Application of calibrated fMRI in Alzheimer's disease

Abstract

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO₂). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO₂ values fell within the range from previous studies using positron emission tomography (PET) with ¹⁵O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO₂ can be imaged with ¹⁵O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.

Keywords: Alzheimer's disease; BOLD calibration constant; Calibrated fMRI; Cerebral blood flow; Cerebrovascular reactivity; Oxidative metabolism; Oxygen extraction fraction.

Fig. 1

Participant retention. Exclusion criteria for the Alzheimer's patients (AD) and healthy controls cohorts. MoCa = Montreal Cognitive Assessment.

Fig. 2

Bias in occipital lobe due to delayed arterial transit time (ATT). Our resting CBF, OEF and CMRO₂ values within each grey matter lobe are compared to those found in the literature. Measurements fall within the range of reported values, excepting in the occipital where the ATT is suspected to be longer than our time acquisition, biasing our ASL measurements, and thus the derived-model M, OEF and CMRO₂ estimates in this region. CBF₀ = the resting oxygen delivery; OEF = the oxygen extraction fraction; CMRO₂ = the resting oxygen consumption.

Fig. 3

Gas manipulations. End-tidal (ET) O₂ and CO₂ values at baseline, during hyperoxia (HO) and during hypercapnia (HC) for both groups. Errors bars indicate standard deviation.

Fig. 4

Volume of the brain analyzed. Analyzed volume (in blue) only includes voxels where a minimum of 20 participants per group had a valid value. Any remained missing data within the analyzed region were interpolated to the respective group-averaged value. Missing data are due to differences in: 1) imaged slice position, 2) susceptibility patterns and 3) pattern of no-solutions across subjects. In the axial slices: left = left. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Voxel-based analysis adjusted for age. For each physiological variable, the colored regions show a significant deficit in AD (primary P < 0.005 and minimum cluster size of 1250 mm³, yielding a FWE cluster-corrected (P < 0.05)). The color bar indicates Student's t-statistic value. Statistically significant clusters are overlaid to different sagittal and axial sections of the ADNI template. Physiological variables are: CBF₀, the resting oxygen delivery; OEF, the oxygen extraction fraction; CMRO₂, the resting oxygen consumption; M, the maximum BOLD signal increase when venous O₂ saturation approaches 100%; R2*₀, the transverse relaxation rate constant; ∆R2*_HC, the R2* change during hypercapnia. In the axial slices: left = left. SC = subject control. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)