Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11C]UCB‐J Positron Emission Tomography Study

• Published in: Movement disorders Vol. 38; no. 7; pp. 1316 - 1326
• Main Authors: Holland, Negin, Jones, P. Simon, Savulich, George, Naessens, Michelle, Malpetti, Maura, Whiteside, David J., Street, Duncan, Swann, Peter, Hong, Young T., Fryer, Tim D., Rittman, Timothy, Mulroy, Eoin, Aigbirhio, Franklin I., Bhatia, Kailash P., O'Brien, John T., Rowe, James B.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2023; Wiley Subscription Services, Inc
• Subjects: [11C]UCB‐J PET; Amyloid; Brain - diagnostic imaging; Brain - metabolism; Clinical trials; Cognition & reasoning; Cognitive ability; Cross-Sectional Studies; Frontal lobe; Humans; longitudinal; Movement disorders; Movement Disorders - metabolism; Neurodegeneration; Neurodegenerative diseases; Paralysis; Positron emission tomography; Positron-Emission Tomography - methods; primary tauopathies; Progressive supranuclear palsy; Supranuclear Palsy, Progressive - diagnosis; Synaptic density; Tau protein; Tauopathies - diagnostic imaging; Tauopathies - metabolism; Therapeutic targets; Tomography; [11C]UCB-J PET; longitudinal; primary tauopathies
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.29421

Background Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. Objective In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. Methods Our cross‐sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid‐negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex‐ and age‐matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11C]UCB‐J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11C]UCB‐J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty‐two participants with PSP/CBD had a follow‐up [11C]UCB‐J positron emission tomography scan after 1 year. We calculated the annualized change in [11C]UCB‐J nondisplaceable binding potential and correlated this with the change in clinical severity. Results We found significant annual synaptic loss within the frontal lobe (−3.5%, P = 0.03) and the right caudate (−3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination–Revised, R = −0.62, P = 0.003). Conclusions We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early‐phase clinical trials of disease‐modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.