The identification and cognitive correlation of perfusion patterns measured with arterial spin labeling MRI in Alzheimer's disease

Abstract

Background: Vascular dysfunction, including cerebral hypoperfusion, plays an important role in the pathogenesis and progression of Alzheimer's disease (AD), independent of amyloid and tau pathology. We established an AD-related perfusion pattern (ADRP) measured with arterial spin labeling (ASL) MRI using multivariate spatial covariance analysis.

Methods: We obtained multimodal MRI including pseudo-continuous ASL and neurocognitive testing in a total of 55 patients with a diagnosis of mild to moderate AD supported by amyloid PET and 46 normal controls (NCs). An ADRP was established from an identification cohort of 32 patients with AD and 32 NCs using a multivariate analysis method based on scaled subprofile model/principal component analysis, and pattern expression in individual subjects was quantified for both the identification cohort and a validation cohort (23 patients with AD and 14 NCs). Subject expression score of the ADRP was then used to assess diagnostic accuracy and cognitive correlations in AD patients and compared with global and regional cerebral blood flow (CBF) in specific areas identified from voxel-based univariate analysis.

Results: The ADRP featured negative loading in the bilateral middle and posterior cingulate and precuneus, inferior parietal lobule, and frontal areas, and positive loading in the right cerebellum and bilateral basal areas. Subject expression score of the ADRP was significantly elevated in AD patients compared with NCs (P < 0.001) and showed good diagnostic accuracy for AD with area under receiver-operator curve of 0.87 [95% CI (0.78-0.96)] in the identification cohort and 0.85 in the validation cohort. Moreover, there were negative correlations between subject expression score and global cognitive function and performance in various cognitive domains in patients with AD. The characteristics of the ADRP topography and subject expression scores were supported by analogous findings obtained with regional CBF.

Conclusions: We have reported a characteristic perfusion pattern associated with AD using ASL MRI. Subject expression score of this spatial covariance pattern is a promising MRI biomarker for the identification and monitoring of AD.

Keywords: Alzheimer’s disease; Arterial spin labeling; Cerebral blood flow; Principal component analysis; Scaled subprofile model.

Fig. 1

Regional topographies of ADRP measured with ASL MRI. The ADRP was identified by combining PC1 and PC2 from SSM/PCA in AD patients and NCs in the identification cohort. Cool color indicates regions with decreased loading, and warm color indicates regions with increased loading. The pattern was overlaid onto a standard MRI brain template to display voxels that were reliable at P < 0.001 based on the bootstrapping algorithm. MCC middle cingulate cortex, PCC posterior cingulate cortex

Fig. 2

Regional CBF changes in patients with AD from univariate analysis without adjusting for the global value in the identification cohort. Cool color indicates regions with decreased CBF in AD patients compared with NCs. A threshold of 3.23 (P < 0.001, uncorrected) was used to overlay SPM maps onto a standard MRI brain template. PCC posterior cingulate cortex

Fig. 3

Regional changes in relative CBF after ANCOVA normalization for the global value in patients with AD in the identification cohort. Cool color indicates regions with relative decreased CBF, and warm color indicates regions with relative increased CBF in AD patients compared to NCs. A threshold of 3.23 (P < 0.001, uncorrected) was used to overlay SPM maps onto a standard MRI brain template. MCC middle cingulate cortex, PCC posterior cingulate cortex

Fig. 4

Subject expression score of ADRP in distinguishing patients with AD from NCs. A Comparison of subject expression score between the AD group and the NC group in the identification cohort. B ROC curve of subject expression score for discrimination between patients with AD and NCs. The AUC value was 0.87 at a cutoff of 1.7 in subject expression score, with a sensitivity of 68.75% and a specificity of 96.88%. In the validation cohort, comparison of subject expression score (C) and its ROC curve (D) for discrimination between patients with AD and NCs. The AUC value was 0.85 at a cutoff of 0.9 in subject expression score, with a sensitivity of 78.26% and a specificity of 78.57%. ***P < 0. 001. ADRP AD-related CBF pattern, ROC receiver operating characteristic, AUC area under the curve

Fig. 5

Difference in global CBF value and relative CBF values for five sample regions between the AD group and the NC group in the identification cohort. A The comparison of global value between AD patients and NCs from the CBF map. B–F The comparisons of relative values in the right precuneus (3, − 66, 44), left posterior cingulate (− 2, − 48, 32), left inferior parietal lobule (− 36, − 62, 45), right inferior parietal lobule (53, − 41, 51), and right inferior temporal gyrus (59, − 44, − 15) between AD patients and NCs, obtained post hoc within a spherical volume of interest (4 mm radius). *P < 0.01; ***P < 0.001

Fig. 6

The correlation between ADRP subject expression and cognitive function in patients with AD. Subject expression score negatively correlated with global cognition measured with the MMSE (A), and various cognitive domains, including attention and information processing speed (C), executive function (D), language (E), and visuospatial function (F) in all AD patients from both the identification cohort and the validation cohort. There was no correlation between subject expression score and memory (B) domain in all AD patients, although a negative correlation was shown in the identification cohort. Raw scores were converted to z-scores for both global cognition and different cognitive domains. Data for cognitive domains was missing from 3 AD patients in the identification cohort