Several sex differences in brain structure and function exist in healthy participants (Ingalhalikar et al., 2014; Ruigrok et al., 2014) and neurological conditions (Ballmaier et al., 2004; Boccalini et al., 2022; Malpetti et al., 2017). These seem to modulate the manifestation and progression of clinical phenotypes.

Sex studies in dementia traditionally report a higher proportion of women with Alzheimer's disease (AD), and men with Parkinson's disease (PD) with a 2:1 male/female ratio in the latter (Caslake et al., 2013; Podcasy and Epperson, 2022). Therefore, sex seems a valuable parameter to be considered when designing predictive models for disease prevention, diagnosis, and possibly treatment response (Ferretti et al., 2018). Moreover, the study of sex differences in neurodegenerative conditions may help us understand how and why male and female brains differ in their predisposition for risk or resilience (Ruigrok et al., 2014).

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after AD. The DLB core symptoms often manifest in different combinations at diagnosis or during the disease course (Abdelnour et al., 2022), and sex might play a role in this heterogeneity (Bayram et al., 2021; Dugger et al., 2012). A diagnosis of DLB is more likely to be done in males than females (Mouton et al., 2018). DLB males express more neocortical “diffuse” Lewy bodies (LB) at post mortem pathology than females (women = 6.4%; men = 9.5%; p < 0.05) (Barnes et al., 2019), and a balanced male/female ratio for mixed AD/LB pathology (Bayram et al., 2022; Nelson et al., 2010). Women were more likely to have AD with advanced TDP-43 or Hippocampal sclerosis than men (women = 27.0%; men = 19.9%; p < 0.01) (Barnes et al., 2019). When controlling for age, women showed less CSF α-synuclein and more β-amyloid 1–42 pathology than men (Van de Beek et al., 2020). There is evidence that a significant proportion of women are clinically diagnosed with AD despite underlying LB pathology (Bayram et al., 2021). LB pathology may not have the same clinical impact on women as on men.

Male brain is characterized by larger within-hemisphere connectivity, with a high level of modularity, whereas female brain shows greater interhemispheric connectivity and greater cross-hemispheric participation. The structural connectivity differences are also supported by behavioral data, with females outperforming males on attention, word and face memory, and social cognition tests, while males performed better on spatial processing and (sensory) motor speed (Gur et al., 2012; Ingalhalikar et al., 2014). Neurodegeneration acts on molecular pathways, and local circuits in specific brain regions, producing reconfigurations and loss of functions in higher-order neural networks (Carli et al., 2021). As for development, sex may differentially affect the trajectories of connectome dysfunction in neurodegeneration.

Previous studies using different neuroimaging modalities show widespread abnormalities within and across brain networks in DLB (recently reviewed by (Habich et al., 2022)). In particular, FDG-PET revealed substantial and widespread impairment of brain metabolic connectivity in DLB (S. P. Caminiti et al., 2017; G. Carli et al., 2020; Sala et al., 2019), with alterations in large-scale resting-state networks also significantly and specifically associated with the core DLB clinical symptoms (Sala et al., 2019).

The neurotransmitter changes reported in DLB mostly include a degeneration of the dopaminergic, cholinergic and noradrenergic systems (Caminiti and Carli, 2023; Francis and Perry, 2007). A dysregulated noradrenergic (NA) innervation, possibly related to α-synuclein pathology, is emerging as pathological mechanisms associated with early rapid eye movement sleep behaviour disorder (RBD), neuropsychiatric symptoms, and autonomic deficits, characterizing DLB (Pfeiffer, 2016). We previously found alterations in the DLB brain metabolic networks connectivity as a result of dysfunction in DA, NA and Ch neurotransmission systems (G. Carli et al., 2020). No study has hitherto investigated sex-related brain connectivity alterations in DLB, which, instead, have been assessed in PD (Boccalini et al., 2022, 2020) and AD (Malpetti et al., 2017) conditions. Notably, studies in PD (which shares with DLB the α-synuclein protein pathology and dopaminergic deficits), have shown a more prevalent impairment of dorsal dopaminergic network in males compared to females (Boccalini et al., 2020).

In the current study, we investigated how sex can modulate brain metabolism and metabolic connectivity of whole-brain networks in DLB. We also tested a comprehensive model focusing on the DA, NA, and Ch-divisions systems to explore connectivity reconfiguration in major biochemical circuits for DLB. We also evaluated connectivity changes in the resting-state networks (RSNs) that are linked to core processes of human cognition (Van Den Heuvel and Pol, 2010) and found to be vulnerable in DLB (Sala et al., 2019).