Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with l-[β-11C]DOPA

doi:10.1016/j.lfs.2006.02.017

Life Sciences

Volume 79, Issue 8, 17 July 2006, Pages 730-736

https://doi.org/10.1016/j.lfs.2006.02.017 Get rights and content

Abstract

Loss of dopamine synthesis in the striatum with normal human aging has been observed in the postmortem brain. To investigate whether there is age-associated change in dopamine synthesis in the extrastriatal brain regions similar to that in the striatum, positron emission tomography studies with ¹¹C-labelled l-DOPA were performed on 21 normal healthy male subjects (age range 20–67 years). Decline in the tissue fraction of gray matter per region of interest was also investigated. The overall uptake rate constant for each region of interest was quantified by the Patlak plot method using the occipital cortex as reference region. Regions of interest were set on the dorsolateral prefrontal cortex, lateral temporal cortex, medial temporal cortex, occipital cortex, parietal cortex, anterior cingulate, thalamus, midbrain, caudate nucleus, and putamen. Test–retest analysis indicated good reproducibility of the overall uptake rate constant. Significant age-related declines of dopamine synthesis were observed in the striatum and extrastriatal regions except midbrain. The decline in the overall uptake rate constant was more prominent than in the tissue fraction of gray matter. These results indicate that the previously demonstrated age-related decline in striatal dopamine synthesis extends to several extrastriatal regions in normal human brain.

Introduction

Morphological and neurochemical changes are believed to take place in the human central nervous system during the aging process, which might lead to increased vulnerabiliby to the development of several physiological disturbances and neuro-psychiatric disorders closely related to age (Arranz et al., 1996). Postmortem studies indicated that the level of dopamine synthesis (Kish et al., 1992) and several other endogenous neurotransmitters declines in the human striatum during aging (Kish et al., 1995). To estimate the changes of extrastriatal dopamine synthesis in vivo in the living human brain, positron emission tomography (PET) can be used. The ligand ¹¹C-labelled l-DOPA in the carboxy group (l-[β-¹¹C]DOPA) has been reported to be useful for the quantification of l-DOPA metabolism in the brain (Tedroff et al., 1992). Labelling of l-DOPA with ¹¹C allows study with a molecule identical to endogenous l-DOPA as a tracer. In the present study, we evaluated the reproducibility of PET measurement with l-[β-¹¹C]DOPA and age-related changes in dopamine synthesis.

It is also known from postmortem and in vivo studies that the brain shrinks with age (Good et al., 2001). To compare the change of dopamine synthesis with aging in the cerebral cortices, we also investigated age-related atrophy of cerebral cortices using images of gray matter fraction derived from magnetic resonance imaging (MRI).

Section snippets

Subjects

Twenty-one healthy male volunteers, age 20 to 67 years (40.0 ± 15.7, mean ± SD), participated in the study, and 7 of them, age 20 to 26 years (22.3 ± 2.1), twice underwent PET scans to assess reproducibility. They had no medical history and no brain abnormalities when examined by MRI. This study was approved by the Ethics and Radiation Safety Committees of the National Institute of Radiological Sciences, Chiba, Japan. All participants gave their written informed consent.

Positron emission tomography study

PET scans were performed using an ECAT EXACT HR+ system (CTI-Siemens, Knoxville, Tennessee, USA) in three-dimensional mode, which provides 63 planes and a 15.5 cm field of view. l-[β-¹¹C]DOPA was synthesized from [¹¹C]carbon dioxide via d,l-[3-¹¹C]alanine as described previously (Bjurling et al., 1990, Sasaki et al., 2000). After a 10-min transmission scan with a ⁶⁸Ge–⁶⁸Ga source, a bolus of 258–392 MBq of l-[β-¹¹C]DOPA was injected with specific radioactivity of 12.2 GBq/μmol to 81.1 GBq/μmol

Results

Test–retest results are summarized in Table 1. The uptake of ¹¹C-labelled l-DOPA was highest in the putamen. Among the extrastriatal regions, K value was highest in the midbrain (mean K = 0.0062) and lowest in the parietal cortex (0.0020). All K value measurements showed good to excellent reproducibility with high intraclass correlation coefficients (0.51–0.90) and small within-subject variability with no systematic differences in K values between test and retest (7.3–10.3%).

