Coupling relationship between glucose and oxygen metabolisms to differentiate preclinical Alzheimer's disease and normal individuals

Changchang Ding, Wenying Du, Qi Zhang, Luyao Wang, Ying Han, Jiehui Jiang, Changchang Ding, Wenying Du, Qi Zhang, Luyao Wang, Ying Han, Jiehui Jiang

Abstract

The discovery of preclinical Alzheimer's disease (preAD) provides a wide time window for the early intervention of AD. The coupling relationships between glucose and oxygen metabolisms from hybrid PET/MRI can provide complementary information on the brain's physiological state for preAD. In this study, we purpose to explore the change of coupling relationship among 27 normal controls (NCs), 20 preADs, and 15 cognitive impairments (CIs). For each subject, we calculated the Spearman partial correlation between the fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) from functional image (fMRI), and the standard uptake value ratio (SUVR) from [18F] fluorodeoxyglucose positron emission tomography (18 F-FDG PET), in the whole-brain and default mode network (DMN) as a novel potential biomarker. The diagnostic performance of this biomarker was evaluated by the receiver operating characteristic analysis. Significant Spearman correlations between the FDG SUVR and the fALFF/ReHo were found in 98% of subjects. For the DMN-based biomarker, there was a significant decreasing trend for the preAD and CI groups compared to the NC group, whereas no significant difference in preAD based on whole-brain. The correlation ρ value for the FDG SUVR/ReHo showed the highest area under curve of the preAD classification (0.787). The results imply the coupling relationship changed during the preAD stage in the DMN area.

Trial registration: ClinicalTrials.gov NCT03370744.

Keywords: default mode network; functional magnetic resonance imaging; position emission tomography; preclinical Alzheimer's disease.

Conflict of interest statement

The authors declare no conflict of interest that is directly relevant or directly related to the work described in this manuscript.

© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
Voxel‐based spatial distribution differences among groups. Figure shows Montreal Neurological Institute (MNI) surface rendering with both transverse views, overlaid with results from between‐group statistical analysis using NC > CI contrast. Default mode network (DMN) is main area where CI decreases glucose metabolism and functional activities. Area of metabolic decline (FDG SUVR) in CI group compared with NC group (a), expressed as z‐scores (p < .05) and are corrected for Gaussian random field (GRF) correction method (voxel level p < .01, cluster level p < .05). The results of ReHo (b) and fALFF (c) were significant (cluster >30) without GRF correction. CI, cognitive impairment; FDG, fluorodeoxyglucose; fALFF, fractional amplitude of low‐frequency fluctuations; IPL, inferior parietal lobule; ITG, inferior temporal gyrus; MTG, middle temporal gyrus; NC, normal control; PCC, posterior cingulate cortex; ReHo, regional homogeneity; SUVR, standardized uptake value ratio
FIGURE 2
FIGURE 2
Resting‐state correlation between FDG SUVR and fMRI indicators within gray matter voxels in individual subjects (all 62). (a) Spearman rank correlation between FDG SUVR and fALFF in normal control (NC), preclinical Alzheimer's disease (preAD), and cognitive impairment (CI) at global brain level, respectively. (b) Same as (a), except that correlation is based on SUVR and ReHo. (c) Same as (a) but at default mode network (DMN) level instead of global brain. (d) Same as (b) but at DMN level instead of entire brain. FDG, fluorodeoxyglucose; fALFF, fractional amplitude of low‐frequency fluctuations; ReHo, regional homogeneity; SUVR, standardized uptake value ratio. *p < .05, **p < .01, ***p < .001
FIGURE 3
FIGURE 3
Location of high coupling and low coupling regions based on AAL template. The cold color shows low coupling region, and the warm color shows high coupling region. (a) The coupling strength of SUVR/fALFF (ρ) in NC and preAD groups. (b) The coupling strength of SUVR/ReHo (ρ) in NC and preAD groups. AAL, Anatomical Automatic Labeling; fALFF, fractional amplitude of low‐frequency fluctuations; NC, normal control; preAD, preclinical Alzheimer's disease; ReHo, regional homogeneity; SUVR, standardized uptake value ratio
FIGURE 4
FIGURE 4
Correlation between Amyloid‐β (Aβ) and FDG‐PET/fMRI correlation metrics. These figures depict partial correlation between FDG‐PET/fMRI correlation metrics and AV45 SUVR in cognitively normal and entire disease development population, respectively, which has statistical significance (p < .05). (a–c) figures show partial correlation between global SUVR/ReHo (ρ), DMN SUVR/fALFF (ρ), and DMN SUVR/ReHo (ρ) and AV45 SUVR, respectively, in cognitively normal group (NC + preAD). (d–f) figures are same as (a–c) but for entire disease development population (NC + preAD + CI). CI, cognitive impairment; DMN, Default Mode Network; FDG, fluorodeoxyglucose; fALFF, fractional amplitude of low‐frequency fluctuations; NC, normal control; preAD, preclinical Alzheimer's disease; ReHo, regional homogeneity; SUVR, standardized uptake value ratio
FIGURE 5
FIGURE 5
Receiver operating characteristic (ROC) curves. (a) ROC curves of fALFF, ReHo, DMN SUVR/fALFF (ρ) and SUVR/ReHo (ρ) between NC and preAD groups at global brain level. (b) ROC curves of fALFF, ReHo, DMN SUVR/fALFF (ρ) and SUVR/ReHo (ρ) between NC and CI groups at global brain level. (c) Same as (a) but at DMN level. (d) Same as (b) but at DMN level. CI, cognitive impairment; DMN, Default Mode Network; fALFF, fractional amplitude of low‐frequency fluctuations; NC, normal control; preAD, preclinical Alzheimer's disease; SUVR, standardized uptake value ratio; ReHo, regional homogeneity
FIGURE 6
FIGURE 6
Receiver operating characteristic (ROC) curve using lasso for clinical information to distinguish NC and preAD. AUC, area under the curve; NC, normal control; preAD, preclinical Alzheimer's disease

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