Introduction
In post mortem studies, alterations of the alpha4beta2 subunits of the nicotinic acetylcholine receptors (alpha4beta2 nAChR) were found in the cortex and in the subcortical nuclei of patients with Parkinson's disease (PD) and Alzheimer's disease (AD) 1 . The availability of alpha4beta2 nAChRs on subcortical projection fibers in the cerebral white matter (WM) in vivo has neither been demonstrated nor quantified in PD or AD. The aims of this study were: (i) to test the hypothesis that the availability of the nAChR in the WM can be assessed quantitatively by using positron emission tomography (PET) and the radioligand 2-[18F]F-A-85380 (2-FA), which binds on alpha4beta2 nACHR with high affinity and selectivity, (ii) to evaluate whether the availability of the nAChR is altered in the WM of patients with PD and AD and (iii) to investigate whether there are systematic differences betwenn PD and AD with regard to axonal damage as studied with diffusion tensor MRI (DTI).
Methods
Seven patients with PD (39–70 yrs; UPDRS-III: 8–49), 4 patients with AD (71–81 yrs; MMSE: 6–22) and 5 normal subjects (37–64 yrs) were studied over a time period of 7 hours using 2-FA PET. In addition, 4 subjects were studied with 2-FA PET before and after smoking of one cigarette (approx. 0.9 mg nicotine; 7–8 hours p.i.). DTI: The fractional anisotropy (FA), which is a measure of the axonal degeneration, was assessed. The results were normalized (reference region: corpus callosum) and expressed as relative FA (rel-FA). 2-FA PET: Distribution volumes were calculated using the Logan plot after correction of the arterial input function for plasma protein binding and radioactive metabolites. After co-registration with the individual MRI (DTI), the binding potential (BP) in 10 ROIs was assessed.
Results
Smoking of one cigarette resulted in a displacement of the radioactivity from thalamus (44.5%), brain stem (29.3%) and periventricular white matter (31.8%). In comparison with normal subjects, increased 2-FA-BP were found in PD and AD in the right capsula interna (PD +58.2% [p<0.05], AD +32.0%), left capsula interna (+14.1%, +5.8%) and periventricular (+48.5%, +32.9%). Rel-FA (DTI) in PD: capsula interna (PD +10.0%; AD +2.0%), periventricular (PD −4%; AD +32%). In patients with PD, a negative correlation between 2-FA-BP in the periventricular white matter and MMSE (Rho=−0,88; p<0.05) was demonstrated.
Conclusions
Smoking of one cigarette results in a relevant displacement of 2-FA all brain regions including the cerebral white matter. This indicates that 2-FA binds specifically on subcortical cholinergic projection fibers. The increased 2-FA-BP in the white matter in patients with PD and AD may be a result of a denervation supersensitivity and / or hyperexpression of nAChRs as a result of neuroinflammation, which may coincide with PD and AD, respectively. The number of patients which have been studied is relatively small. However, our initial results suggest that 2-FA-PET combined with diffusion tensor MRI bears the potential to assess in vivo axonal neurodegeneration and its functional consequences on cholinergic neurotransmission.