Autoradiographic [18F]nifene binding to α4β2* nicotinic acetylcholine receptors is markedly increased in the hippocampus–subiculum of postmortem Parkinson's disease brains compared with controls, with noted sex- and age-related differences.

This identifies upregulated α4β2* nAChRs as a promising PET biomarker for PD diagnosis and stratification and points to a receptor system that could be explored for therapeutic modulation, though functional/mechanistic validation is required for drug discovery use.

Non-motor symptoms in Parkinson's disease (PD) may be influenced by the α4β2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [ 18 F]nifene binding to α4β2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti-α-synuclein immunostaining on adjacent slices were analyzed in QuPath and [ 18 F]nifene binding was quantified in OptiQuant. Subiculum had greater [ 18 F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [ 18 F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [ 18 F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [ 18 F]nifene binding with aging, while females did not exhibit significant differences. In summary, α4β2* nAChR measured by [ 18 F]nifene is significantly upregulated in the PD HP and SUB. This increased [ 18 F]nifene binding may be of diagnostic value using PET imaging.