting physician. The aim of this study was to explore whether efficiency is improved by integrating nuclear medicine technologists into a semiautomated workflow to calculate total MTV.

Thoracic Imaging Manifestations of Treated Lymphomas: Response Evaluation, Posttherapeutic Sequelae, and Complications.

Lymphoma is the most common hematologic malignancy comprising a diverse group of neoplasms arising from multiple blood cell lineages. Any structure of the thorax may be involved at any stage of disease. Imaging has a central role in the initial staging, response assessment, and surveillance of lymphoma, and updated standardized assessment criteria are available to assist with imaging interpretation and reporting. Radiologists should be aware of the modern approaches to lymphoma treatment, the role of imaging in posttherapeutic surveillance, and manifestations of therapy-related complications.

Automated production of [18F]Flortaucipir for PET imaging of tauopathies.

Radiotracer [18F]Flortaucipir is an FDA-approved diagnostic agent for PET imaging of density and distribution of abnormal tau protein deposition (tauopathies) in Alzheimer's disease. A high-yield automated method for routine GMP-compliant [18F]Flortaucipir production is desired to meet increasing clinical need. In this work, we reported an automated radiosynthesis of [18F]Flortaucipir in a RNplus Research module and the quality control (QC) tests for human use under full GMP compliance. Briefly, automated radiosynthesis of [18F]Flortaucipir was processed via nucleophilic radiofluorination of precursor AV1622 and followed by acid hydrolysis in a RNplus Research module, which included the radiosynthesis, semi-preparative high-performance liquid chromatography (HPLC) purification, and the final formulation via solid phase extraction (SPE). The final products were obtained in non-decay corrected radiochemical yields of 14.8-16.6% (n = 3) within total synthesis time of 55 min. The radiochemical purities of [18F]Flortaucipir were > 99.9% and the molar activities were 247.9-384.8 GBq/µmol at end of synthesis. The results of QC tests met all the specifications for human use. In conclusion, [18F]Flortaucipir was reproducibly achieved with desired radiochemical yield and high radiochemical purity and molar activity. Three GMP compliant validation runs and QC results demonstrated the efficacy of this method for automated production of [18F]Flortaucipir for human use.

HPLC-free and cassette-based nucleophilic production of [18F]FDOPA for clinical use.

Radiotracer 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (L-6-[18F]fluorodopa or [18F]FDOPA) is widely used for PET imaging of dopamine metabolism in several diseases including Parkinson's Disease, brain tumor, neuroendocrine tumors, and focal hyperinsulinism of infancy. In 2019, [18F]FDOPA was approved by US FDA for detection of dopaminergic nerve terminals in the striatum of adult patients with suspected Parkinsonian Syndromes. A convenient and reliable method is desired for fully automated production of [18F]FDOPA under cGMP compliance to meet the increasing clinical need. In this study, we reported a cassette-based automated production of [18F]FDOPA using a GE Fastlab 2 module and the quality control (QC) under fully cGMP compliant environment. Briefly, automated radiosynthesis of [18F]FDOPA was processed via nucleophilic radio-fluorination using FDOPA Fastlab cassette and solid phase extraction (SPE) purification. The QC tests of [18F]FDOPA, including appearance, pH, half-life, radiochemical purity and identity, enantiomeric purity, chemical impurities, molecular activity, radioactive concentration, filter integrity, endotoxin, and sterility, were conducted at the end of synthesis (EOS) and 8 h after EOS during the validation runs. Three consecutive productions of [18F]FDOPA were reliably achieved with desired radiochemical yield and high radiochemical/enantiomeric purities and molar activity. The uncorrected radiochemical yields of [18F]FDOPA were 9.3-9.8% with a total synthesis time of ~140 min. Both radiochemical and enantiomeric purities of [18F]FDOPA were >99.9% and the molar activities were 2.1-3.9 Ci/µmole at EOS. The full QC results at EOS and 8 h after EOS showed that the produced [18F]FDOPA met all release criteria for clinical use within 8 hours of expiration time. Three consecutive validation runs and QC results demonstrated the efficacy of cassette-based production of [18F]FDOPA for routine clinical use.

Analysis of [11C]Choline and [13N]Ammonia using a single HPIC method.

A single HPIC method was developed and validated for the analysis of both [11C]Choline and [13N]Ammonia with the same setup. The HPIC system suitability tests were performed and [11C]Choline and [13N]Ammonia were used to verify their performance on this HPIC method. The HPIC setup and method provides qualitative and quantitative analysis information of [11C]Choline and [13N]Ammonia. The data suggested this HPIC method is validated for determining radiochemical/chemical purity and radiochemical identity of [11C]Choline and [13N]Ammonia products in CGMP compliant manufacturing process.

Isolated Intravascular Prostate Carcinoma Recurrence Confirmed With 18F-Fluciclovine PET/CT and MRI.

Late recurrence of prostate cancer after remission with prior radical prostatectomy is uncommon. This is a unique case of biochemical recurrence after being in remission for 12 years. The patient presented with swelling of the right lower extremity with pelvic MRI demonstrating an arterially enhancing filling defect in the right common iliac. An F-fluciclovine PET/CT showed corresponding increased intravascular radiotracer activity. Targeted biopsy of the intravascular lesion showed poorly differentiated carcinoma, suggestive of prostate origin. Although MRI evaluation is the mainstay for pelvic evaluation, characterization with F-fluciclovine PET/CT imaging adds high whole-body specificity and diagnostic accuracy.

Buffering the Suffering of Breast Lymphoscintigraphy.

Breast lymphoscintigraphy with 99mTc-sulfur colloid is frequently performed before breast-conserving surgery to delineate drainage to a sentinel node. Tracer injection for lymphoscintigraphy can be painful. Our aims were to determine whether administering a solution of buffered lidocaine immediately before lymphoscintigraphy injection could both reduce the patients' pain and increase nuclear medicine technologists' satisfaction with performing the procedure. Methods: A pain scale survey was obtained from patients undergoing breast lymphoscintigraphy with or without buffered lidocaine. Our nuclear medicine technologists were also surveyed for their satisfaction with the procedure, both with and without the addition of buffered lidocaine. Results: The patients' reported pain decreased by 86% with the addition of buffered lidocaine. Technologist satisfaction with performing the procedure increased by 36%. Conclusion: Lidocaine buffered with sodium bicarbonate injected before lymphoscintigraphy significantly reduces pain experienced by the patient and improves nuclear medicine technologist satisfaction in performing the procedure.

Expanding the Indication for Novel Theranostic 177Lu-Dotatate Peptide Receptor Radionuclide Therapy: Proof-of-Concept of PRRT in Merkel Cell Cancer.

The field of theranostics is a new nuclear medicine tool being utilized in the treatment of different types of cancers. It couples receptor-specific based imaging predicting and guiding response to receptor-specific based radionuclide therapies. For example, somatostatin-receptor based imaging (Gallium; 68Ga-dotatate scan) is now predicting and guiding the use of treatment with the somatostatin-receptor radiolabeled somatostatin analog (peptide receptor radionuclide therapy PRRT - Lutetium; 177Lu-Dotatate) for neuroendocrine tumors that express the somatostatin receptors. The United States Food and Drug Administration approved the use of 177Lu-Dotatate PRRT for somatostatin-receptor-positive gastroenteropancreatic neuroendocrine tumors only. Here we show proof of concept and results of an outstanding response to this novel therapy in conjunction with immunotherapy in a refractory cancer type where it has not been approved (Merkel Cell Cancer). Our results and data provide proof of principle for considering the use of this novel therapy in a tumor-agnostic approach; similar to approval of immunotherapy for mismatch repair deficient tumors. The response demonstrated has also been unprecedented, likely secondary to use of PRRT with immunotherapy. These observations have profound and broad implications on how to move this novel field of theranostics forward for treatment of many cancer-types.

Evaluation of L-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of Cancer.

PURPOSE: Fluorine-18 labeled tryptophan analog L-1-[18F]fluoroethyl-tryptophan (L-1-[18F]FETrp) was designed for positron emission tomography (PET) imaging of cancer by dual targeting of the overexpressed amino acid transporters and altered indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway of tryptophan metabolism. In our previous study, we described the radiosynthesis and preliminary evaluation of L-1-[18F]FETrp for PET imaging of breast cancer. The aim of this study was to investigate the in vivo imaging mechanism and further evaluate this radiotracer in more wide range types of cancers including prostate cancer, lung cancer, and glioma. PROCEDURES: The mice bearing subcutaneous PC-3 prostate cancer, subcutaneous H2009 and H460 lung cancers, subcutaneous MDA-MB-231, orthotopic A549 lung cancer, and intracranial 73C glioma were employed to evaluate L-1-[18F]FETrp for PET imaging of cancer. The in vivo catabolism of L-1-[18F]FETrp in the tumor was studied by analysis of PC-3 extracts with radio-HPLC. RESULTS: Small animal PET/CT imaging of L-1-[18F]FETrp visualized all tumors in these different mouse models with high accumulations of radioactivity in PC-3 (7.5 ± 0.6 % ID/g), H2009 (5.3 ± 0.8 % ID/g), H460 (9.0 ± 1.4 % ID/g), A549 (4.5 ± 0.5 % ID/g), and 73C (4.1 ± 0.7 % ID/g) tumors. The radio-HPLC analysis of PC-3 tumor extracts revealed that about 30 % of L-1-[18F]FETrp was converted into a highly polar radioactive metabolite. The uptake in H460 cancer was about 1.7-fold higher than that in H2009 cancer, which indicated L-1-[18F]FETrp could differentiate these subtypes of lung cancers (H2009 and H460) by imaging quantification. Furthermore, small animal PET/CT imaging in intracranial glioma revealed L-1-[18F]FETrp could pass blood-brain barrier (BBB) and accumulate in glioma with a favorable imaging contrast (tumor-to-brain 2.9). CONCLUSIONS: L-1-[18F]FETrp highly accumulated in a wide range of malignancies including lung cancer, prostate cancer, and glioma. These results suggested that L-1-[18F]FETrp is a promising radiotracer for PET imaging of cancer.

