title: Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3receptors and sub-cortical volumes in the human basal ganglia: A PET study with18F-MNI-659 and11C-raclopride with correction for partial volume effect.
abstract: Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D2/3receptors (D2/3R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D2/3R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D2/3R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand18F-MNI-659 and D2/3R radioligand11C-raclopride were used. The outcome measure was the binding potential (BPND) estimated with the two-tissue compartment model (18F-MNI-659) and the simplified reference tissue model (11C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D2/3R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D2/3R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D2/3R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BPNDthe female group.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. Electronic address: patrik.fazio@ki.se.
authors.forename: Patrik
authors.initials: P
authors.lastname: Fazio
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Schain
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, NJ, USA.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Mrzljak
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.affiliation: Karolinska Trial Alliance, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Nabil
authors.initials: N
authors.lastname: Al-Tawil
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, NJ, USA.
authors.forename: Cheryl J
authors.initials: CJ
authors.lastname: Fitzer-Attas
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, NJ, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Bronzova
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, NJ, USA.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Landwehrmeyer
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, NJ, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sampaio
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D001479:Basal Ganglia / Q000201:enzymology*; D005260:Female; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010797:Phthalimides; D049268:Positron-Emission Tomography / Q000379:methods; D052999:Quinazolinones; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
chemical_list: C000599323:2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione; D010797:Phthalimides; D052999:Quinazolinones; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D020891:Raclopride; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases