Dopaminergic deficits along the spectrum of Alzheimer’s Disease

Abstract Both post-mortem and in vivo data argue for dopamine dysfunction in patients with Alzheimer’s Disease (AD). However, the timing and regional progression of dopaminergic systems alterations in AD are still debated. Aim of the study was to investigate in vivo the pattern of dopaminergic changes and connectivity using DAT-SPECT imaging in patients across the AD spectrum. Fifty-nine A + T + N + AD patients (n = 21 MCI-AD; n = 38 AD-DEM) and n = 45 age and sex-matched controls (CG) entered the study and underwent 123I-FP-CIT dopaminergic imaging. The occipital binding was used as reference region to obtain single-subject binding in different brain regions. Between-groups differences in 123I-FP-CIT binding in both mesolimbic and nigrostriatal dopaminergic pathways were assessed using an ANCOVA test-adjusting for the effect of center of imaging acquisition, age, and sex. Regions resulting from the voxel-wise direct comparison between MCI-AD and AD-DEM were considered as a seed of interest for a voxel-wise interregional correlation analysis. Both MCI-AD and AD-DEM patients showed dopaminergic depletion within the basal ganglia, whereas cortico-limbic regions (namely hippocampus, amygdala, anterior and middle cingulate, frontal cortex and thalamus) resulted impaired only in the dementia phase. The brain voxel-wise interregional correlation analysis showed a progressive pattern of disruption of caudate/thalamus dopaminergic connectivity to hippocampus and amygdala from MCI-AD to AD-DEM stages. This study indicates basal ganglia dopaminergic alterations and connectivity disruption in the nigrostriatal and mesolimbic systems already in early stage AD, extending to several cortico-limbic regions in dementia phases.