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Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β-negative, 22 cognitively unimpaired elderly amyloid-β-positive, 21 mild cognitive impairment amyloid-β-positive and 17 Alzheimer's disease dementia amyloid-β-positive individuals) with baseline amyloid-β 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer's disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-β-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-β-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer's dementia amyloid-β-positive exhibited tau accumulation in Braak regions III-VI but not I-II. Cognitively impaired amyloid-β-positive individuals that were Braak II-IV at baseline displayed a 4.6-7.5% annual increase in tau accumulation in the Braak III-IV regions, whereas those who were cognitively impaired amyloid-β-positive Braak V-VI at baseline showed an 8.3-10.7% annual increase in the Braak regions V-VI. Neuropathological assessments confirmed PET-based Braak stages V-VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual's baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99mTc-methylene diphosphonate (99mTc-MDP) single-photon emission CT (SPECT) and 18F-sodium fluoride (18F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer.Methods: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18F-NaF PET-CT and 99mTc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99mTc-MDP SPECT and 18F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete.Findings: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18F-NaF PET-CT and 99mTc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18F-NaF PET-CT was more accurate than 99mTc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited.Interpretation: 18F-NaF has the potential to displace 99mTc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer.Funding: Canadian Institutes of Health Research. [ABSTRACT FROM AUTHOR]