Background and Objectives:The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this system may play a pivotal role in amyloid β (Aβ) accumulation. However, its involvement in Alzheimer’s disease (AD) pathogenesis is not fully understood. Here, we investigated the changes in noninvasive MRI measurements related to the perivascular network in patients with mild cognitive impairment (MCI) and AD. Additionally, we explored the associations of MRI measures with neuropsychological score, PET standardized uptake value ratio (SUVR), and Aβ deposition.Methods:MRI measures, including perivascular space (PVS) volume fraction (PVSVF), fractional volume of free water in white matter (FW-WM), and index of diffusivity along the perivascular space (ALPS index) of patients with MCI, those with AD, and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative database were compared. MRI measures were also correlated with the levels of CSF biomarkers, PET SUVR, and cognitive score in the combined subcohort of patients with MCI and AD. Statistical analyses were performed with age, sex, years of education, and APOE status as confounding factors.Results:In total, 36 patients with AD, 44 patients with MCI, and 31 healthy controls were analyzed. Patients with AD had significantly higher total, WM, and basal ganglia PVSVF (Cohen’s d = 1.15-1.48; p < 0.001), and FW-WM (Cohen’s d = 0.73; p < 0.05) and a lower ALPS index (Cohen’s d = 0.63; p < 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen’s d = 0.99; p < 0.05) and WM (Cohen’s d = 0.91; p < 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 (rs = 0.41, pfdr = 0.026), FDG-PET uptake (rs = 0.54, pfdr < 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 (rs = −0.47, pfdr = 0.021) and worse cognitive performances.Conclusion:Our study indicates that changes in PVS-related MRI parameters occur in MCI and AD, possibly due to impairment of the glymphatic system. We also report the associations between MRI parameters and Aβ deposition, neuronal change, and cognitive impairment in AD.

When analyzing the multi-site diŠusion MRI (dMRI) data, metrics should be harmonized to remove the site eŠect. In this study, we applied the combined association test (ComBat), which used the regression of covariates with an empirical Bayes framework for diŠusion metrics based on diŠusion tensor imaging (DTI), neurite orientation dispersion, and density imaging (NODDI). The results showed that the ComBat could harmonize the site-related eŠects in DTI and NODDI metrics based on multi-site dMRI while preserving the biological information of the participant, such as sex diŠerences and correlation with age. Thus, the ComBat could be applied in large multi-site studies to identify subtle white matter changes.

When analyzing multi-site diffusion MRI (dMRI) data, metrics should be harmonized to remove the site effect. In this study, we applied the combined association test (ComBat), which uses regression of covariates with an empirical Bayes framework, for diffusion metrics based on diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). The results showed that ComBat can harmonize site-related effects in DTI and NODDI metrics based on multi-site dMRI while preserving subject biological information, such as sex differences and correlation with age. Thus, ComBat could be applied in large multi-site studies to identify subtle white matter changes.