title: Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET.
abstract: Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Gjerløff
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Fedorova
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Karoline
authors.initials: K
authors.lastname: Knudsen
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Ole L
authors.initials: OL
authors.lastname: Munk
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Adjmal
authors.initials: A
authors.lastname: Nahimi
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Jacobsen
authors.affiliation: 2 Department of Neurology, Aarhus University Hospital, Denmark.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Danielsen
authors.affiliation: 2 Department of Neurology, Aarhus University Hospital, Denmark.
authors.forename: Astrid J
authors.initials: AJ
authors.lastname: Terkelsen
authors.affiliation: 3 Department of Health Science and Technology, Aalborg University, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Hansen
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark 4 Division of Brain Sciences, Imperial College, London, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Pavese
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark 4 Division of Brain Sciences, Imperial College, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark perborgh@rm.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Borghammer
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology; D016022:Case-Control Studies; D002800:Cholinesterase Inhibitors; D003248:Constipation / Q000209:etiology; D004064:Digestive System / Q000000981:diagnostic imaging* / Q000473:pathology; D000077265:Donepezil; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007189:Indans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines; D049268:Positron-Emission Tomography; D011795:Surveys and Questionnaires; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Parkinson's disease; acetylcholinesterase; autonomic nervous system; parasympathetic nervous system; positron emission tomography