Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease

Background There is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease. Method We analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p<0.05 FWE corrected, with subsequent cluster‐level FDR correction p<0.05. In addition, only anatomical regions with more than 10 voxels were described. Result Significant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance. Conclusion Hyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.