Association of Amyloid Positron Emission Tomography With Changes in Diagnosis and Patient Treatment in an Unselected Memory Clinic Cohort: The ABIDE Project.

Importance: Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. Objective: To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort. Design, Setting, and Participants: Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned. Main Outcomes and Measures: Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment. Results: Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy. Conclusions and Relevance: This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.

Alzheimer's biomarkers in daily practice (ABIDE) project: Rationale and design.

INTRODUCTION: The Alzheimer's biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI). METHODS: ABIDE is a 3-year project with a multifaceted design and is structured into interconnected substudies using both quantitative and qualitative research methods. RESULTS: Based on retrospective data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations. DISCUSSION: Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results.

Radioisotopic Purity of Sodium Pertechnetate 99mTc Produced with a Medium-Energy Cyclotron: Implications for Internal Radiation Dose, Image Quality, and Release Specifications.

UNLABELLED: Cyclotron production of 99mTc is a promising route to supply 99mTc radiopharmaceuticals. Higher 99mTc yields can be obtained with medium-energy cyclotrons in comparison to those dedicated to PET isotope production. To take advantage of this capability, evaluation of the radioisotopic purity of 99mTc produced at medium energy (20-24 MeV) and its impact on image quality and dosimetry was required. METHODS: Thick 100Mo (99.03% and 99.815%) targets were irradiated with incident energies of 20, 22, and 24 MeV for 2 or 6 h. The targets were processed to recover an effective thickness corresponding to approximately 5-MeV energy loss, and the resulting sodium pertechnetate 99mTc was assayed for chemical, radiochemical, and radionuclidic purity. Radioisotopic content in final formulation was quantified using γ-ray spectrometry. The internal radiation dose for 99mTc-pertechnetate was calculated on the basis of experimentally measured values and biokinetic data in humans. Planar and SPECT imaging were performed using thin capillary and water-filled Jaszczak phantoms. RESULTS: Extracted sodium pertechnetate 99mTc met all provisional quality standards. The formulated solution for injection had a pH of 5.0-5.5, contained greater than 98% of radioactivity in the form of pertechnetate ion, and was stable for at least 24 h after formulation. Radioisotopic purity of 99mTc produced with 99.03% enriched 100Mo was greater than 99.0% decay corrected to the end of bombardment (EOB). The radioisotopic purity of 99mTc produced with 99.815% enriched 100Mo was 99.98% or greater (decay corrected to the EOB). The estimated dose increase relative to 99mTc without any radionuclidic impurities was below 10% for sodium pertechnetate 99mTc produced from 99.03% 100Mo if injected up to 6 h after the EOB. For 99.815% 100Mo, the increase in effective dose was less than 2% at 6 h after the EOB and less than 4% at 15 h after the EOB when the target was irradiated at an incident energy of 24 MeV. Image spatial resolution and contrast with cyclotron-produced 99mTc were equivalent to those obtained with 99mTc eluted from a conventional generator. CONCLUSION: Clinical-grade sodium pertechnetate 99mTc was produced with a cyclotron at medium energies. Quality control procedures and release specifications were drafted as part of a clinical trial application that received approval from Health Canada. The results of this work are intended to contribute to establishing a regulatory framework for using cyclotron-produced 99mTc in routine clinical practice.

Assessment of radionuclidic impurities in cyclotron produced (99m)Tc.

INTRODUCTION: The commercial viability of cyclotron-produced (99m)Tc as an alternative to generator-produced (99m)Tc depends on several factors. These include: production yield, ease of target processing and recycling of (100)Mo, radiochemical purity, specific activity as well as the presence of other radionuclides, particularly various Tc radioisotopes that cannot be separated chemically and will remain in the final clinical preparation. These Tc radionuclidic impurities are derived from nuclear interactions of the accelerated protons with other stable Mo isotopes present in the enriched (100)Mo target. The aim of our study was to determine experimentally the yields of Tc radioisotopes produced from these stable Mo isotopes as a function of incident beam energy in order to predict radionuclidic purity of (99m)Tc produced in highly enriched (100)Mo targets of known isotopic composition. METHODS: Enriched molybdenum targets of (95)Mo, (96)Mo, (97)Mo, (98)Mo and (100)Mo were prepared by pressing powdered metal into an aluminum target support. The thick targets were bombarded with 10 to 24MeV protons using the external beam line of the U-120M cyclotron of the Nuclear Physics Institute, Rez. The thick target yields of (94)Tc, (94m)Tc, (95)Tc, (95m)Tc, (96m+g)Tc and (97m)Tc were derived from their activities measured by γ spectrometry using a high purity Ge detector. These data were then used to assess the effect of isotopic composition of highly enriched (100)Mo targets on the radionuclidic purity of (99m)Tc as a function of proton beam energy. Estimates were validated by comparison to measured activities of Tc radioisotopes in proton irradiated, highly enriched (100)Mo targets of known isotopic composition. RESULTS: The measured thick target yields of (94)Tc, (94m)Tc, (95)Tc, (95m)Tc, (96m+g)Tc and (97m)Tc correspond well with recently published values calculated via the EMPIRE-3 code. However, the measured yields are more favourable with regard to achievable radionuclidic purity of (99m)Tc. Reliability of the measured thick target yields was demonstrated by comparison of the estimated and measured activities of (94)Tc, (95)Tc, (95m)Tc, and (96m+g)Tc in highly enriched (100)Mo (99%) targets that showed good agreement, with maximum differences within estimated uncertainties. Radioisotopes (94m)Tc and (97m)Tc were not detected in the irradiated (100)Mo targets due to their low activities and measurement conditions; on the other hand we detected small amounts of the short-lived positron emitter (93)Tc (T(½)=2.75h). In addition to (99m)Tc and trace amounts of the various Tc isotopes, significant activities of (96)Nb, (97)Nb and (99)Mo were detected in the irradiated (100)Mo targets. CONCLUSIONS: Radioisotope formation during the proton irradiation of Mo targets prepared from different, enriched stable Mo isotopes provides a useful data base to predict the presence of Tc radionuclidic impurities in (99m)Tc derived from proton irradiated (100)Mo targets of known isotopic composition. The longer-lived Tc isotopes including (94)Tc (T(½)=4.883h), (95)Tc (T(½)=20.0h), (95m)Tc (T(½)=61 d), (96m+g)Tc (T(½)=4.24 d) and (97m)Tc (T(½)=90 d) are of particular concern since they may affect the dosimetry in clinical applications. Our data demonstrate that cyclotron production of (99m)Tc, using highly enriched (100)Mo targets and 19-24MeV incident proton energy, will result in a product of acceptable radionuclidic purity for applications in nuclear medicine.