The Effects of Cerebrovascular Reactivity on the Coupling Between CSF Dynamics and Global Neurovascular Fluctuations in the Alzheimer's Disease Continuum

BACKGROUND: Mounting evidence revealed that the weakened coupling between CSF flow and global brain activity (gBOLD-CSF coupling) is associated with Alzheimer's Disease (AD) pathology and cognitive impairments. However, the mechanisms underlying this weakened coupling remain unclear. PURPOSE: To investigate the region-specific effects of cerebrovascular reactivity (CVR) on the gBOLD-CSF coupling. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-eight cognitively normal controls (70.2 ± 8.7 years; 128 female, 70 male), 115 mild cognitive impairment patients (73.1 ± 7.1 years; 50 female, 65 male), and 24 dementia patients (75 ± 9.3 years; 14 female, 10 male) from ADNI. FIELD STRENGTH/SEQUENCE: 3 T gradient-echo blood-oxygenation-level-dependent (BOLD). ASSESSMENT: gBOLD-CSF coupling and CVR maps were respectively derived from resting-state fMRI. The former reflects the temporal coordination between CSF dynamics and global neurovascular fluctuations, while the latter quantifies the capacity of vessels to dilate or constrict. AD-related clinical scales including Aβ-PET, tau-PET, and cognitive assessments were also involved. STATISTICAL TESTS: Linear regression models were employed to examine the association of gBOLD-CSF coupling with AD-related clinical scales and with CVR of major cerebral arteries. Mediation analyses were employed to investigate the potential pathways linking these metrics. p < 0.05 was considered significant. RESULTS: gBOLD-CSF coupling was significantly associated with cognitive assessments (CDR Global: β = 0.366; ADAS-Cog: β = 10.613), accumulation of cortical summary Aβ (β = 37.937) and tau in Braak stage ROIs (Braak I-II: β = 0.444; Braak III-IV: β = 0.565; Braak V-VI: β = 0.474). Analysis also revealed the regional differences in the association of gBOLD-CSF coupling with CVR. CVR, especially in posterior cerebral arteries (PCA) region, was significantly associated with gBOLD-CSF coupling (β = -0.313). The gBOLD-CSF coupling, both directly and through its effect on the accumulation of Aβ and tau, mediated the association between CVR and cognition. DATA CONCLUSION: Data revealed a significant CVR-coupling association in the PCA region and potential pathways linking CVR, gBOLD-CSF coupling, AD pathology, and cognition, providing deeper insights into weakened gBOLD-CSF coupling in AD. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.