In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease.
Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic 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 [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed 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 relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]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
C S
CS
Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre, British Columbia, Canada.
Samii
A
A
Sossi
V
V
Ruth
T J
TJ
Schulzer
M
M
Holden
J E
JE
Wudel
J
J
Pal
P K
PK
de la Fuente-Fernandez
R
R
Calne
D B
DB
Stoessl
A J
AJ
D000368:Aged; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D015536:Down-Regulation / Q000502:physiology; D005462:Fluorine Radioisotopes; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D013747:Tetrabenazine / Q000031:analogs & derivatives; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C032811:dihydrotetrabenazine; D004298:Dopamine; D006719:Homovanillic Acid; D013747:Tetrabenazine