Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations.
We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 +/- 5.7 years) than the patients with a stable response to levodopa (4.3 +/- 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 +/- 8.9 versus 54.1 +/- 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered "buffering" capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.
de la Fuente-Fernández
R
R
Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre, BC, Canada.
Pal
P K
PK
Vingerhoets
F J
FJ
Kishore
A
A
Schulzer
M
M
Mak
E K
EK
Ruth
T J
TJ
Snow
B J
BJ
Calne
D B
DB
Stoessl
A J
AJ
D000978:Antiparkinson Agents / Q000008:administration & dosage; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D009069:Movement Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D014055:Tomography, Emission-Computed
D000978:Antiparkinson Agents; D005462:Fluorine Radioisotopes; C043437:fluorodopa F 18; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D004298:Dopamine