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

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, Franklin I. Aigbirhio, Eoin Mulroy, Kailash P. Bhatia, Timothy Rittman, John T. O’Brien and James B. Rowe
Additional contact information
David J. Whiteside: University of Cambridge
Negin Holland: University of Cambridge
Kamen A. Tsvetanov: University of Cambridge
Elijah Mak: University of Cambridge
Maura Malpetti: University of Cambridge
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
Young T. Hong: University of Cambridge
Franklin I. Aigbirhio: University of Cambridge
Eoin Mulroy: University College London
Kailash P. Bhatia: University College London
Timothy Rittman: University of Cambridge
John T. O’Brien: Cambridge University Hospitals NHS Foundation Trust
James B. Rowe: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44307-7

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