Acquired Whole-lung Mismatched Perfusion Defects on Pulmonary Ventilation/Perfusion Scintigraphy.

Despite the increasing use of computed tomography pulmonary angiography to evaluate for pulmonary embolism (PE), ventilation/perfusion (V/Q) scintigraphy is still a fairly common examination. A rare finding on V/Q scintigraphy is whole-lung mismatched perfusion defect. Although this finding can occur with PE, it has an important, limited differential diagnosis. In this pictorial essay, we describe different causes of acquired whole-lung mismatched perfusion defect.

A Care Process Model to Deliver 177Lu-Dotatate Peptide Receptor Radionuclide Therapy for Patients With Neuroendocrine Tumors.

Purpose: To develop a care process model for the delivery of peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-Dotatate for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: A multidisciplinary, structured PRRT process model was established. Over the last 9 months, meetings were held bi-weekly to discuss the logistics of clinical trials. Meetings are still held regularly at the Mayo Clinic Florida to discuss plans regarding commercially available PRRT treatments. The process model has evolved as we have treated patients on both clinical trials and commercial treatments. Results: An effective process model was formulated. We had 5 patients on our Expanded Access Program (EAP) clinical trial. Our ability to be a part of the EAP allowed us to understand the mechanics of how to treat these patients, and what was involved before it became commercially available. Since commercial availability of the 177Lu-Dotatate, more than 50 treatments (>20 patients) have already been completed, with several new patients getting started on treatment every week. Our nuclear medicine department receives continual requests to schedule new patients for PRRT. This can be attributed to our streamlined approach in delivering PRRT to our patients. Conclusion: A thorough procedural approach was formulated to provide patients with PRRT. Experiences and challenges led to refinement, which has allowed the process to advance. This development could lead to better patient outcomes, treatment efficiency, and a reference standard for other institutions trying to develop this at their location.

Severe Hypercalcemia Related to Silicone Granulomas, as Discovered by FDG-PET.

Silicone injected for cosmetic purposes can provoke an inflammatory granulomatous response. In turn, silicone granulomas can lead to hypercalcemia, which is a rare, though potentially life-threatening condition. Hypercalcemia is a nonspecific laboratory finding with many potential etiologies. It may be difficult for clinicians to diagnose silicone-induced hypercalcemia, since the history of cosmetic silicone injections may not be elicited from the patient. Positron emission tomography using F-18-fluorodeoxyglucose (FDG-PET) can be used to evaluate patients with unexplained hypercalcemia as a means of searching for an occult malignancy or granulomatous process. FDG-PET findings may be the initial and perhaps only indication of silicone granulomas as the cause of hypercalcemia. Nuclear medicine physicians should have a low threshold for suggesting this diagnosis, particularly in the setting of unexplained hypercalcemia. This case report highlights the value of FDG-PET in diagnosing silicone granuloma-induced hypercalcemia.

Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer.

BACKGROUND: Intercessory prayer is widely believed to influence recovery from illness, but claims of benefits are not supported by well-controlled clinical trials. Prior studies have not addressed whether prayer itself or knowledge/certainty that prayer is being provided may influence outcome. We evaluated whether (1) receiving intercessory prayer or (2) being certain of receiving intercessory prayer was associated with uncomplicated recovery after coronary artery bypass graft (CABG) surgery. METHODS: Patients at 6 US hospitals were randomly assigned to 1 of 3 groups: 604 received intercessory prayer after being informed that they may or may not receive prayer; 597 did not receive intercessory prayer also after being informed that they may or may not receive prayer; and 601 received intercessory prayer after being informed they would receive prayer. Intercessory prayer was provided for 14 days, starting the night before CABG. The primary outcome was presence of any complication within 30 days of CABG. Secondary outcomes were any major event and mortality. RESULTS: In the 2 groups uncertain about receiving intercessory prayer, complications occurred in 52% (315/604) of patients who received intercessory prayer versus 51% (304/597) of those who did not (relative risk 1.02, 95% CI 0.92-1.15). Complications occurred in 59% (352/601) of patients certain of receiving intercessory prayer compared with the 52% (315/604) of those uncertain of receiving intercessory prayer (relative risk 1.14, 95% CI 1.02-1.28). Major events and 30-day mortality were similar across the 3 groups. CONCLUSIONS: Intercessory prayer itself had no effect on complication-free recovery from CABG, but certainty of receiving intercessory prayer was associated with a higher incidence of complications.