Sex‐specific cerebral blood flow trajectories in mouse models of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) therapies targeting the aggregation of amyloid‐beta during the late stages have been largely unsuccessful. Growing evidence indicates that cerebral blood flow (CBF) plays a key role during the early AD stages by limiting the energy supply to the brain and impairing the clearance of harmful metabolites1. Recent studies suggest that CBF can be used as a predictor of AD2. Despite the CBF potential as a biomarker, its sex‐specific changes during AD progression are still poorly characterized. In the present study we quantify CBF trajectories in male and female mouse model of AD across lifespan. We also measure the tissue plaques and the vascular deposits in the form of cerebral amyloid angiopathy (CAA) to assess their relationship with CBF.MethodWe used 9.4T MRI of APPswe.PSEN1dE9 mice (12 male,10 female, 6‐24 months) and matched controls (n=15). We quantified CBF (qCBF) using T1‐weighted mapping (TE=12ms, TR=10 sec, 9 inversion times between 15‐8000ms and continuous arterial spin labeling (CASL) with TE=0.32ms and TR=2625ms with a label offset 12mm, duration 2.4s. Both had 64×64 matrix with 210 μm/voxel. We computed qCBF as previously described.3 Smooth muscle actin (SMA) and X34 staining was performed on free floating sections. Two‐way ANOVA was used to evaluate the age and sex effects on parenchymal plaques, CAA and qCBF.ResultWe found CBF to be significantly reduced in AD mice compared to controls (Fig 1, t‐test p=0.00017). Two‐way ANOVA showed a significance in the effects of sex and AD as factors on CBF (p=0.015) and an impact of both sex and age on the tissue plaque accumulation (Fig 2A), CAA was affected by age, with trend for higher CAA in females (Fig 2B), particularly after 13 months when qCBF declined.ConclusionWhen interpreting blood flow as AD biomarker both age and sex should be taken into consideration. The accumulation of tissue and vascular plaques appears to occur at different rates and depends both on age and sex. Further studies are needed on the CAA and CBF interaction and the sex‐specific vascular contributions to AD onset and progression. 1.Kisler et al. (2017). 2.Iturria‐Medina et al. (2015). 3.Zhang et al. (1992).