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Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study

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Abstract

Purpose

Progressive supranuclear palsy (PSP) is primary 4-repeat tauopathy. Evidence spanning from imaging studies indicate aberrant connectivity in PSPs. Our goal was to assess functional connectivity network alterations in PSP patients and the potential link between regional tau-burden and network-level functional connectivity using the next-generation tau PET tracer [18F]PI-2620 and resting-state functional MRI (fMRI).

Material and methods

Twenty-four probable PSP patients (70.9 ± 6.9 years, 13 female), including 14 Richardson syndrome (RS) and 10 non-RS phenotypes, underwent [18F]PI-2620 PET/MRI imaging. Distribution volume ratios (DVRs) were estimated using non-invasive pharmacokinetic modeling. Resting-state fMRI was also acquired in these patients as well as in thirteen older non-AD MCI reference group (64 ± 9 years, 4 female). The functional network was constructed using 141 by 141 region-to-region functional connectivity metrics (RRC) and network-based statistic was carried out (connection threshold p < 0.001, cluster threshold pFDR < 0.05).

Results

In total, 9870 functional connections were analyzed. PSPs compared to aged non-AD MCI reference group expressed aberrant connectivity evidenced by the significant NBS network consisting of 89 ROIs and 118 connections among them (NBS mass 4226, pFDR < 0.05). Tau load in the right globus pallidus externus (GPe) and left dentate nucleus (DN) showed significant effects on functional network connectivity. The network linked with increased tau load in the right GPe was associated with hyperconnectivity of low-range intra-opercular connections (NBS mass 356, pFDR < 0.05), while the network linked with increased tau load in the left cerebellar DN was associated with cerebellar hyperconnectivity and cortico-cerebellar hypoconnectivity (NBS mass 517, pFDR < 0.05).

Conclusions

PSP patients show altered functional connectivity. Network incorporating deep gray matter structures demonstrate hypoconnectivity, cerebellum hyperconnectivity, while cortico-cortical connections show variable changes. Tau load in the right GPe and left DN is associated with functional networks which strengthen low-scale intra-opercular and intra-cerebellar connections and weaken opercular-cerebellar connections. These findings support the concept of tau load-dependent functional network changes in PSP, by that providing evidence for downstream effects of neuropathology on brain functionality in this primary tauopathy.

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Data availability

Raw and preprocessed data will be made available upon reasonable request.

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Acknowledgements

The study was presented during the European Association of Nuclear Medicine 34th Annual Congress (EANM’21): Featured Session: Molecular Imaging of Movement Disorders (OP-0590).

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Author notes

  1. O. Sabri and H. Barthel contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany

    Gayane Aghakhanyan, M. Rullmann, M. Patt, O. Sabri & H. Barthel

  2. Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy

    Gayane Aghakhanyan

  3. Department of Neurology, University of Leipzig, Leipzig, Germany

    J. Rumpf & J. Classen

  4. Max Planck Institute for Human Cognitive and Brain Sciences & Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany

    M. L. Schroeter

  5. Department of Neuroradiology, University of Leipzig, Leipzig, Germany

    C. Scherlach & K. T. Hoffmann

  6. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany

    M. Brendel

  7. Life Molecular Imaging GmbH, Berlin, Germany

    N. Koglin & A. W. Stephens

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  1. Gayane Aghakhanyan
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Contributions

All authors contributed to the study conception and design. Conceptualization: G. Aghakhanyan, M. Rullmann, O. Sabri, H. Barthel; methodology: G. Aghakhanyan, M. Rullmann, O. Sabri, H. Barthel; formal analysis and investigation: G. Aghakhanyan, M. Rullmann; writing—original draft preparation: G. Aghakhanyan; writing—review and editing: M. Rullmann, Jost-Julian Rumpf, M. L. Schroeter, C. Scherlach, M. Patt, M. Brendel, N. Koglin, A. W. Stephens, J. Classen, K. T. Hoffmann, O. Sabri, H. Barthel; resources: Jost-Julian Rumpf, M. L. Schroeter, C. Scherlach, M. Patt, M. Brendel, N. Koglin, A. W. Stephens, J. Classen, K. T. Hoffmann, O. Sabri, H. Barthel; supervision: M. Rullmann, O. Sabri, H. Barthel. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Gayane Aghakhanyan.

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Ethics approval

The study was approved by the local Ethics Committee of the University of Leipzig.

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Informed consent was obtained from all participants.

Conflict of interest

Authors G. Aghakhanyan, M. Rullmann, M. Patt, J. Classen, and O. Sabri declare that they have no relevant financial conflicts of interests and nothing to disclose. Author J. J. Rumpf has received speaker and consultant honoraria from GE Healthcare. M. L. Schroeter has been supported by the German Research Foundation (DFG; SCHR 774/5–1) and eHealthSax Initiative of the Sächsische Aufbaubank (SAB). M. Brendel received speaker honoraria from Roche, GE Healthcare, and LMI and is an advisor of LMI. A. Stephens and N. Koglin are full-time employees of Life Molecular Imaging, GmbH. K. T. Hoffmann has received speaker and consultant honoraria from Bayer. H. Barthel received speaker honoraria from AAA/Novartis and reader honoraria from LMI.

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Aghakhanyan, G., Rullmann, M., Rumpf, J. et al. Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study. Eur J Nucl Med Mol Imaging 50, 103–114 (2022). https://doi.org/10.1007/s00259-022-05952-0

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