Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases

Abstract

Background: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. Purpose: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). Study Type: Prospective cross-sectional. Population: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. Field Strength/Sequence: 3T T 2-relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). Assessment: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. Statistical Tests: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. Results: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = −2.70 AE 1.15, T = −2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 AE 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 AE 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 AE 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 AE 0.71, T = 3.08, P = 0.004). Data Conclusion: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. Level of Evidence: 1 Technical Efficacy: Stage 3

Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers

“…2 One major strength of our study was our use of participant specific Y a , hematocrit, and hemoglobin values in the calculation OEF and CMRO 2 , which have often been assumed as reference values in previous studies associating brain health with TRUST MRI variables. 2,3,6 In models where CMRO 2 significantly related to an outcome, no CMRO 2 component variable was significantly related to the outcome, indicating that associations between CMRO 2 and outcomes were not driven by any single CMRO 2 component variable, highlighting the potential importance of capturing all such variables. Nonetheless, it is possible that regional CBF may explain associations between CMRO 2 and outcomes among APOE-e4 carriers even though the component variable grey matter CBF did not.…”

“…Compared to cognitively unimpaired peers, older adults with mild cognitive impairment (MCI) have similar global CBF but lower global OEF and CMRO 2 . 2 As low OEF has been linked to increased amyloid burden, 6 and hypometabolism precedes atrophy in MCI, 7 low OEF and CMRO 2 may be important early correlates of an underlying Alzheimer's disease (AD) neurodegenerative process.…”

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

“…Recent advances in MRI technology have allowed noninvasive and rapid measurements of OEF and metabolism on clinical MRI scanners, 36,51–59 providing a new opportunity to examine the utility of oxygen metabolism as a candidate biomarker in AD. Previous human studies have provided evidence that OEF and CMRO 2 can differentiate between patient populations and are correlated with cognitive function 12,14,15 . However, the associations between oxygen metabolism and major hallmarks of AD (e.g.…”

“…Moreover, cognitively normal carriers of the apolipoprotein E4 gene, which is a risk factor for AD, manifested lower global brain oxygen extraction compared with noncarriers 14 . Another report revealed that lower OEF was associated with poorer cognitive scores 15 . Therefore, brain oxygen metabolism may provide a rapid and noninvasive functional biomarker for neurodegeneration in AD.…”

Editorial for “Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases”

“…In this issue of JMRI, Jiang et al report a prospective cross-sectional study on changes in brain oxygen extraction fraction (OEF) in AD and vascular diseases, suggesting the OEF as a useful biomarker. 3 They based their study on the hypothesis that tissue metabolic demand is reduced in AD due to amyloidosis, tauopathy, and neurodegeneration, with preserved vascular function. In contrast, vascular disease is associated with reduced brain perfusion, and thus high OEF for metabolic needs.…”