Abstract
BackgroundPreclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course.MethodsWe 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.ResultsWe found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions 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 [123I]FP-CIT binding, 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).ConclusionLocal- 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.
Highlights
Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD)
We included 22 patients diagnosed with probable AD dementia (AD-D); 16 subjects with AD-Mild cognitive impairment (MCI), in accordance with current clinical/research criteria [26, 27]; and 74 age-matched healthy controls (HC), all with available [123I]FP-CIT SPECT imaging
Molecular imaging assessment demonstrated a significant reduction of [123I]FP-CIT specific binding ratios (SBRs) in both AD-MCI and AD-D, predominantly in the regions belonging to the mesocorticolimbic dopaminergic pathway
Summary
Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD). Several post-mortem studies subsequently showed alterations in the substantia nigra (SN) [2,3,4,5,6] and ventral tegmental area (VTA) [3] and both pre- [7,8,9,10,11] and post-synaptic [5, 12,13,14,15,16,17,18] neurotransmission alterations in several dopaminergic targets [5, 7, 8, 10, 11, 14,15,16, 18] These pathology results were complemented, more recently, by more limited neuroimaging evidence, reporting alterations in the striatal [19,20,21,22,23] and hippocampal [24] dopaminergic function limitedly to patients with overt AD dementia (AD-D). Lack of comprehensive information about dopaminergic deficits in AD hinders the discovery and application of neurotransmission-targeting therapeutic strategies along the AD course
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