Imaging dopamine system transporter activity and connectivity in Alzheimer’s dementia

Abstract

AbstractBackgroundNeuropsychiatric symptoms and cognitive deficits in Alzheimer’s Disease (AD) dementia can be related to changes in the brain dopamine (DA) system. In order to investigate whether and how the DA pathways, namely the nigrostriatal and mesocortico‐limbic, are involved in the pathophysiology of AD, we relied on imaging measures of DA transporter activity, using [123I]FP‐CIT SPECT. We tested (i) presence and degree of alterations in the ventral and dorsal dopamine structures and their major cortical targets; (ii) presence of alterations in DA molecular connectivity within the two DA pathways.MethodsSixteen amyloid‐positive subjects with amnestic mild cognitive impairment (aMCI), twenty‐two amyloid‐positive patients with probable Alzheimer’s dementia (AD) and seventy‐two healthy controls, were selected from three centres. Each subjects underwent an [123I]FP‐CIT SPECT scan. The subcortical/cortical dopaminergic structures showed significant tracer binding, as compared to the reference region, and were thus selected for further analyses, which included the assessment of regional differences in [123I]FP‐CIT bindings, via MANCOVA and differences in molecular connectivity within the dopamine pathways via partial‐correlation analysis, among the three groups. Gender, age and reconstruction method were included as nuisance covariates in all statistical analyses. Results deemed significant at p<0.05, following Bonferroni correction for multiple comparisons.ResultsThe assessment of DA transporter activity demonstrated a significant reduction in aMCI subjects and AD patients in subcortical and cortical targets of the ventro‐tegmental area, namely the ventral striatum and hippocampus, bilaterally, and the middle cingulate gyrus. Within the nigrostriatal projections, only the dorsal caudate was affected, bilaterally. Molecular connectivity measures demonstrated a widespread loss of inter‐connections among targets of the ventro‐striatal pathway only, with a sparing of the nigrostriatal projections.ConclusionsThe selective and significant decrease in dopaminergic transporter activity in the ventro‐striatal subcortical/cortical dopaminergic regions is indicative of an axonal degeneration starting from the projections arising from the dopaminergic ventro‐tegmental brainstem nuclei, and involving the mesolimbic pathways. Our data, consistent with previous post‐mortem evidence [1], support the involvement of the ventral dopaminergic system in AD, since the prodromal phases. The mesolimbic subcortical/cortical DA alterations might play a role in the pathophysiology of memory function and neuropsychiatric symptoms in AD.