Lower baseline cerebral oxygen extraction and metabolic rate are associated with faster cognitive decline and brain atrophy over a longitudinal follow‐up period

Abstract

AbstractBackgroundOxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) are complexly interrelated. Low OEF and CMRO2 are promising early indicators of Alzheimer’s disease (AD) pathophysiology. To better understand how alterations in cerebral oxygen utilization relate to abnormal brain aging, we investigated baseline oxygen metabolism variables (OEF, CBF, CMRO2) in relation to longitudinal cognition and brain structure, and if these associations were different among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐ε4 carriers).MethodsVanderbilt Memory and Aging Project participants (n=244, 74±7 years, mean follow‐up=3.7 years) underwent serial neuropsychological testing and multimodal 3T brain MRI. We used T2‐relaxation‐under‐spin‐tagging to calculate OEF and pseudo‐continuous arterial spin‐labeling to assess grey matter CBF. CMRO2 was calculated as: CMRO2=OEF*CBF*arterial oxygen content. Linear mixed‐effects regression models related time x oxygen metabolism variable (one predictor per model) to longitudinal cognitive and brain MRI outcomes. Models were adjusted for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, intracranial volume (for MRI outcomes), APOE‐ε4 status, and time. Models were repeated testing anAPOE‐ε4 status x oxygen metabolism variable x time interaction term.ResultsLower baseline OEF was associated with faster hippocampal atrophy (p=0.02). Lower baseline CBF was associated with faster cortical thinning in regions susceptible to AD‐related neurodegeneration (p=0.008). Lower baseline CMRO2 was associated with faster language decline (p=0.01) and hippocampal atrophy (p=0.01) and inferior lateral ventricle volume increase (reflecting faster atrophy of adjacent tissue; p=0.02). OEF interacted with APOE‐ε4 status on executive function (p=0.002), language (p=0.006), and visuospatial performances (p=0.02), and inferior lateral ventricle volume (p=0.007). CBF interacted with APOE‐ε4 status on executive function performance (p=0.0003). CMRO2 interacted with APOE‐ε4 status on temporal lobe volume (p=0.03). In stratified models, lower baseline OEF and CMRO2 tended to relate to faster brain health decline among APOE‐ε4 carriers.ConclusionsLower OEF, CBF, and CMRO2 are associated with worse brain health trajectories over a 4‐year follow‐up. Assessing oxygen metabolism variables in combination may provide more comprehensive insight into longitudinal brain aging and serve as an early biomarker of disease, particularly among older adults at genetic risk for AD.FundingT32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980