Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies,European Journal of Nuclear Medicine and Molecular Imaging

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Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2024-02-17 , DOI: 10.1007/s00259-024-06637-6
Christian Ferschmann ₁ , Konstantin Messerschmidt ₂ , Johannes Gnörich ₁ , Henryk Barthel ₂ , Ken Marek _{3,

4} , Carla Palleis _{5,

6,

7} , Sabrina Katzdobler ₇ , Anna Stockbauer ₇ , Urban Fietzek ₇ , Anika Finze ₁ , Gloria Biechele _{1,

8} , Jost-Julian Rumpf ₉ , Dorothee Saur ₉ , Matthias L Schroeter _{10,

11,

12} , Michael Rullmann ₂ , Leonie Beyer ₁ , Florian Eckenweber ₁ , Stephan Wall ₁ , Andreas Schildan ₂ , Marianne Patt ₂ , Andrew Stephens ₁₃ , Joseph Classen ₉ , Peter Bartenstein _{1,

5} , John Seibyl _{3,

4} , Nicolai Franzmeier _{5,

14} , Johannes Levin _{5,

6,

7} , Günter U Höglinger _{6,

7} , Osama Sabri ₂ , Matthias Brendel _{1,

5,

6} , Maximilian Scheifele ₁ ,

Affiliation

Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany.
Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
InviCRO, LLC, Boston, MA, USA.
Molecular Neuroimaging, A Division of inviCRO, New Haven, CT, USA.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany.
Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
Department of Neurology, University Hospital Leipzig, Leipzig, Germany.
Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany.
LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Life Molecular Imaging GmbH, Berlin, Germany.
Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany.

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.

中文翻译：

在四次重复的 tau 蛋白病中，tau 蛋白积累与体内多巴胺缺乏有关

目的

我们假设，参与基底神经节直接或间接通路的大脑区域中严重的 tau 蛋白负担与四重复 (4R) tau蛋白病中更严重的纹状体多巴胺缺乏相关。因此，我们将[ ¹⁸ F]PI-2620 tau 正电子发射断层扫描（PET）成像与[ ¹²³ I]-碘氟烷单光子发射计算机断层扫描（SPECT）相关联，以了解多巴胺转运蛋白（DaT）的可用性。

方法

38 名临床诊断为 4R-tau 蛋白病的患者（21 名男性；69.0 ± 8.5 岁）和 15 名临床诊断为 α-突触核蛋白病的患者（8 名男性；66.1 ± 10.3 岁）接受了 [ ¹⁸ F]PI-2620 tau-PET 和评估时间间隔为 3 ± 5 个月的 DaT-SPECT 成像。 4R-tau蛋白病和 α-突触核蛋白病患者的区域 Tau-PET 信号和 DaT 可用性及其主要成分相关。这两种生物标志物及其相关残差均与 4R-tau蛋白病的临床严重程度评分相关。

结果

在 4R-tau蛋白病患者中，基底神经节和中脑区域的 [ ¹⁸ F]PI-2620 结合与纹状体 DaT 可用性（即苍白球内部和壳核）呈负相关（β = − 0.464， p = 0.006，Durbin-Watson 统计 = 1.824）相反，齿状核中的 [ ¹⁸ F]PI-2620 结合显示纹状体中 DaT 可用性没有显着的回归因子（β = 0.078， p = 0.662，Durbin-Watson 统计 = 1.686）。 α-突触核蛋白病患者并未表明 [ ¹⁸ F]PI-2620 结合与 DaT 可用性之间存在任何区域关联。相对于 tau 负荷，较高的 DaT-SPECT 结合与更好的临床表现相关（β = − 0.522， p = 0.011， Durbin-Watson 统计数据 = 2.663) 4R-tau蛋白病患者。