The Lancet medical imaging & theranostics · 2026
Low-dose CT for MRI-free quantification of tau PET in Alzheimer's disease: a multicentre, cross-sectional, comparison study.
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Matuck Bruno F, Huynh Khoa L A, Pereira Diana, Easter Quinn T, Zhang XiuYu, Kunz Meik, Kumar Nikhil, Pratapa Aditya, Rupp Brittany T, Ghodke Ameer, Predeus Alexander V, Fernandes Alexandre, Szabó Lili, Hartmann Stefan, Harnischfeger Nadja, Khavandgar Zohreh, Beach Margaret, Perez Paola, Nilges Benedikt, Moreno Maria M, Ko Kang I, Singh Rohit, Tata Purushothama Rao, Teichmann Sarah A, Kimple Adam, Pringle Sarah, Kretzschmar Kai, Warner Blake M, Sequeira Inês, Liu Jinze, Byrd Kevin M
Аннотация
BACKGROUND: Tau PET quantification typically requires structural MRI for reference-region definition, normalisation, and segmentation. We evaluated whether low-dose CT can serve as a reliable MRI alternative for tau PET quantification when MRI is unavailable.
METHODS: In this multicentre cross-sectional methods comparison study, we developed a PET-CT pipeline using low-dose CT as the sole anatomical reference for tau PET quantification. Participants were recruited from six sites in the multicentre Head-to-head Harmonisation of tau PET tracers (HEAD) study. The cohort comprised cognitively unimpaired (CU) young adults (<28 years), CU middle-aged adults (50-65 years), CU elderly (>65 years), and participants with mild cognitive impairment (MCI) or dementia. Participants underwent [18F]MK6240 and [18F]Flortaucipir PET-CT, T1-weighted MRI, and amyloid PET. SUVRs were calculated for three AD-relevant composite regions and 34 individual cortical regions using a template-based cerebellar reference and compared with PET-MR pipelines using template-based or FreeSurfer subject-space segmentation. Agreement was assessed using linear regression, intraclass correlation coefficients (ICC), Bland-Altman analysis, equivalence testing (two one-sided tests, TOST), and Cohen's kappa (κ) for binary positivity concordance.
FINDINGS: A total of 387 participants were included, with recruitment spanning from November 11, 2022 and July 7, 2025 (205 [53%] female, 182 [47%] male; 6 [2%] aged 19-25 years, 130 [34%] aged 50-65 years and 251 [65%] aged 66-89 years). Against the template-based PET-MR pipeline, CT-derived SUVRs showed near-perfect linear correspondence with the template-based PET-MR pipeline for MK6240 (R2 0·959-0·975) and Flortaucipir (R2 0·925-0·964), with high absolute agreement (ICC 0·976-0·985 and 0·955-0·978, respectively). Against the FreeSurfer subject-space pipeline, correspondence remained strong for MK6240 (R2 0·952-0·971) and Flortaucipir (R2 0·909-0·949). Mean R2 across 34 cortical regions was 0·917 (SD 0·049) for MK6240 and 0·874 (SD 0·057) for Flortaucipir. Tau-positivity concordance was high (92·0-96·6%; κ 0·802-0·895; all p<0·0001), with discordant cases near the classification threshold. Associations with amyloid burden and memory were preserved across pipelines (Steiger's test, all p>0·05). Equivalence was formally confirmed by TOST (all p<0·0001).
INTERPRETATION: CT-only processing enables robust tau PET quantification comparable to standard MRI-based pipelines, including computationally intensive FreeSurfer-based approaches. This method was validated across different radiotracers and represents a reliable alternative when MRI is unavailable or contraindicated. Because low-dose CT is routinely acquired during PET-CT sessions, this approach enables quantification of legacy datasets lacking MRI, broadens participant inclusion in clinical trials, and may reduce imaging costs in settings where MRI is not clinically indicated.
METHODS: In this multicentre cross-sectional methods comparison study, we developed a PET-CT pipeline using low-dose CT as the sole anatomical reference for tau PET quantification. Participants were recruited from six sites in the multicentre Head-to-head Harmonisation of tau PET tracers (HEAD) study. The cohort comprised cognitively unimpaired (CU) young adults (<28 years), CU middle-aged adults (50-65 years), CU elderly (>65 years), and participants with mild cognitive impairment (MCI) or dementia. Participants underwent [18F]MK6240 and [18F]Flortaucipir PET-CT, T1-weighted MRI, and amyloid PET. SUVRs were calculated for three AD-relevant composite regions and 34 individual cortical regions using a template-based cerebellar reference and compared with PET-MR pipelines using template-based or FreeSurfer subject-space segmentation. Agreement was assessed using linear regression, intraclass correlation coefficients (ICC), Bland-Altman analysis, equivalence testing (two one-sided tests, TOST), and Cohen's kappa (κ) for binary positivity concordance.
FINDINGS: A total of 387 participants were included, with recruitment spanning from November 11, 2022 and July 7, 2025 (205 [53%] female, 182 [47%] male; 6 [2%] aged 19-25 years, 130 [34%] aged 50-65 years and 251 [65%] aged 66-89 years). Against the template-based PET-MR pipeline, CT-derived SUVRs showed near-perfect linear correspondence with the template-based PET-MR pipeline for MK6240 (R2 0·959-0·975) and Flortaucipir (R2 0·925-0·964), with high absolute agreement (ICC 0·976-0·985 and 0·955-0·978, respectively). Against the FreeSurfer subject-space pipeline, correspondence remained strong for MK6240 (R2 0·952-0·971) and Flortaucipir (R2 0·909-0·949). Mean R2 across 34 cortical regions was 0·917 (SD 0·049) for MK6240 and 0·874 (SD 0·057) for Flortaucipir. Tau-positivity concordance was high (92·0-96·6%; κ 0·802-0·895; all p<0·0001), with discordant cases near the classification threshold. Associations with amyloid burden and memory were preserved across pipelines (Steiger's test, all p>0·05). Equivalence was formally confirmed by TOST (all p<0·0001).
INTERPRETATION: CT-only processing enables robust tau PET quantification comparable to standard MRI-based pipelines, including computationally intensive FreeSurfer-based approaches. This method was validated across different radiotracers and represents a reliable alternative when MRI is unavailable or contraindicated. Because low-dose CT is routinely acquired during PET-CT sessions, this approach enables quantification of legacy datasets lacking MRI, broadens participant inclusion in clinical trials, and may reduce imaging costs in settings where MRI is not clinically indicated.