Low-dose CT for MRI-free quantification of tau PET in Alzheimer's disease: a multicentre, cross-sectional, comparison...

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.

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.

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).

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.