Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies

Abstract

Purpose: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [¹⁸F]PI-2620 tau-positron-emission-tomography (PET) imaging with [¹²³I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability.

Methods: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [¹⁸F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies.

Results: In patients with 4R-tauopathies, [¹⁸F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (β = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [¹⁸F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (β = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [¹⁸F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (β = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies.

Conclusion: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Keywords: 4R-Tau; DaT imaging; Motor reserve; [18F]PI-2620 tau-PET.

Fig. 1

Quantitative tau-PET and DaT-SPECT comparison of patients with clinical diagnosis of 4R-tauopathies (4RT) and α-synucleinopathies (α-syn). A Z-score distribution of tau-PET including p-value and effect size η² in representative brain regions of patients with 4R-tauopathies and patients with α-synucleopathies. SUVr = standardized uptake value ratio. B Z-score distribution of DaT-SPECT including p-value and effect size η² in comparison of patients with 4R-tauopathies and patients with α-synucleopathies. C Tau-PET SUVr and DaT-SPECT ratio images show the group average of patients with clinically diagnosed 4R-tauopathies and clinically diagnosed α-synucleinopathies

Fig. 2

Regional associations between tau-PET and DaT-SPECT in patients with 4R-tauopathies (4RT) and α-synucleinopathies (α-syn). A Heat maps show regional associations between tau-PET (y-axis) and DaT-SPECT (x-axis). Significant associations providing a p value < 0.05 are indicated with *. Blue colors indicate negative multiple regression coefficients (β). Orange colors indicate positive multiple regression coefficients (β). Regions analyzed for tau-PET: putamen right, left (PUT r/l), globus pallidus externus right, left (GPe r/l), globus pallidus internus right, left (GPi r/l), subthalamic nucleus right, left (STN r/l), substantia nigra (SN r/l), dorsal midbrain (DMB) and dentate nucleus right, left (Dentate r/l). Regions analyzed for DaT-SPECT: caudate right, left, anterior putamen right, left (aPUT r/l) and posterior putamen right, left (pPUT r/l). B The scheme shows the basic idea of the connection between high tau burden in brain regions involved in direct or indirect pathways of the basal ganglia and striatal dopaminergic loss. Arrow thickness shows the level of correlation of the examined regions for patients with 4R-tauopathies, whereas no significant correlations were found in α-synucleopathies (dashed lines). C Linear correlation between tau burden in the globus pallidus internus and the DaT availability in the posterior putamen of the right hemisphere

Fig. 3

Data driven correlation between tau burden and DaT availability. A Visualization of the brain regions resulting from the principal component analysis of tau-PET target regions. The color bar indicates corresponding loading values. Two principal components emerged, consisting of putamen, globus pallidus, subthalamic nucleus and the substantia nigra (principal component 1) as well as dentate nucleus and dorsal midbrain (principal component 2). B Visualized values of the rotated component matrix derived from the principal component analysis. C Tau-PET principal component 1 (tau-PET PC1) indicated a significant negative association with the DaT-SPECT principal component (DaT-SPECT PC), whereas tau-PET principal component 2 (tau-PET PC2) was not associated with the DaT-SPECT PC in a multiple regression model

Fig. 4

Preserved DaT availability relative to tau burden suggests concept of a motor reserve in patients with 4RT. A Residuals of the linear regression between the tau-PET principal component 1 (tau-PET PC1) and the DaT-SPECT principal component (DaT-SPECT PC) positive (green) and negative (red) were obtained as an index of preserved DaT availability despite tau burden. Preserved DaT availability was associated with lower disease severity in the PSP rating scale (right panel). Only patients with PSP rating scale scores are depicted. B Exemplary patients with 4R-tauopathies showing high tau burden, preserved DaT availability and mild clinical severity (upper row, 73y, female, PSP-CBS, PSP rating scale: 26) as well as moderate tau burden, strongly decreased DaT availability and severe clinical deterioration (lower row, 79y, female, PSP-CBS, PSP rating scale: 49). Axial slices show individual tau-PET z-scores on a standard MRI-template in contrast against healthy controls and individual DaT SPECT ratio images

Fig. 5

Comparison PSP rating scale items for motor function and mentation. Preserved DaT availability was associated with lower disease severity in the PSP rating scale scores for motor function (left panel), while there was no significant association between preserved DaT availability and lower disease severity in the PSP rating scale scores for mentation (right panel). Only patients with PSP rating scale scores for motor function and mentation items are depicted