Background: Behavioral and psychological symptoms of dementia (BPSD) are a distressful condition. We aimed to investigate the BPSD distribution in subjects with cognitive impairment, and the potential correlations between BPSD and neurodegeneration in terms of cerebrospinal fluid (CSF) tau and brain atrophy. Materials and Methods: One-hundred patients with mild cognitive impairment (MCI) or dementia (Alzheimer’s disease; Dementia with Lewy-body disease, DLB; frontotemporal dementia; vascular dementia) underwent a complete diagnostic workup, including 3T-MRI and/or CT and CSF. Cortical atrophy was assessed i) first with visual rating scales (medial temporal atrophy MTA, posterior atrophy PA and global cortical atrophy-frontal lobe GCA-F scales), ii) secondly with quantitative measures (such as cortical thickness CT and volume V). BPSD were rated using Neuropsychiatric Inventory (NPI), and BPSD clusters were defined according to the European Alzheimer Disease Consortium. Results: Delusions, hallucinations and psychosis cluster were differently distributed among the diagnostic groups (p<0.05, p<0.001, and p<0.05), with DLB patients showing higher scores for hallucinations (vs MCI, p<0.001, and AD, p<0.05) and psychosis cluster (vs MCI, p<0.05). In primary dementias, we found a negative correlation between NPI total score and tau levels (p=0.08), confirmed by beta regression (p<0.01), while a positive non-significant relationship was observed in MCI. Higher GCA-F scores were associated with delusions and apathy (p<0.05, on both hemispheres) and to hallucinations (left: p<0.01, right: p<0.05). GCA-F scores were positively correlated with psychosis cluster (right: p<0.05), and agitation/aggression (left: p<0.05). With regard to the quantitative measures od atrophy, significant correlations were observed for 4 main neuropsychiatric symptoms: delusions, hallucinations, agitation, and apathy. Delusions showed negative correlations with CT and V of frontal areas (dorsolateral and orbital, with a prevalent involvement on the right side) and of areas of the limbic system (anterior and posterior cingulate, isthmus and entorhinal cortex). As well, hallucinations showed an involvement of the frontal lobe (dorsolateral) and the limbic system (anterior and posterior cingulate, isthmus, fusiform gyrus and hippocampus). A decrease in CT and V of the opercular region (insula and temporal pole) and the limbic system (entorhinal, parahippocampal and fusiform cortex and amygdala) was instead correlated with agitation/aggression. Finally, apathy showed a negative correlation with regions of the frontal lobe (dorsolateral, orbital, opercular, precentral and paracentral) insula and the limbic system (anterior cingulate and isthmus). Conclusion: This study provides a real-world overview of the most clinically relevant BPSD occurring in patients attending a memory clinic due to dementing conditions. The gathered evidence suggests that, in a future perspective, CSF biomarkers and visual rating scales for cortical atrophy could be hopefully included in a multidimensional evaluation of demented patients, aimed to predict prognosis and occurrence of BPSD. Moreover, quantitative measures of atrophy suggest that the limbic system cover a paramount role in the their pathophysiology through the dysfunction of the mesolimbic circuitry.Background: Behavioral and psychological symptoms of dementia (BPSD) are a distressful condition. We aimed to investigate the BPSD distribution in subjects with cognitive impairment, and the potential correlations between BPSD and neurodegeneration in terms of cerebrospinal fluid (CSF) tau and brain atrophy. Materials and Methods: One-hundred patients with mild cognitive impairment (MCI) or dementia (Alzheimer’s disease; Dementia with Lewy-body disease, DLB; frontotemporal dementia; vascular dementia) underwent a complete diagnostic workup, including 3T-MRI and/or CT and CSF. Cortical atrophy was assessed i) first with visual rating scales (medial temporal atrophy MTA, posterior atrophy PA and global cortical atrophy-frontal lobe GCA-F scales), ii) secondly with quantitative measures (such as cortical thickness CT and volume V). BPSD were rated using Neuropsychiatric Inventory (NPI), and BPSD clusters were defined according to the European Alzheimer Disease Consortium. Results: Delusions, hallucinations and psychosis cluster were differently distributed among the diagnostic groups (p<0.05, p<0.001, and p<0.05), with DLB patients showing higher scores for hallucinations (vs MCI, p<0.001, and AD, p<0.05) and psychosis cluster (vs MCI, p<0.05). In primary dementias, we found a negative correlation between NPI total score and tau levels (p=0.08), confirmed by beta regression (p<0.01), while a positive non-significant relationship was observed in MCI. Higher GCA-F scores were associated with delusions and apathy (p<0.05, on both hemispheres) and to hallucinations (left: p<0.01, right: p<0.05). GCA-F scores were positively correlated with psychosis cluster (right: p<0.05), and agitation/aggression (left: p<0.05). With regard to the quantitative measures od atrophy, significant correlations were observed for 4 main neuropsychiatric symptoms: delusions, hallucinations, agitation, and apathy. Delusions showed negative correlations with CT and V of frontal areas (dorsolateral and orbital, with a prevalent involvement on the right side) and of areas of the limbic system (anterior and posterior cingulate, isthmus and entorhinal cortex). As well, hallucinations showed an involvement of the frontal lobe (dorsolateral) and the limbic system (anterior and posterior cingulate, isthmus, fusiform gyrus and hippocampus). A decrease in CT and V of the opercular region (insula and temporal pole) and the limbic system (entorhinal, parahippocampal and fusiform cortex and amygdala) was instead correlated with agitation/aggression. Finally, apathy showed a negative correlation with regions of the frontal lobe (dorsolateral, orbital, opercular, precentral and paracentral) insula and the limbic system (anterior cingulate and isthmus). Conclusion: This study provides a real-world overview of the most clinically relevant BPSD occurring in patients attending a memory clinic due to dementing conditions. The gathered evidence suggests that, in a future perspective, CSF biomarkers and visual rating scales for cortical atrophy could be hopefully included in a multidimensional evaluation of demented patients, aimed to predict prognosis and occurrence of BPSD. Moreover, quantitative measures of atrophy suggest that the limbic system cover a paramount role in the their pathophysiology through the dysfunction of the mesolimbic circuitry