Repeated measures

Discussion

We demonstrated very small within-subject variability and high ICC. ROI-based analysis revealed variability of 7.3–10.1% and ICC of 0.51–0.90 for the regions. ICC has often been used as a measure of reliability, with values between 0.4 and 0.75 regarded as fair to good reliability, and greater than 0.9 as excellent (Fleiss, 1986). This criterion also supports the accuracy of the test–retest reliability of l-[β-¹¹C]DOPA measurement of these regions. Regional distribution of K value in the brain

Conclusion

We confirmed the reproducibility of l-[β-¹¹C]DOPA quantification. Significant age-related declines of dopamine synthesis in the striatum and extrastriatal regions were observed, indicating that the previously demonstrated age-related decline in the striatal dopamine synthesis extends to several extrastriatal regions in normal human males. Our results also showed that the rate of dopamine synthesis decline was the same magnitude as the loss of dopamine D₁ and D₂ receptors and transporters.

Acknowledgements

We wish to extend our gratitude to Mr. Katsuyuki Tanimoto, Mr. Akira Ando, Mr. Takahiro Shiraishi, and Mr. Masaru Ohno for operation of the PET scanner, and to Mr. Kazutoshi Suzuki, cyclotron personnel, for synthesizing the radioligand. We also gratefully acknowledge Drs. Jun Kosaka, Yota Fujimura, Akihiro Takano, and Ms Yoshiko Fukushima for their helpful discussions and PET data acquisition. This research was supported by grants from the National Institute of Radiological Sciences.

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Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with l-[β-11C]DOPA

Abstract

Introduction

Section snippets

Subjects

Positron emission tomography study

Results

Discussion

Conclusion

Acknowledgements

Neuroimage

Life Sciences

Neurobiology of Aging

Biochemical Pharmacology

Applied Radiation and Isotopes

Neurobiology of Aging

Neuropsychopharmacology

Life Sciences

Brain monoaminergic and neuropeptidergic variations in human aging

Journal of Neural Transmission

Multi-enzymatic syntheses of beta-11C-labeled l-tyrosine and l-DOPA

Acta Chemica Scandinavica

Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET

Brain

Permeability of capillaries in various organs as determined by use of the indicator diffusion method

Acta Physiologica Scandinavica

Combined FDOPA and 3OMFD PET studies in Parkinson's disease

Journal of Nuclear Medicine

Striatal 18F-DOPA uptake: absence of an aging effect

Journal of Cerebral Blood Flow and Metabolism

The Design and Analysis of Clinical Experiments

Statistical parametric maps in functional imaging: a general linear approach

Human Brain Mapping

Different corticostriatal patterns of l-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine

Scandinavian Journal of Psychology

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Brain

Aging effect on neutral amino acid transport at the blood–brain barrier measured with l-[2-18F]-fluorophenylalanine and PET

Journal of Nuclear Medicine

Effects of tissue heterogeneity on cerebral vascular response to acetazolamide stress measured by an I-123 IMP autoradiographic method with single-photon emission computed tomography

Annals of Nuclear Medicine

Sex differences in extrastriatal dopamine d(2)-like receptors in the human brain

American Journal of Psychiatry

Aging produced a specific pattern of striatal dopamine loss: implication for the etiology of idiopathic Parkinson's disease

Journal of Neurochemistry

Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with l-[β-¹¹C]DOPA

Multi-enzymatic syntheses of beta-¹¹C-labeled l-tyrosine and l-DOPA

Striatal ¹⁸F-DOPA uptake: absence of an aging effect

Aging effect on neutral amino acid transport at the blood–brain barrier measured with l-[2-¹⁸F]-fluorophenylalanine and PET