Assessment of Alzheimer's disease risk with functional magnetic resonance imaging: an arterial spin labeling study.

Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer's disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] ε4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE ε4 carriers and 15 noncarriers]; 16 MCI [8 APOE ε4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE ε4 allele demonstrated increased MTL resting state CBF relative to ε4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE ε4 carriers demonstrated significantly greater percent change in CBF relative to ε4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD.

Differential age effects on cerebral blood flow and BOLD response to encoding: associations with cognition and stroke risk.

Changes in the cerebrovascular system due to age or disease can significantly alter the blood-oxygenation-level-dependent (BOLD) signal and complicate its interpretation. The simultaneous acquisition of arterial spin labeling (ASL) and BOLD data represents a useful technique to more fully characterize the neurovascular underpinnings of functional brain response to cognition. We conducted a functional magnetic resonance imaging (FMRI) study of episodic memory encoding to investigate whether age is related to cerebral blood flow (CBF) and BOLD response in the medial temporal lobe (MTL). Results demonstrated a significant reduction in resting-state CBF in older compared to young adults. Conversely, older adults showed significantly increased CBF but not BOLD response in the MTL during picture encoding relative to young adults. Correlations between CBF response and cognition were demonstrated whereas associations with BOLD were not observed. Stroke risk was associated with both CBF and BOLD response. Results suggest that aging effects on CBF and BOLD responses to encoding are dissociable and that cerebrovascular alterations contribute to findings of age-related differences.

Calibrated fMRI in the medial temporal lobe during a memory-encoding task.

Prior measures of the blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF) responses to a memory-encoding task within the medial temporal lobe have suggested that the coupling between functional changes in CBF and changes in the cerebral metabolic rate of oxygen (CMRO(2)) may be tighter in the medial temporal lobe as compared to the primary sensory areas. In this study, we used a calibrated functional magnetic resonance imaging (fMRI) approach to directly estimate memory-encoding-related changes in CMRO(2) and to assess the coupling between CBF and CMRO(2) in the medial temporal lobe. The CBF-CMRO(2) coupling ratio was estimated using a linear fit to the flow and metabolism changes observed across subjects. In addition, we examined the effect of region-of-interest (ROI) selection on the estimates. In response to the memory-encoding task, CMRO(2) increased by 23.1+/-8.8% to 25.3+/-5.7% (depending upon ROI), with an estimated CBF-CMRO(2) coupling ratio of 1.66+/-0.07 to 1.75+/-0.16. There was not a significant effect of ROI selection on either the CMRO(2) or coupling ratio estimates. The observed coupling ratios were significantly lower than the values (2 to 4.5) that have been reported in previous calibrated fMRI studies of the visual and motor cortices. In addition, the estimated coupling ratio was found to be less sensitive to the calibration procedure for functional responses in the medial temporal lobe as compared to the primary sensory areas.

SNR and functional sensitivity of BOLD and perfusion-based fMRI using arterial spin labeling with spiral SENSE at 3 T.

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies using parallel imaging to reduce the readout window have reported a loss in temporal signal-to-noise ratio (SNR) that is less than would be expected given a purely thermal noise model. In this study, the impact of parallel imaging on the noise components and functional sensitivity of both BOLD and perfusion-based fMRI data was investigated. Dual-echo arterial spin labeling data were acquired on five subjects using sensitivity encoding (SENSE), at reduction factors (R) of 1, 2 and 3. Direct recording of cardiac and respiratory activity during data acquisition enabled the retrospective removal of physiological noise. The temporal SNR of the perfusion time series closely followed the thermal noise prediction of a radicalR loss in SNR as the readout window was shortened, with temporal SNR values (relative to the R=1 data) of 0.72 and 0.56 for the R=2 and R=3 data, respectively, after accounting for physiological noise. However, the BOLD temporal SNR decreased more slowly than predicted even after accounting for physiological noise, with relative temporal SNR values of 0.80 and 0.63 for the R=2 and R=3 data, respectively. Spectral analysis revealed that the BOLD trends were dominated by low-frequency fluctuations, which were not dominant in the perfusion data due to signal processing differences. The functional sensitivity, assessed using mean F values over activated regions of interest (ROIs), followed the temporal SNR trends for the BOLD data. However, results for the perfusion data were more dependent on the threshold used for ROI selection, most likely due to the inherently low SNR of functional perfusion data.

A component based noise correction method (CompCor) for BOLD and perfusion based fMRI.

A component based method (CompCor) for the reduction of noise in both blood oxygenation level-dependent (BOLD) and perfusion-based functional magnetic resonance imaging (fMRI) data is presented. In the proposed method, significant principal components are derived from noise regions-of-interest (ROI) in which the time series data are unlikely to be modulated by neural activity. These components are then included as nuisance parameters within general linear models for BOLD and perfusion-based fMRI time series data. Two approaches for the determination of the noise ROI are considered. The first method uses high-resolution anatomical data to define a region of interest composed primarily of white matter and cerebrospinal fluid, while the second method defines a region based upon the temporal standard deviation of the time series data. With the application of CompCor, the temporal standard deviation of resting-state perfusion and BOLD data in gray matter regions was significantly reduced as compared to either no correction or the application of a previously described retrospective image based correction scheme (RETROICOR). For both functional perfusion and BOLD data, the application of CompCor significantly increased the number of activated voxels as compared to no correction. In addition, for functional BOLD data, there were significantly more activated voxels detected with CompCor as compared to RETROICOR. In comparison to RETROICOR, CompCor has the advantage of not requiring external monitoring of physiological fluctuations.

