In Vivo Positron Emission Tomographic Evidence for Compensatory Changes in Presynaptic Dopaminergic Nerve Terminals in Parkinson’s Disease Chong S. Lee, MD, FRCPC,* Ali Samii, MD, FRCPC,* Vesna Sossi, PhD,† Thomas J. Ruth, PhD,† Michael Schulzer, MD, PhD,* James E. Holden, PhD,‡ Jess Wudel, LPN,* Pramod K. Pal, MD,* Raul de la Fuente-Fernandez, MD,* Donald B. Calne, DM, FRCPC,* and A. Jon Stoessl MD, FRCPC* Clinical symptoms of Parkinson’s disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptom- atic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ; labeling the vesicular monoamine transporter type 2), [ 11 C]methylphenidate (labeling the plasma mem- brane DA transporter), and [ 18 F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were per- formed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug- naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative rela- tionships of [ 18 F]dopa and [ 11 C]DTBZ, and of [ 11 C]methylphenidate and [ 11 C]DTBZ, were compared between the PD and the normal control subjects. We found that [ 18 F]dopa K i was reduced less than the binding potential (B max /K d ) for [ 11 C]DTBZ in the parkinsonian striatum, whereas the [ 11 C]methylphenidate binding potential was reduced more than [ 11 C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD. Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, Wudel J, Pal PK, de la Fuente-Fernandez R, Calne DB, Stoessl AJ. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47:493–503 Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, the main pathology of which is the loss of dopamine (DA) neurons in the substantia nigra and of DA nerve terminals in the stri- atum. It has been widely accepted that there is a pre- clinical stage in which patients with PD are asymptom- atic despite a substantial loss of nigrostriatal DA neurons. 1,2 The mechanisms of functional compensa- tion during this preclinical stage are not fully under- stood. Nevertheless, evidence from experimental studies suggests that the loss of DA neurons is functionally compensated by an increase in synthesis and release of DA from surviving DA nerve terminals, as well as a reduced rate of DA inactivation in presynaptic DA nerve terminals. 3 Dopaminergic transmission, like other monoaminer- gic transmission, is dependent on six processes: (1) DA is synthesized, and then (2) packaged into synaptic ves- icles by type 2 vesicular monoamine transporters (VMAT2). (3) Depolarization releases DA from pre- synaptic vesicles into the synaptic cleft. (4) DA inter- acts with presynaptic and postsynaptic DA receptors. (5) Extracellular DA is taken back into presynaptic DA nerve terminals via the plasma membrane DA trans- porter. (6) Any persisting extracellular DA is degraded by catechol O-methyltransferase. Biochemical studies have shown that tissue DA content and the activity of enzymes involved in the synthesis of DA are reduced in the DA denervated striatum. 4 The synthesis and release of DA per residual DA nerve terminal (fractional DA synthesis and DA release) are increased in the striatum of patients with PD and in an animal model of From the *Neurodegenerative Disorders Centre, Vancouver Hospi- tal and Health Sciences Centre, and †TRIUMF, University of Brit- ish Columbia, Vancouver, British Columbia, Canada; and ‡Depart- ment of Medical Physics, University of Wisconsin, Madison, WI. Received Jul 12, 1999, and in revised form Nov 19. Accepted for publication Dec 9, 1999. Address correspondence to Dr Lee, Neurodegenerative Disorders Centre, Purdy Pavilion, Vancouver Hospital and Health Sciences Centre, 2221 Wesbrook Mall, Vancouver, British Columbia, Can- ada V6T 2B5. Copyright © 2000 by the American Neurological Association 493