OBJECTIVE: To investigate differences in distribution of alpha4beta2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand (1)(2)(3)I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. (1)(2)(3)I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. METHODS: Thirty subjects (14 vascular dementia and 16 controls) underwent (1)(2)(3)I-5IA-85380 and rCBF ((99m)Tc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). RESULTS: Compared to controls, reductions in relative (1)(2)(3)I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled (1)(2)(3)I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with (1)(2)(3)I-5IA-85380 changes. CONCLUSIONS: Reduced (1)(2)(3)I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer’s disease. Elevation of normalised (1)(2)(3)I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus.