title: The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.
abstract: OBJECTIVE
  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 [18F]MNI-659 (2-(2-(3-(4-(2-[18F]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.
  
  
  METHODS
  A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging.
  
  
  METHODS
  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 [18F]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 [18F]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
  As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may 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.
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: David S
authors.initials: DS
authors.lastname: Russell
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Danna L
authors.initials: DL
authors.lastname: Jennings
authors.affiliation: Department of Neurology, Alpert Medical School of Brown, Providence, Rhode Island.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Friedman
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Gilles D
authors.initials: GD
authors.lastname: Tamagnan
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut4currently with Department of Pharmaceutical Sciences, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Thomae
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Morley
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Caroline
authors.initials: C
authors.lastname: Papin
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc, Cambridge, Massachusetts.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Papapetropoulos
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc, Cambridge, Massachusetts.
authors.forename: Rikki N
authors.initials: RN
authors.lastname: Waterhouse
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: John P
authors.initials: JP
authors.lastname: Seibyl
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Marek
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging*; D042241:Early Diagnosis; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005462:Fluorine Radioisotopes; D010727:Phosphoric Diester Hydrolases