Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy

Abstract

We measured brain acetylcholinesterase activity in 16 patients with Parkinson's disease (PD), 12 patients with progressive supranuclear palsy (PSP), and 13 age‐matched controls, using N‐methyl‐4‐[11C]piperidyl acetate and positron emission tomography. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. In PD patients, there was a significant reduction (−17%) of cerebral cortical k3 compared with normal controls, whereas there was only a nonsignificant reduction (−10%) of cortical k3 in PSP patients. However, there was a prominent reduction (−38%) of thalamic k3 in PSP patients compared with normal controls, whereas there was only a nonsignificant reduction (−13%) of thalamic k3 in PD patients. The results suggest that there is a loss of cholinergic innervation to the cerebral cortex in association with cholinergic innervation to the thalamus in PD, whereas there is a preferential loss of cholinergic innervation to the thalamus in PSP. When the thalamic to cerebral cortical k3 ratio was taken for each subject, PD and PSP were separated, suggesting that positron emission tomography measurement of acetylcholinesterase activity may be useful for differentiating the two similar disorders. Ann Neurol 1999;46:62–69

Heterogeneity of Cholinergic Denervation in Parkinson's Disease without Dementia

“…In vivo imaging studies have also shown that the presence of dementia in PD is associated with more severe and widespread cholinergic denervation compared with PD without dementia (Bohnen et al, 2003;Hilker et al, 2005;Kuhl et al, 1996;Shinotoh et al, 1999). These imaging results are consistent with post-mortem evidence that basal forebrain cholinergic system degeneration appears early in PD and worsens in parallel with the appearance of dementia (Ruberg et al, 1986).…”

“…In contrast to severe striatal dopaminergic terminal losses, exceeding 50% to 80% in PD subjects with clinically manifest motor symptoms Guttman et al, 1997), in vivo acetylcholinesterase studies show cholinergic projection losses in the magnitude of 5% to 25% in PD subjects without or with dementia (Bohnen et al, 2003;Hilker et al, 2005;Shimada et al, 2009;Shinotoh et al, 1999). The more limited and variable cholinergic losses suggest the presence of overlap in cholinergic projection system integrity between PD and control groups.…”

History of falls in Parkinson disease is associated with reduced cholinergic activity

“…22 The same authors reported a greater loss of thalamic AChE activity (Ϫ38%) in patients with progressive supranuclear palsy (PSP). The much higher incidence of falls in PSP compared to PD may reflect the more prominent degree of thalamic cholinergic denervation and PPN pathology in PSP.…”

“…The importance of thalamic cholinergic denervation in PSP is further emphasized by the relatively preserved cortical cholinergic innervation in this disorder compared to PD. 22 In PSP patients, experimental administration of the antimuscarinic drug scopolamine has been reported to worsen gait in a dose-dependent manner. 23 Although scopolamine worsened gait functions, it did not negatively affect UPDRS motor ratings of bradykinesia or rigidity.…”

“…A previous study found a correlation between lower cortical AChE activity and higher total UPDRS scores in patients with PD. 22 These authors interpreted these findings that the ascending cholinergic system from the NBM to the cerebral cortex is impaired more severely as PD advances. We also found similar findings for cortical AChE activity.…”