title: Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease.
abstract: The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, The University of Michigan Medical School, Ann Arbor, 48109-0028, USA.
authors.forename: Nicolaas I
authors.initials: NI
authors.lastname: Bohnen
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Wernette
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Satoshi
authors.initials: S
authors.lastname: Minoshima
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000465:Algorithms; D015306:Biogenic Monoamines / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013572:Synaptic Vesicles / Q000378:metabolism*; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D019275:Radiopharmaceuticals; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine