Table 1.
Participant baseline characteristics.
Fig 1.
The global BOLD signal is coupled with CSF changes.
(A) The global BOLD signal was averaged across the gray matter regions (the green mask on an exemplary T1-weighted image in the left panel), whereas the CSF signal was extracted from the CSF regions at the bottom slice of the fMRI acquisition (the middle and right panel). The CSF appears much brighter than the surrounding areas in the T2*-weighted fMRI image (the right panel). (B) The global BOLD signal and the CSF signal from a representative participant showed corresponding changes (indicated by black arrows). We also included a different version of the global BOLD signal in percentage changes to show the amplitude of signal fluctuation (S12A Fig). (C) The cross-correlation function between the global BOLD signal and the CSF signal averaged across 158 sessions (upper) and the one between the negative derivative of global BOLD signal and the CSF signal (lower). The gray shaded region denotes 95% confidence intervals calculated with shuffled signals (see Materials and methods for details; see S12B Fig for all the 158 cases and their standard deviation (SD) of the BOLD–CSF cross-correlation function). Gray dashed lines in the shaded region shows mean correlation of the null distribution from permutation test at each time lag. Error bar in this figure represents the SEM. These cross-correlation functions show a very similar shape to those reported in the previous study [48]. The cross-correlation (−0.17, p < 0.0001, permutation test) at the +3-second lag (red dashed line), which also showed the strongest coupling in the previous study [48], was used for quantifying the BOLD–CSF coupling for subsequent analyses. The data underlying this figure can be found in S1 Data. BOLD, blood oxygen level–dependent; CSF, cerebrospinal fluid; fMRI, functional magnetic resonance imaging; SEM, standard error of the mean.
Fig 2.
The dependency of the BOLD–CSF coupling on AD risk factors and disease conditions.
(A) The strength of the BOLD–CSF coupling, quantified as the correlation between the global BOLD signal and CSF at +3-second lag, shows a significant correlation (Spearman’s r = 0.24, p = 0.011, the linear mixed model with Satterthwaite method) with age across the 158 sessions. The linear regression line was estimated based on the linear least-squares fitting [49]. (B) Male participants showed a larger amplitude of the BOLD–CSF coupling as compared with females (p = 0.026). (C) The BOLD–CSF coupling, after adjusting for age and gender, decreases gradually (p = 0.035) from the HCs, to SMC, to the MCI, and then to AD group. (D) The age- and gender-adjusted BOLD–CSF coupling is also marginally (p = 0.077) correlated with the APOE ε4 allele. Error bar in this figure represents the SEM. The sample sizes of each subgroups are shown by numbers on the bars of the bar plots. The data underlying this figure can be found in S1 Data. The analysis was repeated for an augmented sample with more AD patients and HCs; see S1 Fig for the results. AD, Alzheimer disease; APOE, apolipoprotein E; BOLD, blood oxygen level–dependent; CSF, cerebrospinal fluid; HC, healthy control; MCI, mild cognitive impairment; SEM, standard error of the mean; SMC, significant memory concern.
Fig 3.
The BOLD–CSF coupling is correlated with the cortical Aβ and cognitive decline.
(A, B) The BOLD–CSF coupling adjusted for age and gender is significantly correlated (Spearman’s r = 0.20, p = 0.019, N = 158, the linear mixed model with Satterthwaite method) with the cortical Aβ SUVRs at baseline (A) but not their changes in the following 2 years (B). (C, D) The BOLD–CSF coupling adjusted for age and gender is significantly correlated (Spearman’s r = −0.20, p = 0.013, N = 158) with the MMSE score changes in the following 2 years (D) but not with its baseline value (C). Each dot represents a single session. AD, MCI, SMC, and HC sessions are colored with blue, light gray, dark gray, and orange, respectively. The data underlying this figure can be found in S1 Data. Aβ, amyloid-β; AD, Alzheimer disease; BOLD, blood oxygen level–dependent; CSF, cerebrospinal fluid; HC, healthy control; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; SMC, significant memory concern; SUVR, standardized uptake value ratio.
Fig 4.
The role of global BOLD amplitude in the associations between BOLD–CSF coupling and AD-related markers.
(A) The strength of the BOLD–CSF coupling is dependent (Spearman’s r = −0.23, p < 0.001, N = 158 sessions) on the fluctuation amplitude of the global BOLD signal after adjusting for age and gender. (B, C) The amplitude of the global BOLD signal, adjusted for age and gender, is not significantly correlated (p > 0.13) with either the cortical Aβ level (B) or the 2-year longitudinal change of MMSE score (C). (D, E) The BOLD–CSF coupling remains significantly correlated (p < 0.05) with the cortical Aβ level (D) and the MMSE changes (E) after adjusting for age, gender, and global BOLD amplitude. Each dot represents a single session. AD, MCI, SMC, and HC sessions are colored with blue, light gray, dark gray, and orange, respectively. The data underlying this figure can be found in S1 Data. Aβ, amyloid-β; AD, Alzheimer disease; BOLD, blood oxygen level–dependent; CSF, cerebrospinal fluid; HC, healthy control; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; SMC, significant memory concern; SUVR, standardized uptake value ratio.