Background and ObjectivesSynaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo.MethodsIn this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with 11C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed 18F-fluorodeoxyglucose (18F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest– and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated.ResultsEighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11C-UCB-J and 18F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment.DiscussionOur data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11C-UCB-J PET is more sensitive than 18F-FDG-PET for detection of extrastriatal changes in early HD.Classification of EvidenceThis study provides Class III evidence that 11C-UCB-J PET accurately discriminates individuals HD from normal controls.

ObjectiveTo investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI).MethodsIn this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11C-UCB-J (synaptic vesicle protein 2A), 18F-MK-6240 (tau deposition), and 11C-Pittsburgh compound B (β-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18F-MK-6240 and 11C-UCB-J binding with cognitive performance.ResultsCompared to controls, patients with aMCI showed a decreased 11C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%–51%, pcluster = 0.02). Increased 18F-MK6240 binding in the same region was observed (42%–44%, pcluster = 0.0003), spreading to association cortices. In the MTL, higher 18F-MK-6240 binding inversely related to lower 11C-UCB-J binding (p = 0.02, r = −0.76). Decreased performance on cognitive tests was associated with both increased 18F-MK-6240 and decreased 11C-UCB-J binding in the hippocampus (p < 0.01, r > 0.7), although in a multivariate analysis only 18F-MK-6240 binding was significantly related to cognitive performance.ConclusionsPatients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = −0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = −0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.