David Matuskey1, Patrick Worhunksy2, Elizabeth Correa2, Brian Pittman3, Jean-Dominique Gallezot2, Nabeel Nabulsi2, Jim Ropchan2, Venkatesh Sreeram2, Rohit Gudepu2, Edward Gaiser4, Kelly Cosgrove4, Yu-Shin Ding5, Marc N Potenza6, Yiyun Huang2, Robert T Malison3, Richard E Carson2. 1. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA. Electronic address: david.matuskey@yale.edu. 2. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. 3. Department of Psychiatry, Yale University, New Haven, CT, USA. 4. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA. 5. Department of Radiology, New York University School of Medicine, New York, NY, USA; Department of Psychiatry, New York University School of Medicine, New York, NY, USA. 6. Department of Psychiatry, Yale University, New Haven, CT, USA; Department of Neurobiology, Yale University, New Haven, CT, USA; Department ofChild Study Center, Yale University, New Haven, CT, USA.
Abstract
OBJECTIVE: Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [(11)C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. METHODS: Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [(11)C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. RESULTS: Regional [(11)C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. CONCLUSION: In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [(11)C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.
OBJECTIVE: Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [(11)C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. METHODS: Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [(11)C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. RESULTS: Regional [(11)C](+)PHNOBPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. CONCLUSION: In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [(11)C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.
Authors: Isabelle Boileau; Doris Payer; Sylvain Houle; Arian Behzadi; Pablo M Rusjan; Junchao Tong; Diana Wilkins; Peter Selby; Tony P George; Martin Zack; Yoshiaki Furukawa; Tina McCluskey; Alan A Wilson; Stephen J Kish Journal: J Neurosci Date: 2012-01-25 Impact factor: 6.167
Authors: O Mawlawi; D Martinez; M Slifstein; A Broft; R Chatterjee; D R Hwang; Y Huang; N Simpson; K Ngo; R Van Heertum; M Laruelle Journal: J Cereb Blood Flow Metab Date: 2001-09 Impact factor: 6.200
Authors: Nathalie Ginovart; Matthaeus Willeit; Pablo Rusjan; Ariel Graff; Peter M Bloomfield; Sylvain Houle; Shitij Kapur; Alan A Wilson Journal: J Cereb Blood Flow Metab Date: 2006-10-11 Impact factor: 6.200
Authors: P Sokoloff; J Diaz; B Le Foll; O Guillin; L Leriche; E Bezard; C Gross Journal: CNS Neurol Disord Drug Targets Date: 2006-02 Impact factor: 4.388
Authors: Bernard Le Foll; Alan A Wilson; Ariel Graff; Isabelle Boileau; Patricia Di Ciano Journal: Front Pharmacol Date: 2014-07-10 Impact factor: 5.810
Authors: Linh C Dang; Jaime J Castrellon; Scott F Perkins; Nam T Le; Ronald L Cowan; David H Zald; Gregory R Samanez-Larkin Journal: Neuroimage Date: 2017-01-10 Impact factor: 6.556
Authors: Fernando Caravaggio; Enzo Scifo; Etienne L Sibille; Sergio E Hernandez-Da Mota; Philip Gerretsen; Gary Remington; Ariel Graff-Guerrero Journal: Exp Eye Res Date: 2018-06-05 Impact factor: 3.467
Authors: Edward C Gaiser; Jean-Dominique Gallezot; Patrick D Worhunsky; Ania M Jastreboff; Brian Pittman; Lauren Kantrovitz; Gustavo A Angarita; Kelly P Cosgrove; Marc N Potenza; Robert T Malison; Richard E Carson; David Matuskey Journal: Neuropsychopharmacology Date: 2016-07-04 Impact factor: 7.853
Authors: Kenneth Blum; Rajendra D Badgaiyan; Georgia M Dunston; David Baron; Edward J Modestino; Thomas McLaughlin; Bruce Steinberg; Mark S Gold; Marjorie C Gondré-Lewis Journal: Mol Neurobiol Date: 2017-09-30 Impact factor: 5.590
Authors: Patrick D Worhunsky; David Matuskey; Jean-Dominique Gallezot; Edward C Gaiser; Nabeel Nabulsi; Gustavo A Angarita; Vince D Calhoun; Robert T Malison; Marc N Potenza; Richard E Carson Journal: Neuroimage Date: 2017-01-19 Impact factor: 6.556
Authors: David Matuskey; Gustavo A Angarita; Patrick Worhunsky; Sheida Koohsari; Paul Gravel; Brian Pittman; Edward C Gaiser; Jean-Dominque Gallezot; Nabeel Nabulsi; Yiyun Huang; Richard E Carson; Marc N Potenza; Robert T Malison Journal: Drug Alcohol Depend Date: 2021-01-08 Impact factor: 4.492
Authors: Katina C Calakos; Aleksandra Rusowicz; Brian Pittman; Jean-Dominique Gallezot; Marc N Potenza; Kelly P Cosgrove; David Matuskey Journal: Neurosci Lett Date: 2022-01-17 Impact factor: 3.046
Authors: Matthew M Nour; Tarik Dahoun; Philipp Schwartenbeck; Rick A Adams; Thomas H B FitzGerald; Christopher Coello; Matthew B Wall; Raymond J Dolan; Oliver D Howes Journal: Proc Natl Acad Sci U S A Date: 2018-10-08 Impact factor: 11.205