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Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration

Author

Listed:
  • David J. Whiteside

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Negin Holland

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Kamen A. Tsvetanov

    (University of Cambridge)

  • Elijah Mak

    (University of Cambridge)

  • Maura Malpetti

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • George Savulich

    (University of Cambridge)

  • P. Simon Jones

    (University of Cambridge)

  • Michelle Naessens

    (University of Cambridge)

  • Matthew A. Rouse

    (University of Cambridge)

  • Tim D. Fryer

    (University of Cambridge
    University of Cambridge)

  • Young T. Hong

    (University of Cambridge
    University of Cambridge)

  • Franklin I. Aigbirhio

    (University of Cambridge
    University of Cambridge)

  • Eoin Mulroy

    (University College London)

  • Kailash P. Bhatia

    (University College London)

  • Timothy Rittman

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • John T. O’Brien

    (Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

  • James B. Rowe

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

Abstract

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Suggested Citation

  • David J. Whiteside & Negin Holland & Kamen A. Tsvetanov & Elijah Mak & Maura Malpetti & George Savulich & P. Simon Jones & Michelle Naessens & Matthew A. Rouse & Tim D. Fryer & Young T. Hong & Frankli, 2023. "Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44307-7
    DOI: 10.1038/s41467-023-44307-7
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