A BS TRACT: Background: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads transsynaptically. Objectives: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract. Methods: A total of 30 patients with early PD and 20 age-and gender-matched healthy controls underwent positron emission tomography with 11 C-UCB-J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the dopamine transporter ligand 18 F-FE-PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3-dimensional T1 magnetic resonance imaging. BP ND images were calculated. Results: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of dopamine transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or dopamine transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel-based analysis in the PD group showed significant correlations between SV2A and dopamine transporter binding in the caudate and substantia nigra. Conclusions: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a transsynaptic mode of propagation of the disease process.

An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. 18 F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-ofinterest (VOI) and voxel-based (using a support vector machine [SVM] approach) 18 F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a prioriderived classifiers. Furthermore, the prognostic value of 18 F-FDG PET was evaluated. Methods: A prospective cohort of patients with a suspected diagnosis of a motor neuron disorder (n 5 119; mean age ± SD, 61 ± 12 y; 81 men and 38 women) was recruited. One hundred five patients were diagnosed with ALS (mean age ± SD, 61.0 ± 12 y; 74 men and 31 women) (group 2), 10 patients with primary lateral sclerosis (mean age ± SD, 55.5 ± 12 y; 3 men and 7 women), and 4 patients with progressive muscular atrophy (mean age ± SD, 59.2 ± 5 y; 4 men). The mean disease duration of all patients was 15.0 ± 13.4 mo at diagnosis, with PET conducted 15.2 ± 13.3 mo after the first symptoms. Data were compared with a previously gathered dataset of 20 screened healthy subjects (mean age ± SD, 62.4 ± 6.4 y; 12 men and 8 women) and 70 ALS patients (mean age ± SD, 62.2 ± 12.5 y; 44 men and 26 women) (group 1). Data were spatially normalized and analyzed on a VOI basis (statistical software (using the Hammers atlas) and voxel basis using statistical parametric mapping. Discriminant analysis and SVM were used to classify new cases based on the classifiers derived from group 1. Results: Compared with controls, ALS patients showed a nearly identical pattern of hypo-and hypermetabolism in groups 1 and 2. VOI-based discriminant analysis resulted in an 88.8% accuracy in predicting the new ALS cases. For the SVM approach, this accuracy was 100%. Brain metabolism between ALS and primary lateral sclerosis patients was nearly identical and not separable on an individual basis. Extensive frontotemporal hypometabolism was predictive for a lower survival using a Kaplan-Meier survival analysis (P , 0.001). Conclusion: On the basis of a previously acquired training set, 18 F-FDG PET with advanced discriminant analysis methods is able to accurately distinguish ALS from controls and aids in assessing individual prognosis. Further validation on multicenter datasets and ALS-mimicking disorders is needed to fully assess the general applicability of this approach.

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.

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