Open Access

Johannes Gnörich, Julia Kusche-Palenga, Agnes Kling, Amir Dehsarvi, Angela Bronte, Lukas Frontzkowski, Artem Zatcepin, Mirlind Zaganjori, Florian Schöberl, Sebastian N. Roemer-Cassiano, Boris-Stephan Rauchmann, Carolin Kurz, Carla Palleis, Alexander M. Bernhardt, Alexander Jäck, Sabrina Katzdobler, Maximilian Scheifele, Theresa Bauer, Gérard N. Bischof, Thilo van Eimeren, Alexander Drzezga, Jan Häckert, Robert Perneczky, Michael Rullmann, Katharina Buerger, Rudolf A. Werner, Andreas Zwergal, Johannes Levin, Peter Bartenstein, Osama Sabri, Henryk Barthel, Sophia Stöcklein, Günter Höglinger, Nicolai Franzmeier, Matthias Brendel

• AbstractBackgroundPatients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, A/T/N assessment incorporates β-amyloid-PET (A), tau-PET (T), and [18F]FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration in individual patients using a single imaging session.MethodsWe studied 129 patients with tauopathies, comprising 47 patients with β-amyloid-positive 3/4-repeat tauopathy and 82 patients with β-amyloid-negative primary 4-repeat tauopathies, alongside 17 healthy controls. Participants underwent 60-minute dynamic [18F]PI-2620 tau-PET. Kinetic modelling simultaneously provided tracer efflux rate (K2a) as a predictor for β-amyloid status, distribution volume ratio (DVR) for regional tau burden, and relative perfusion (R1) as aAbstractBackgroundPatients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, A/T/N assessment incorporates β-amyloid-PET (A), tau-PET (T), and [18F]FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration in individual patients using a single imaging session.MethodsWe studied 129 patients with tauopathies, comprising 47 patients with β-amyloid-positive 3/4-repeat tauopathy and 82 patients with β-amyloid-negative primary 4-repeat tauopathies, alongside 17 healthy controls. Participants underwent 60-minute dynamic [18F]PI-2620 tau-PET. Kinetic modelling simultaneously provided tracer efflux rate (K2a) as a predictor for β-amyloid status, distribution volume ratio (DVR) for regional tau burden, and relative perfusion (R1) as a marker of neurodegeneration. These parameters were validated against β-amyloid-PET, [18F]FDG-PET, volumetric MRI, and cerebrospinal fluid biomarkers using receiver operating characteristic and correlation analyses and visual assessments. [18F]PI-2620K2a-based prediction of β-amyloid positivtiy was additionally tested in an independent, clinically heterogeneous validation cohort of 97 individuals.Results[18F]PI-2620K2a differentiated tau isoform compositions despite clinically overlapping presentations and tau-PET patterns, demonstrating reduced cortical tracer clearance in 3/4-repeat compared with 4-repeat tauopathies. [18F]PI-2620K2a remained sensitive in individuals with visually negative or low [18F]PI-2620DVR signals and outperformed both tau burden and perfusion for predicting β-amyloid status, achieving an area under the curve of 0.99, a positive predictive value of 91.5%, and a negative predictive value of 95.1%. Performance remained robust in the independent validation cohort, with an area under the curve of 0.98, a positive predictive value of 87.9%, and a negative predictive value of 95.3%. [18F]PI-2620DVR quantified regional tau patterns, with cortical predominance in 3/4-repeat tauopathy and subcortical involvement in 4-repeat tauopathies. [18F]PI-2620R1 exhibited strong quantitative and visual associations with established markers of neurodegeneration. Integration of K2a, DVR, and R1 in disease-specific composite regions enabled individualized three-dimensional A/T/N staging.ConclusionsDynamic [18F]PI-2620 PET imaging facilitates assessment of the β-amyloid status and regional staging of tau and neurodegeneration during a single acquisition. This one-stop-shop approach may reduce radiation exposure, streamline diagnostic workflows, and facilitate personalized disease profiling.Graphical Abstract…