Sex‐specific decoupling of cerebral blood flow and glucose metabolism in Alzheimer’s disease mouse model

Abstract

AbstractBackgroundCerebral blood flow (CBF) dysregulation and neurovascular impairment are central to Alzheimer’s disease (AD) etiology1. Even though two‐thirds of the AD patients are women, the sex differences in vascular and metabolic risk factors are still unclear2. Previously, we described sex‐specific CBF trajectories in mouse model of AD3. In the present study, we connect these CBF changes with cerebral glucose metabolism in the same males and females. We quantify the correlation between metabolic rate and vascular flow and identify unique points of divergence across lifespan.MethodWe used 9.4T MRI of APPswe.PSEN1dE9 mice (23 males, 24 females; young 3‐7 months, middle age 7‐15 months, and old 15‐24 months) and B6C3F1/J controls (n=20). We quantified CBF (qCBF) using T1‐weighted mapping and continuous arterial spin labeling (CASL) as previously described3.The glucose uptake rate (ΔR1ρ) was measured using chemical exchange‐sensitive spin lock (CESL) and computed as the difference between the steady state before and after intravenous injection of 2‐Deoxy‐d‐glucose (2DG)4. Region of interests were drawn manually on the cortex and subcortical areas.ResultWe found that AD females, but not AD males had lower cortical glucose metabolism than age‐matched controls, while both AD groups had lower CBF than controls. These differences were not significant in the subcortical regions. The metabolic trajectory during aging was similar between AD males and females (Fig 1A), however, the CBF trajectory of AD males showed a transient increase from young to middle age, while the female group showed an opposite trend (Fig 1B). The sex‐specific divergence between glucose consumption and CBF appeared during middle age. Male AD mice had higher positive correlation between glucose metabolism and CBF in the cortex compared to females (Fig 2A). Additionally, in both AD groups, this correlation was positive in the cortex but not in the subcortical region (Fig 2).ConclusionWhen interpreting metabolic rate of glucose and CBF as AD biomarkers, age, sex and brain region should be taken into consideration.