A spatial covariance 123I-5IA-85380 SPECT study of α4β2 nicotinic receptors in dementia with Lewy bodies

Background Cholinergic dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs), contributes to cognitive and psychiatric symptoms in dementia with Lewy bodies (DLB), yet spatial covariance patterns remain unexplored. We aimed to characterise these patterns using 123 I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) SPECT (α4β2 nAChR assessment) and examine their association with cognitive function. Methods Fifteen DLB and 16 healthy controls underwent 123 5IA-85380 and rCBF 99m Tc-exametazime SPECT scanning. Voxel principal components analysis (PCA), generated PC images representing common intercorrelated voxels across subjects. Linear regression identified α4β2 nAChR and rCBF patterns distinguishing DLB from controls. Results A distinct α4β2 nAChR pattern differentiated DLB from controls (F 1,29 = 165.1, p < 0.001), that was dissimilar to rCBF changes. This pattern was characterised by decreased uptake in temporal pole, inferior frontal cortex, amygdala, olfactory cortex, insula, anterior/mid cingulate, and putamen, alongside preserved/increased uptake in sensorimotor cortex, fusiform and occipital lobe. These regions mapped onto default, salience, limbic, frontostriatal, sensorimotor and visual hubs. We then derived from patients, α4β2 nAChR patterns that correlated with CAMCOG total ( r = – 0.52, p = 0.04), MMSE ( r = – 0.68, p = 0.01) and CAMCOG memory ( r = – 0.70, p = 0.01), demonstrating a common topography of relative decreased binding in lateral/medial prefrontal, lateral temporal, fusiform, inferior parietal and thalamus along with relative preserved/increased binding in cingulate, insula, occipital and medial temporal regions: structures within a range of networks supporting executive, language, attention, motor and visual processing. Conclusion These findings provide novel insights into the pathophysiology of DLB and may inform future therapeutic strategies targeting nAChRs.