Additive value of [18F]PI-2620 perfusion imaging in four-repeat tauopathies
Authors: Katzdobler Sabrina , Nitschmann Alexander , Barthel Henryk , Bischof Gerard , Beyer Leonie , Marek Ken , Song Mengmeng , Wagemann Olivia , Palleis Carla , Weidinger Endy , Nack Anne , Fietzek Urban , Kurz Carolin , Häckert Jan , Stapf Theresa , Ferschmann Christian , Scheifele Maximilian , Eckenweber Florian , Biechele Gloria , Franzmeier Nicolai , Dewenter Anna , Schönecker Sonja , Saur Dorothee , Schroeter Matthias L. , Rumpf Jost-Julian , Rullmann Michael , Schildan Andreas , Patt Marianne , Stephens Andrew W. , van Thilo Eimeren , Neumaier Bernd , Drzezga Alexander , Danek Adrian , Classen Joseph , Bürger Katharina , Janowitz Daniel , Rauchmann Boris-Stephan , Stöcklein Sophia , Perneczky Robert , Schöberl Florian , Zwergal Andreas , Höglinger Günter U. , Bartenstein Peter , Villemagne Victor , Seibyl John , Sabri Osama , Levin Johannes , Brendel Matthias 
Published: January 2022

Abstract
Purpose

Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate 4-repeat tauopathies (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs.
Methods

Seventy-eight patients with 4RTs (71±7y, 39 female), 79 patients with other neurodegenerative diseases (67±12y, 35 female) and twelve age-matched controls (69±8y, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value-ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p<0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value-2SD threshold). Additionally, perfusion and tau pattern expression levels were tested for discrimination of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n=37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living).
Results

Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression discriminated patients with 4RTs well from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was validated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = -0.431; p = 0.0005).
Conclusion

[18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression provides an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.