Rationale and Objectives
The relative roles of arterial spin-labeling (ASL) perfusion imaging and magnetic resonance morphological assessment in diagnosing Alzheimer’s disease (AD) have not been established. Our purposes were to directly compare the diagnostic performance of ASL regional cerebral blood flow (rCBF) measurement and that of morphological assessment, and to determine whether or not the combination of the two methods improves diagnostic performance.
Materials and Methods
We analyzed 23 consecutive, retrospectively identified AD patients and 23 healthy control subjects. For each subject, both high-resolution T1-weighted images and ASL perfusion images were obtained. A linear discriminant analysis was performed to distinguish the AD patients from the control subjects based on the three imaging parameters: 1) globally normalized gray matter (GM) density determined by voxel-based morphometry (VBM) procedures, 2) normalized rCBF calculated from ASL data, and 3) the combination of the two. The discriminative abilities of these methods were evaluated by the area under the curve (AUC) derived from receiver-operating characteristics analysis.
Results
The morphological assessment based on the globally normalized GM density resulted in an AUC of 0.779, whereas ASL-normalized rCBF analysis achieved better performance (AUC = 0.893). The combination of the two methods performed better (AUC = 0.919) than either method alone.
Conclusion
Normalized rCBF measurement by ASL may perform better than morphological analysis based on the VBM procedure in discriminating AD patients from healthy control subjects. The combination of the two approaches was more effective than either method alone.
Alzheimer’s disease (AD) has elicited a special research interest in brain imaging techniques to visualize its neurodegenerative evolution, particularly to assist in early diagnosis for the opportune start of recently developed efficacious therapies such as the administration of cholinesterase inhibitors. Moreover, early stages of AD are considered a relevant target for future therapies. Imaging studies using positron emission tomography with 18 F-fluoro-deoxyglucose (FDG-PET) and single-photon emission tomography (SPECT) have revealed a characteristic regional pattern of diminished glucose metabolism and cerebral blood flow (CBF) in posterior cingulate and temporoparietal cortices in the early stages of AD . Although functional studies are considered promising biomarkers for early AD stages, morphometric studies have been the mainstream approach with magnetic resonance imaging (MRI). Volume loss of gray matter (GM) in medial temporal structures such as the entorhinal cortex and hippocampus has been reported to be diagnostic for AD . MRI is advantageous over functional nuclear medicine techniques because it does not expose the patient to radiation and because it is available more widely. The recent introduction of quantitative and fully automated image analysis methods facilitates bias-free analysis of structural MR images, and its usefulness in characterizing and diagnosing AD has been proven by multiple researchers. Voxel-based morphometry (VBM) is one of the most widely used among such automated techniques.
In addition to morphological imaging, recent advances in MRI allow for the assessment of functional parameters, such as cerebral perfusion. In particular, arterial spin labeling (ASL) has recently drawn much attention as a new tool for cerebral perfusion imaging . ASL has been considered a promising functional MR technique for AD diagnosis by virtue of its noninvasiveness and its ability to quantitate regional CBF (rCBF) .
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Materials and methods
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Subjects
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MRI
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Data Analysis
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ASL Perfusion Imaging
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Statistical Analyses
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Results
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Table 1
Demographic and Clinical Characteristics of the Study Subjects
AD ( n = 23) HC ( n = 23)P Value Age (y) ∗ 74.6 ± 8.9 73.2 ± 6.9 NS Sex (M/F) 9/14 11/12 NS MMSE score ∗ 21.1 ± 4.4 29.4 ± 0.9 < .0001
AD, Alzheimer’s disease patients; HC, healthy controls.
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Table 2
Areas with Significantly ( P < .001, uncorrected) Reduced Globally Normalized GM Density in AD Patients Compared with HC Subjects
Region Location (mm) Extent (voxels) t Value x y z L hippocampus −30 −12 −12 241 4.97 R hippocampus 27 −12 −15 779 4.63 L hippocampus −21 −33 −3 388 4.58 R inferior frontal gyrus 48 6 34 45 4.35 L inferior frontal gyrus −44 20 6 114 4.26 R middle frontal gyrus 23 35 −14 33 4.04 R superior temporal gyrus 38 6 −20 66 3.86 L gyrus rectus 0 60 −15 9 3.82 R hippocampus 24 −33 −5 34 3.78 R inferior frontal gyrus 36 33 13 20 3.71 L thalamus −5 −4 1 30 3.71 R insula 36 6 6 18 3.70 R postcentral gyrus 53 −22 45 21 3.69 R middle temporal gyrus 66 −13 −12 20 3.67 L inferior frontal gyrus −33 38 15 14 3.65 L inferior frontal gyrus −32 29 1 5 3.46 L caudate nucleus −15 20 4 24 3.44 L uncus −21 3 −39 7 3.43 L superior temporal gyrus −39 3 −17 1 3.35 L superior temporal gyrus −45 −54 16 1 3.30
R, right; L, left.
Table 3
Results of Linear Discriminant Analysis Including the Globally Normalized GM Density, nrCBF, and Their Combinations at Different P Values
P Value Sensitivity (%) Specificity (%) Accuracy (%) AUC VBM (Globally normalized GM density) .001 73.9 87.0 80.4 0.779 .0005 69.6 87.0 78.3 0.763 .0001 65.2 78.3 71.7 0.760 ASL (nrCBF) .001 91.3 60.9 80.4 0.875 .0005 91.3 73.9 82.6 0.877 .0001 82.6 73.9 78.3 0.893 .00005 82.6 82.6 82.6 0.872 .00001 82.6 82.6 82.6 0.877 Combined VBM .001 87.0 82.6 84.8 0.919 ASL .0001 Cross-validated 82.6 82.6 82.6 —
ASL, arterial spin labeling; AUC, area under the curve; nrCBF, normalized regional cerebral blood flow; VBM, voxel-based morphometry.
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Table 4
Areas with Significantly ( P < .001, uncorrected) Reduced nrCBF in AD Patients Compared with HC Subjects
Region Location (mm) Extent (voxels) t Value x y z L precuneus −10 −60 38 507 5.73 L posterior cingulate −10 −52 38 114 4.33 R inferior parietal lobule 42 −60 46 208 4.27 R posterior cingulate 4 −49 34 12 3.84 R precuneus 6 −63 40 283 3.77 L precentral −34 2 30 2 3.31 L inferior parietal lobule −54 −60 48 2 3.30
nrCBF, normalized regional cerebral blood flow; R, right; L, left.
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Discussion
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Conclusion
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