In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Abstract Background Preclinical and pathology evidence suggest an involvement of brain dopamine (DA) circuitry in Alzheimer’s Disease (AD). We in vivo investigated, if, when and in which target regions, DA signaling and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D) and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial-correlation analysis. Results were deemed significant at p<0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of dopamine transporter density in both AD-MCI and AD-D compared to controls. Dopaminergic deficits were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced dopaminergic transporter density, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient < 0.25), and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.