Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes

Abstract

Objectives: Cholinergic projections to cerebral cortical and subcortical regions are decreased in Parkinson disease (PD), but not evaluated in the parkinsonian syndromes of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). We studied cholinergic innervation in these disorders as compared to age-appropriate normal control subjects.

Methods: We used PET with [(11)C]PMP to measure acetylcholinesterase (AChE) activity in multiple cerebral cortical and subcortical regions. We studied 22 normal controls, 12 patients with PD, 13 patients with MSA-P, and 4 patients with PSP.

Results: We found significantly decreased AChE activity in most cerebral cortical regions in PD and MSA-P, and a similar but nonsignificant decrease in PSP. No differences were found between PD and MSA-P. Significantly decreased AChE activity was found in PD in striatum, cerebellum, and thalamus, with a marginally significant decrease in mesencephalon and no change in pons. Significantly greater declines in AChE activity in all subcortical regions were seen in MSA-P and PSP vs in PD. Decreased AChE activity in brainstem and cerebellum of all 3 disorders correlated with disturbances of balance and gait.

Conclusions: Cerebral cortical cholinergic activity is decreased to a similar level in Parkinson disease (PD), parkinsonian syndromes of multiple system atrophy (MSA-P), and progressive supranuclear palsy (PSP) as compared to normal controls. Subcortical cholinergic activity is significantly more decreased in MSA-P and PSP than in PD. The more substantial decrease reflects greater impairment in the pontine cholinergic group, which is important in motor activity, particularly gait. These differences may account for the greater gait disturbances in the early stages of MSA-P and PSP than in PD.

Figure PMP k₃ activity in 4 brain levels. Maps of mean PMP k₃ activity in the following groups: normal control (NC), Parkinson disease (PD), multiple system atrophy of the parkinsonian type (MSA-P), and progressive supranuclear palsy (PSP). The column on the far left shows the group average PMP map for the 22 normal controls for all 4 brain levels displayed to the same peak (3.0 min⁻¹) (see the single long color bar to the left of this column). As using the same peak does not permit evaluation of changes within individual structures of interest owing to the large dynamic range of acetylcholinesterase (AChE) values in the brain, we scaled the PMP maps to suit individual regions (see the 4 color bars corresponding to thalamus, basal ganglia, mesencephalon, and pons/cerebellum). The 4 columns to the right of the color bars show regional AChE values from group averages in the 4 groups, from left to right NC, PD, MSA-P, and PSP. In the NC column, 1 arrow points to the thalamus, and a second arrow points to the mesencephalon. The individual images show that AChE activity is reduced in the thalamus in all 3 patient groups, with the greatest decrease seen in MSA-P; decreased in the striatum in all 3 groups, with greater declines in MSA-P and PSP than in PD; slightly decreased in the mesencephalon in PD and markedly decreased in MSA-P and PSP; markedly decreased in all 3 patient groups in the cerebellum, greatest in the MSA-P group; and unchanged in the pons in PD, but significantly decreased in MSA-P and PSP groups.