Linking PI-2620 tau-PET, fluid biomarkers, MRI, and cognition to advance diagnostics for progressive supranuclear palsy
Authors: Dilcher Roxane , Malpas Charles B. , O’Brien William T. , McDonald Stuart J. , Despott Craig , Bertram Kelly , Pase Matthew P. , Law Meng , O’Brien Terence J. , Vivash Lucy 
Published: October 2024

Importance

Identifying biomarkers for primary tauopathies such as progressive supranuclear palsy (PSP) is crucial for improving diagnosis and establishing clinical trial and treatment endpoints.

Objective

To determine whether brain tau deposition, measured by18F-PI-2620 tau-PET, is associated with fluid biomarkers, regional atrophy, and cognition in PSP. We hypothesized that increased subcortical tau uptake correlates with elevated fluid biomarkers and explored its relationship with brain volume and cognition, providing insights into disease progression.

Design

Cross-sectional analysis of baseline data from the SEL003 clinical trial of sodium selenate for PSP, conducted from July 2021 to August 2024.

Setting

Multicentre study across six clinical sites in Australia.

Participants

28 patients with probable PSP (Richardson’s syndrome) and 11 age- and sex-matched healthy controls from the Monash University Brain and Cognitive Health (BACH) study. Patients were over 40 years old, had symptom onset within five years, and had no structural abnormalities on MRI.

Exposures

18F-PI-2620 tau-PET, MRI, and cognitive testing were conducted in all patients. A subset of 24 patients and 10 healthy controls had blood and CSF samples analysed for NfL, GFAP, and t-tau.

Main Outcome and Measures

Associations between tau-PET uptake, fluid biomarkers (NfL, GFAP, t-tau, NfL/t-tau, GFAP/t-tau, GFAP/NfL), brain volume, and cognition. Secondary outcomes included group differences (patients vs controls) in fluid biomarkers. Standardized uptake value ratio (SUVr) values were calculated using cerebellar grey matter as the reference. Cognitive testing was performed using a battery of tests.

Results

Among 28 patients (median [IQR] age, 66 [62-70] years; 43% females), subcortical tau uptake was significantly associated with elevated NfL/t-tau (β=0.01; 95% CI, -0.01-0.02), reduced GFAP/NfL (β=-0.02; 95% CI, -0.01--0.01), reduced brain volume, and executive function impairment. Patients exhibited higher fluid biomarker levels in both plasma and CSF compared to controls (median [IQR] age, 65 [62-68] years; 60% female), particularly in biomarker ratios (NfL/t-tau: 98.9%, 95% CI 96.16%-100%).

Conclusions and Relevance

These findings highlight the utility of18F-PI-2620 as an in-vivo biomarker of tau pathology in PSP, with fluid biomarkers serving as valuable surrogate markers. Integrating both could improve diagnostic accuracy and treatment evaluation.

Trial Registration:Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).

Key points

Question:Is tau accumulation, as measured by18F-PI-2620 tau-PET, associated with fluid biomarkers, brain volume, and cognitive function in patients with progressive supranuclear palsy (PSP)?

Findings: In this cross-sectional study of 28 patients with probable PSP, subcortical tau uptake correlated positively with NfL levels and NfL/t-tau ratios, and negatively with GFAP levels and GFAP/NfL ratios in CSF and plasma. Tau-PET was associated with lower brain volume and cognitive impairments.

Meaning:These findings suggest that18F-PI-2620 tau-PET is a valuable tool for assessing tau pathology and its relationship with neurodegeneration and clinical outcomes in PSP. Fluid biomarker ratios may serve as surrogate markers in future clinical trials.