Measuring Cortical Acetylcholine Esterase Activity by PET in Dementia: Clinical Correlates

The acetylcholine analogue C-11-N-methyl-4-piperidinyl-acetate (MP4A) is a tracer for positron emission tomography (PET) to investigate the integrity of the cerebral cholinergic system. It is a substrate of acetylcholine esterase (AChE), which is associated with cholinergic axons in human cortex. We used this technique to determine whether cortical reductions of AChE activity in dementia are associated with clinical symptoms and progression.

We examined the following age-matched subjects: 12 normal controls, 8 mild cognitive impairment (MCI, MMSE 27 ± 2), 10 mild Alzheimer’s disease (AD, MMSE 21 ± 4), 10 Parkinson’s disease dementia (PDD, MMSE 21 ± 6), and 10 non-demented PD (MMSE 27 ± 2). Cortical AChE activity was reduced significantly in all demented subjects and in those four MCI patients, who progressed to dementia within 18 months. The most severe reduction (by 30 ± 5%) was seen in PDD, followed by AD (23 ± 2%) and nondemented PD (12 ± 2%, p < 0.01 compared to controls). Thus, the manifestation of dementia in PD was associated with a significant reduction of cortical AChE activity, which was most severe in the left inferior parietal lobule, the left precental gyrus, and the right posterior cingulate gyrus (SPM, p < 0.001). In mild to moderate AD, regional AChE activity in temporal, parietal, and frontal association cortices was associated with attention-dependent test performance (Rey-Osterrieth figure copy, digit span forward and reverse, visual span reverse).

We conclude that a reduction of cortical AChE activity is a common feature of Alzheimer’s and Parkinson’s dementia and appears to be related mainly to impairment of attention. It is present very early during the course of the disease, even at a predementia stage. It is likely to indicate functional impairment of the synapses or of axonal transport of ascending cholinergic neurons.