At an early motor stage, Parkinson’s disease (PD) is predominantly characterized by a progressive loss of the nigrostriatal dopaminergic neurons leading to a severe state of dopamine depletion. In addition to the decline in dopaminergic function, other neurotransmitter systems are involved in PD, including the nicotinic cholinergic system. We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with PD at an early stage of the disease.
Fourteen patients with PD (8 males; median age: 64 years, range 52–78 years, median UPDRS-III motor part score 21, range 9–33, in meds-off phase), and 13 healthy subjects were imaged with single photon emission computed tomography (SPECT) and the radiotracer 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([123I]5IA). Clinical inclusion criteria for subjects with PD were as follows: (1) UPDRS part I score of 0; (2) disease duration <7 years (anamnestic to first motor symptoms onset); (3) Hoehn and Yahr scale, stage 2; (4) no psychiatric disorders or other neurological diseases other than PD; and (5) absence of any signs indicative for atypical parkinsonism. The data was calculated as the ratio of mean count per voxel to mean count per voxel of the global [123I]5IA brain uptake for each region and each subject. Also a voxel-based analysis was performed using SPM8 applying the proportional scaling global mean, thresholded at p<0.05 corrected for family wise-error.
We found significant differences in [123I]5IA binding values within the striatum of cognitively intact PD patients at an early disease stage compared to controls. In particular, the putamen showed a higher density of nAChRs bilaterally (1.36±0.1 vs. 1.08±0.1, contralateral to the clinically most affected hemibody and 1.37±0.13 vs. 1.09±0.09, ipsilateral; p<0.001 all), whereas the caudate nucleus had a lower nAChRs density (0.86±0.12 vs. 1.04±0.15, contralateral and 0.81±0.2 vs. 1.11±0.21 ipsilateral; p<0.01 all). Two functionally correlated cortical areas, namely the insular cortex and the orbitofrontal cortex showed higher and lower nAChR density, respectively. Disease duration positively correlated with nAChR density in ipsilateral (=0.56, p<0.05) but not contralateral (=0.49, p=0.07) putamen.
The SPM analysis confirmed a reduced nAChRs density in the (right) caudate nucleus. This analysis also showed in PD patients a lower density of nAChRs in left middle frontal gyrus (BA11) and left middle temporal gyrus (BA21). On the contrary, cholinergic activity was increased in the supplementary motor area (SMA) (i.e. right precentral gyrus and right middle frontal gyrus, BA6).
We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.