Cerebral blood flow and BOLD responses to a memory encoding task: a comparison between healthy young and elderly adults.

Functional magnetic resonance imaging (fMRI) studies of the medial temporal lobe have primarily made use of the blood oxygenation level dependent (BOLD) response to neural activity. The interpretation of the BOLD signal as a measure of medial temporal lobe function can be complicated, however, by changes in the cerebrovascular system that can occur with both normal aging and age-related diseases, such as Alzheimer's disease. Quantitative measures of the functional cerebral blood flow (CBF) response offer a useful complement to BOLD measures and have been shown to aid in the interpretation of fMRI studies. Despite these potential advantages, the application of ASL to fMRI studies of cognitive tasks and at-risk populations has been limited. In this study, we demonstrate the application of ASL fMRI to obtain measures of the CBF and BOLD responses to the encoding of natural scenes in healthy young (mean 25 years) and elderly (mean 74 years) adults. The percent CBF increase in the medial temporal lobe was significantly higher in the older adults, whereas the CBF levels during baseline and task conditions and during a separate resting-state scan were significantly lower in the older group. The older adults also showed slightly higher values for the BOLD response amplitude and the absolute change in CBF, but the age group differences were not significant. The percent CBF and BOLD responses are consistent with an age-related increase in the cerebral metabolic rate of oxygen metabolism (CMRO(2)) response to memory encoding.

Physiological noise reduction for arterial spin labeling functional MRI.

Three methods for the reduction of physiological noise in arterial spin labeling (ASL) functional magnetic resonance imaging (fMRI) are presented and compared. The methods are based upon a general linear model of the ASL measurement process and on a previously described retrospective image-based method (RETROICOR) for physiological noise reduction in blood oxygenation level dependent fMRI. In the first method, the contribution of physiological noise to the interleaved control and tag images that comprise the ASL time series are assumed to be equal, while in the second method this assumption is not made. For the third method, it is assumed that physiological noise primarily impacts the perfusion time series obtained from the filtered subtraction of the control and tag images. The methods were evaluated using studies of functional activity in the visual cortex and the hippocampal region. The first and second methods significantly improved statistical performance in both brain regions, whereas the third method did not provide a significant gain. The second method provided significantly better performance than the first method in the hippocampal region, whereas the differences between methods were less pronounced in visual cortex. The improved performance of the second method in the hippocampal region appears to reflect the relatively greater effect of cardiac fluctuations in this brain region. The proposed methods should be particularly useful for ASL studies of cognitive processes where the intrinsic signal to noise ratio is typically lower than for studies of primary sensory regions.

Caffeine alters the temporal dynamics of the visual BOLD response.

The blood oxygenation level-dependent (BOLD) responses to visual stimuli, using both a 1-s long single trial stimulus and a 20-s long block stimulus, were measured in a 4-T magnetic field both before and immediately after a 200-mg caffeine dose. In addition, resting levels of cerebral blood flow (CBF) were measured using arterial spin labeling. For the single trial stimulus, the caffeine dose significantly (p<0.05) reduced the time to peak (TTP), the time after the peak at which the response returned to 50% of the peak amplitude (TA50), and the amplitude of the poststimulus undershoot in all subjects (N=5). Other parameters, such as the full-width half-maximum (FWHM) and the peak amplitude, also showed significant changes in the majority of subjects. For the block stimulus, the TTP, TA50, and the time for the response to reach 50% of the peak amplitude (T50) were significantly reduced. In some subjects, oscillations were observed in the poststimulus portion of the response with median peak periods of 9.1 and 9.5 s for the single trial and block responses, respectively. Resting CBF was reduced by an average of 24%. The reproducibility of the results was verified in one subject who was scanned on 3 different days. The dynamic changes are similar to those previously reported for baseline CBF reductions induced by hypocapnia and hyperoxia.

Coupling of cerebral blood flow and oxygen consumption during physiological activation and deactivation measured with fMRI.

The physiological basis of the blood oxygenation level dependent (BOLD) signal and its dependence on baseline cerebral blood flow (CBF) were investigated by comparing responses to a visual stimulus after physiological changes of the baseline. Eight human subjects were imaged with 3 and 4 T MRI scanners, and both BOLD signal and CBF were simultaneously measured. Subjects viewed a flickering radial checkerboard in a block design experiment, alternating between eyes open or closed during the off periods. Compared to a baseline state with eyes open in a darkened room, substantial deactivation (average change: 2.9 +/- 0.3% BOLD, 22 +/- 2.1% CBF) in the occipital cortex was observed when the eyes were closed. The absolute response during stimulation (average change: 4.4 +/- 0.4% BOLD, 36.3 +/- 3.1% CBF) was independent of the preceding resting condition. We estimated the fractional change in CBF to be approximately 2.2 +/- 0.15 times greater than the fractional change in metabolic rate of oxygen (CMRO2). The changes in CBF and CMRO2 were consistently linearly coupled during activation and deactivation with CBF changes being between approximately 60% and 150% compared to baseline with eyes open. Relative to an assumed baseline oxygen extraction fraction (OEF) of 40%, the estimated OEF decreased to 33 +/- 1.4% during activation and increased to 46 +/- 1.2% during rest with eyes closed. In conclusion, we found that simply closing the eyes creates a large physiological deactivation in the visual cortex, and provides a robust paradigm for studying baseline effects in fMRI. In addition, we propose a feed-forward model for neurovascular coupling which accounts for the changes in OEF seen following baseline changes, including both the current physiological perturbations as well as previously reported pharmacologically induced changes.