Differences in cholinergic terminal density in adults with Down syndrome compared to neurotypical controls measured by [18F]-fluoroethoxybenzovesamicol positron emission tomography imaging

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Adults with Down syndrome are genetically predisposed to developing Alzheimer’s disease after the age of 40. The cholinergic system, which is critical for cognitive functioning, is known to decline in Alzheimer’s disease and although first investigated in individuals with Down syndrome 40 years ago, remains relatively understudied. Existing studies suggest individuals with Down syndrome have an intact cholinergic system at birth that declines through adulthood alongside the development of Alzheimer’s disease pathology. The present study provides the first description of cholinergic terminals in vivo in non-demented adults with Down syndrome utilizing [ 18 F]-fluoroethoxybenzovesamicol PET imaging. In addition, we investigated age-associated decline in cholinergic terminal density. Sixteen (16) non-demented adults with Down syndrome (mean age 35.5, 8 females) and 20 neurotypically developed individuals (mean age 35.5, 10 females) were studied, comparing radiotracer uptake groupwise and associations with age utilizing a voxel-based approach. Adults with Down syndrome displayed significantly increased [ 18 F]-fluoroethoxybenzovesamicol uptake in the cerebellum, brainstem, thalamus, and numerous cortical regions compared to age-matched controls following an unpaired t-test thresholded at p < 0.001 and minimum cluster size 50. Cholinergic terminal density in numerous cortical regions showed a steeper decline associated with older age in adults with Down syndrome than observed in neurotypically developed adults in the age range tested following a generalized linear model testing the interaction between age and group, thresholded at p < 0.005 and minimum cluster size 50. These data suggest higher cholinergic terminal density in early adulthood in individuals with Down syndrome, with a greater age-related difference than is observed in neurotypically developed individuals. • [ 18 F]-FEOBV uptake is increased in adults with Down syndrome compared to controls. • Adults with Down syndrome display markedly lower [ 18 F]-FEOBV uptake at older ages. • [ 18 F]-FEOBV uptake shows a steeper age-associated decline in adults with DS than controls.

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