Role of fronto-limbic circuit in neuropsychiatric symptoms of dementia: clinical evidence from an exploratory study

Background: Neuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment.

Methods: Of 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer's disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry.

Results: All significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT.

Conclusion: Our findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed.