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Additional file 1: Supplementary Figure 1. Differentially expressed genes at follow-up compared to baseline in amyloid non-accumulators. Data points are based coloured on significance: grey = non-significant, blue = non-significant but with FDR p-value < 0.05, red = significant with FDR p-value < 0.05 and log2FoldChange ± 1. N = 53. Pval on y-axis represents the uncorrected p-value < 0.05 threshold for visualisation. Supplementary Figure 2. Detection of modules using baseline expression data. (A) Scale independence and (B) mean connectivity used to derive the soft power threshold. (C) Clustering of module eigengenes, where similar clusters were merged using a cutHeight =0.25 (red line). (D) Cluster dendrogram of co-expression modules shown, both with the 28 dynamic modules (top row) and final merged 17 modules (bottom row). Supplementary Figure 3. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the baseline blue WGCNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferronicorrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 4. Detection of modules using follow-up expression data. (A) Scale independence and (B) mean connectivity used to derive the soft power threshold. (C) Clustering of module eigengenes, where similar clusters were merged using a cutHeight =0.25 (red line). (D) Cluster dendrogram of co-expression modules shown, both with the 32 dynamic modules (top row) and final merged 35 modules (bottom row). Supplementary Figure 5. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the follow-up blue WGCNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferronicorrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 6. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the follow-up turquoise WCGNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferroni-corrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p-value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 7. Detection of modules using follow-up expression data. (A) Scale independence and mean connectivity used to derive the soft power threshold. (B) Cluster dendrogram of consensus modules.

BACKGROUND: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. METHODS: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. RESULTS: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. DISCUSSION: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. HIGHLIGHTS: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. ispartof: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS vol:9 issue:1 ispartof: location:United States status: published

Additional file 2: Supplementary Table 1. APOE4 follow-up versus baseline significant differentially expressed genes. Supplementary Table 2. APOE4 non-carriers follow-up versus baseline significant differentially expressed genes. Supplementary Table 3. Cell deconvolution contributions generated using CIBERSORT. Supplementary Table 4. Amyloid non-accumulators follow-up versus baseline significant differentially expressed genes. Supplementary Table 5. Follow-up versus baseline significant differentially expressed genes in amyloid negative-positive and amyloid positive-positive individuals. Supplementary Table 6. Follow-up versus baseline significant differentially expressed genes in amyloid negative individuals. Supplementary Table 7. Direct association scores of significant differentially expressed genes at follow-up versus baseline in APOE4 carriers. Supplementary Table 8. Direct association scores of significant differentially expressed genes at follow-up versus baseline in amyloid negativepositive and amyloid positive-positive individuals. Supplementary Table 9. APOE4 carriers gene set enrichment analysis gene ontology upregulated. Supplementary Table 10. APOE4 non-carriers gene set enrichment analysis gene ontology upregulated. Supplementary Table 11. APOE4 carriers gene set enrichment analysis gene ontology downregulated. Supplementary Table 12. APOE4 non-carriers gene set enrichment analysis gene ontology downregulated. Supplementary Table 13. Amyloid non-accumulators gene set enrichment analysis gene ontology upregulated. Supplementary Table 14. Amyloid non-accumulators gene set enrichment analysis gene ontology downregulated. Supplementary Table 15. Amyloid negative-positive/positive-positive gene set enrichment analysis gene ontology upregulated. Supplementary Table 16. Amyloid negative-negative gene set enrichment analysis gene ontology upregulated. Supplementary Table 17. Amyloid negative-positive/positive-positive gene set enrichment analysis gene ontology downregulated. Supplementary Table 18. Amyloid negative-negative gene set enrichment analysis gene ontology downregulated. Supplementary Table 19. Baseline Blue module enrichment. Supplementary Table 20. Follow-up Blue module enrichment. Supplementary Table 21. Follow-up Turquoise module enrichment.

Background Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [F-18]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [F-18]AlF-OC PET/CT outperforms [Ga-68]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [F-18]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [F-18]AlF-OC ("incremental lesions").Methods Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [Ga-68]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [F-18]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient.Results In total, 195 unique lesions were detected: 167 with [Ga-68]Ga-DOTATATE and 193 with [F-18]AlF-OC. The DR for [F-18]AlF-OC was 99.1% versus 91.4% for [Ga-68]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [F-18]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [F-18]AlF-OC, of which 91% were confirmed by MRI and considered true positives.Conclusion The DR of [F-18]AlF-OC was numerically higher and non-inferior to the DR of [Ga-68]Ga-DOTATATE. [F-18]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [F-18]AlF-OC as a new alternative for SSTR PET in clinical practice.