Alterations in α4β2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology

Abstract

Nicotinic acetylcholine receptor subtype α4β2 is considered important in the regulation of attention and memory, and cholinergic degeneration is known as one pathophysiology of Alzheimer's disease. Brain amyloid-β protein deposition is also a key pathological marker of Alzheimer's disease. Recent amyloid-β imaging has shown many cognitively normal subjects with amyloid-β deposits, indicating a missing link between amyloid-β deposition and cognitive decline. To date, the relationship between the α4β2 nicotinic acetylcholine receptor and amyloid-β burden has not been elucidated in vivo. In this study we investigated the relation between α4β2 nicotinic acetylcholine receptor availability in the brain, cognitive functions and amyloid-β burden in 20 non-smoking patients with Alzheimer's disease at an early stage and 25 age-matched non-smoking healthy elderly adults by measuring levels of α4β2 nicotinic acetylcholine receptor binding estimated from a simplified ratio method (BPRI) and Logan plot-based amyloid-β accumulation (BPND) using positron emission tomography with α4β2 nicotinic acetylcholine receptor tracer (18)F-2FA-85380 and (11)C-Pittsburgh compound B. The levels of tracer binding were compared with clinical measures for various brain functions (general cognition, episodic and spatial memory, execution, judgement, emotion) using regions of interest and statistical parametric mapping analyses. Between-group statistical parametric mapping analysis showed a significant reduction in (18)F-2FA-85380 BPRI in the cholinergic projection region in patients with Alzheimer's disease with a variety of (11)C-Pittsburgh compound B accumulation. Spearman rank correlation analyses showed positive correlations of (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region with scores of the Frontal Assessment Battery (a test battery for executive functions and judgement) in the Alzheimer's disease group (P < 0.05 corrected for multiple comparison), and also positive correlations of the prefrontal and superior parietal (18)F-2FA-85380 BPRI values with the Frontal Assessment Battery score in the normal group (P < 0.05 corrected for multiple comparison). These positive correlations indicated an in vivo α4β2 nicotinic acetylcholine receptor role in those specific functions that may be different from memory. Both region of interest-based and voxelwise regression analyses showed a negative correlation between frontal (11)C-Pittsburgh compound B BPND and (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region in patients with Alzheimer's disease (P < 0.05 corrected for multiple comparison). These findings suggest that an impairment of the cholinergic α4β2 nicotinic acetylcholine receptor system with the greater amount of amyloid deposition in the system plays an important role in the pathophysiology of Alzheimer's disease.