Sex differences in dementia with Lewy bodies: an imaging study of neurotransmission pathways

Abstract Purpose: Dementia with Lewy bodies (DLB) is characterized by a wide clinical and biological heterogeneity, with sex differences reported in both clinical and pathologically confirmed DLB cohorts. No research evidence is available on sex differences regarding molecular neurotransmission. This study aimed to assess whether sex can influenceneurotransmitter systems in patients with probable DLB (pDLB). Methods: We included 123 pDLB patients (male/female: 77/46) and 78 control subjects (male/female: 34/44) for comparison, who underwent 123I-FP-CIT-SPECT imaging. We assessed sex differences in the dopaminergic activity of the nigrostriatal and mesolimbic systems using regional-based and voxel-wise analyses of 123I-FP-CIT binding. We tested whether sex-specific binding alterations would also pertain to the serotoninergic and noradrenergic systems by applying spatial correlation analyses. We applied molecular connectivity analyses to assess potential sex differences in the dopaminergic pathways. Results: We found comparable 123I-FP-CIT binding decreases in the striatum for pDLB males and females compared to controls. However, females showed more severe alterations in the extrastriatal projections of the nigrostriatal and mesolimbic dopaminergic systems. According to the spatial correlation analysis, sex-specific molecular alterations were also associated with serotonergic and noradrenergic systems. Nigrostriatal and mesolimbicsystems’ connectivity was impaired in both groups, with males showing local alterations and females presenting long-distance disconnections between subcortical and cortical regions. Conclusions: pDLB females showed different patterns of monoaminergic depletion and dopaminergic systems’ connectivity compared to males, mostly involving extrastriatal regions. The results indicate distinct sex-related regional vulnerabilities possibly due to the high prevalence of Alzheimer’s disease co-pathology, as reported in pDLB females.