The Phosphodiesterase 10 Positron Emission Tomography Tracer, [18F]MNI-659, as a Novel Biomarker for Early Huntington Disease

IMPORTANCE In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE To evaluate whether [F-18]MNI-659 (2-(2-(3-(4-(2-[F-18] fluoroethoxy) phenyl)-7-methyl- 4-oxo-3,4-dihydroquinazolin-2-yl) ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [F-18]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [F-18]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [F-18]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE As a promising striatal imaging biomarker, [F-18]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [F-18]MNI-659may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.