Inverse correlation between cognition and α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) binding in the normal aging brain as investigated with (-)-[F-18]Flubatine PET

Ziel/Aim: α4β2-nAChRs are widely expressed in the brain and important modulators of cognition. In the event of brain damage, there may be a compensatory process involving α4β2-nAChRs to counterbalance the development of cognitive dysfunction in early neurodegeneration or normal aging. In mild AD dementia, using (-)-[F-18]Flubatine PET, we reported lower (sub)cortical α4β2-nAChR binding (α4β2-nAChR) that was related with impaired episodic memory (EM), executive function/working memory (E/WM), and attention (A) (Sabri et al. 2018). Aim of this PET study was to investigate the relation between α4β2-nAChR and cognition in normal aging. [1]

Methodik/Methods: Nonsmoking, normal aging subjects (n=15; 71±5yrs; 8M; education 14±2yrs; MMSE 28±1) were investigated using (-)-[F-18]Flubatine-PET and neuropsychological testing (5 cognitive domains [Z-scores]: EM [0.29±0.75], E/WM [0.44±0.80], A [0.78±0.63], language (L) [0.59±0.51], visuospatial function (V) [-0.19±0.82]). To quantify α4β2-nAChR, kinetic modeling was performed and distribution volume (V_T) calculated (1TCM; Logan plot). SPM-regression analyses were carried out.

Ergebnisse/Results: There were positive and/or negative correlations between the 5 cognitive domains and V_T: EM: negative: para-hippocampus (hppc), temporal-occipital lobe, insula, thalamus, putamen, cerebellum (cb). E/WM: positive: frontal lobe; negative: hppc, amygdala, temporal-occipital lobe, precuneus, ins, cb; L: positive: fronto-parietal lobe, precuneus; negative: temporo-parieto-occipital lobe, MCC, amygdala, insula, cb; V: positive: fronto-parietal lobe, ACC; negative: hppc, cb; A: positive: fronto-parietal lobe, thalamus, putamen, insula (T>3,12; p<0.005; k=30 voxels).

Schlussfolgerungen/Conclusions: In contrast to our previous PET findings in mild AD, in normal aging, there were specific inverse (and positive) correlation patterns btw. partial cognitive functions and (sub)cortical-cerebellar α4β2-nAChR. These patterns may show specific circuits underlying compensatory cognition. Thus, in normal elderly subjects, higher α4β2-nAChR may represent mild neuropathology that is associated with lower partial cognitive functions (Z-scores). Our PET findings indicate pivotal relevance of α4β2-nAChR for compensatory cognition in normal aging.

• Literatur/References

• 1 Sabri et al. Brain. 2018 141. 1840-54

Publication History

Article published online:
12 March 2025