Sex Difference In Neurovascular Coupling And Its Correlation With General Cognition In The Alzheimer’s Disease

Objective Alzheimer’s disease(AD)is a progressive age-related neurodegenerative disorder that results in irreversible cognitive impairments.Nonetheless,there are numerous sex-related differences in clinical course that may provide clues to disease pathogenesis and more effective individualized treaments.This study mainly explores the sex difference in neurovascular coupling in the AD and its correlation with general cognitive function.Methods Resting-state 3D T1-weighted high-resolution structural magnetic resonance images,blood oxygen level dependent functional magnetic resonance images and 3D pseudo-continuous arterial spin labeling images were collected from 50 AD patients(28females),52 amnesic mild cognitive impairment(aMCI)patients(31 females),and 59 healthy controls(HC,36 females),and standard neuropsychological assessments were performed.We calculated short-and long-range functional connectivity strength(s FCS and l FCS)and cerebral blood flow(CBF)values for all participants.Considering the effect of global signal on FCS,long-range and short-range FCS for regression global signal and without regression global signal were calculated respectively during preprocessing.Then,the long-and short-range neurovascular coupling(i.e.,CBF/FCS coupling ratio)for each voxel of all participants was calculated,which represents the amount of blood supply required per unit of functional connection strength.Two-way ANOVA was performed to identify group × sex interactions and main effects of group.Correlation analysis was used to assess associations between neurovascular coupling and Mini-Mental State Examination(MMSE)scores.Results In the demographic baseline statistical analysis,we found that there was a group × sex interaction effect on MMSE score(P = 0.017),MMSE scores were significantly lower in the entire AD group than the entire HC and aMCI groups(P <0.0001).In the aMCI group,MMSE scores were roughly similar for males and females,but were higher in males than females of the HC and AD groups(P = 0.011).We found that there were significant group × sex interaction effects in the CBF/s FCS ratios of the right middle temporal gyrus,left angular gyrus,left inferior orbital gyrus and left superior frontal gyrus(all P < 0.05,cluster level FDR corrected).Similarly,there also were CBF/l FCS ratios in the right middle temporal gyrus,left precuneus,left posterior cingulate gyrus,left angular gyrus,left medial orbital frontal gyrus and bilateral precuneus(all P < 0.05,cluster level FDR corrected).Correlation analysis showed that CBF/FCS ratios in all brain regions with group × sex interactions were significantly negatively correlated with MMSE scores in female patient group(aMCI and AD group combined),while there was a positive correlation between the CBF/FCS ratios of some brain regions and MMSE scores in male patients.Conclusion There are significant sex differences in neurovascular coupling mechanisms in AD disease.In some brain regions of the default mode network,frontal parial network and executive control network,the neurovascular coupling ratio increases in females and decreases in males,which is correlated with cognitive function.This provides a novel perspective and relevant theoretical basis for further understanding of sex differences in AD.It is suggests that we should take into account sex differences in the diagnosis,treatment and prevention of AD disease in the future.