Direct Quantitative Comparison Between [11C]UCB-J and [18F]SynVest-1 PET as Markers for Synaptic Density in Huntington's Disease.
Positron Emission Tomography (PET) is a functional imaging technique, which enables in vivo visualization of biological molecules expressed in human tissues. Brain PET is most powerful to study a vast range of neurological and psychiatric disorders in vivo, targeting neuronal and glial activity, metabolism, cerebral blood flow, receptor proteins or misfolded proteins. In vivo imaging of synaptic density in the human brain has become feasible through development of \[11C\]UCB-J, a PET radioligand for the synaptic vesicle protein SV2A, which is ubiquitously and homogeneously present in presynaptic terminals throughout the brain. A first study in Huntington's disease (HD) mutation carriers showed loss of striatal \[11C\]UCB-J binding (also when corrected for atrophy), as well as in the neocortex (Delva et al, Neurology 2022). Moreover, regional synaptic loss was highly correlated to motor impairment. In order to be able to use SV2A PET as widespread available biomarker tool to assess synaptic integrity, disease progression and/or response to mHTT lowering drugs, the short half-life of 11C (20 minutes) for \[11C\]UCB-J remains a hurdle. Recently, \[18F\]SynVesT-1, an optimized 18F-labeled analogue of \[11C\]UCB-J with similar kinetics, binding affinity, and test-retest precision properties has been evaluated in humans. However, there is evidence from preclinical studies conducted at University of Antwerp that in the zQ175DN knock-in mouse model of HD, larger variability and lower effect-sizes are seen with \[18F\]SynVest-1 than with \[11C\]UCB-J. In order to ascertain a similar effect size and quantification properties for \[18F\]SynVest-1 and \[11C\]UCB-J PET in human HD patients and to validate simplified measures (such as SUVR with white matter as reference region) and SynVest, this head-to-head fully quantitative study is performed.
• Healthy controls (n = 10-20)
‣ Subject is judged to be in good health by the investigator on the basis of medical history, physical examination including vital signs, clinical laboratory test and urinalysis.
⁃ No history or evidence of current major neurological, internal or psychiatric disorder, based on the medical assessment as described hereabove and neuropsychological assessment.
⁃ In subjects \< 60 years of age, an unremarkable structural MRI scan as assessed by expert radiologist. In subjects \>= 60 years of age white matter hyperintensities corresponding to a white matter lesion (WML) Fazekas score \< 2 on the Age-Related White Matter changes scale are acceptable.
• HD-ISS stage 3 HD mutation carriers (n = 10)
‣ HTT CAG repeat expansion 40 - 50
⁃ stage 3 as determined by the HD-ISS staging criteria
⁃ UHDRS TFC \>/= 10
• HD-ISS stage 2 HD mutation carriers (n = 10)
‣ HTT CAG repeat expansion 40 - 50
⁃ stage 2 as determined by the HD-ISS staging criteria
⁃ PIN score 0.47 - 1.84