Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer's disease

Abstract

Purpose: In vivo Alzheimer's disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [¹⁸F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [¹⁸F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy.

Methods: We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [¹⁸F]flortaucipir PET scans were acquired to generate binding potential (BP_ND) images using receptor parametric mapping and standardized uptake values ratios of 80-100 min (SUVr_80-100min) post injection. We obtained regional BP_ND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only).

Results: Higher [¹⁸F]flortaucipir BP_ND was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43-0.46; all p < 0.01). [¹⁸F]flortaucipir BP_ND was more strongly associated with cognition and atrophy than CSF p-tau. When [¹⁸F]flortaucipir BP_ND and CSF p-tau were entered simultaneously, [¹⁸F]flortaucipir BP_ND (range sβ = - 0.20 to - 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BP_ND.

Conclusion: Regional [¹⁸F]flortaucipir BP_ND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.

Keywords: Atrophy; CSF; Cognition; PET; Tau; [18F]flortaucipir.