Down syndrome postmortem brains exhibit reduction in [ 18 F]nifene binding to α4β2* nicotinic acetylcholinergic receptors.

UNLABELLED: Alzheimer's disease (AD) pathology including amyloid beta (Aβ) plaques and tau tangles accumulate with age in Down Syndrome (DS). Cholinergic abnormalities such as expression of nicotinic acetylcholine receptors (nAChRs) adversely contribute to cognitive decline and neurodegeneration in AD with similar features possible in DSAD. As a radiotracer for α4β2* nAChRs, [ 18 F]nifene was quantitatively evaluated in the frontal cortex (FCX) and temporal cortex (TCX) of DSAD, AD, and cognitively normal (CN) brain tissue using autoradiography. Anti-tau and anti-Aβ immunostaining in adjacent sections confirmed the presence of tau tangles and Aβ plaques. [ 18 F]Nifene binding in brain sections demonstrated significantly more binding in gray matter (GM) than white matter (WM), with FCX exhibiting more binding than TCX (OptiQuant). Nicotine substantially displaced [ 18 F]nifene binding in adjacent sections, resulting in average GM/nicotine ratios (DSAD=9.74, AD=10.5, CN=17; suggesting a 38% decrease in AD and a 43% decrease in DSAD) and WM/nicotine ratios (DSAD=2.73, AD=3.31, CN=5.62; suggesting a 41% decrease in AD and a 51% decrease in DSAD). [ 18 F]Nifene was correlated with [ 125 I]IBETA (Aβ), showing a strong positive relationship between α4β2* nAChRs and Aβ in DSAD. [ 18 F]Nifene GM/nicotine and WM/nicotine ratios were positively correlated with age in TCX and FCX. The findings of this study suggest that [ 18 F]nifene has potential use in diagnostic investigations of the cholinergic system in DSAD using positron emission tomography. The study also points to a possible need for earlier therapeutic interventions to address the α4β2* nAChRs deficit in DSAD. SIGNIFICANCE STATEMENT: People with Down syndrome are vulnerable to Alzheimer disease along with decreased cholinergic function, which may be linked to cognitive decline. The accumulation of amyloid plaques and tau associated with Alzheimer's disease initiation and progression may be linked to cholinergic dysfunction in Down syndrome. Here we report decreases in α4β2 nicotinic acetylcholine receptors in Down syndrome frontal and temporal cortex. This receptor subtype is important for several brain functions, and loss of this receptor therefore contributes to some of the cognitive deficits seen in Down syndrome with increasing age.