Association of MRI Indices of Glymphatic System With Amyloid Deposition and Cognition in Mild Cognitive Impairment and Alzheimer Disease

Neurology. 2022 Dec 12;99(24):e2648-e2660. doi: 10.1212/WNL.0000000000201300.


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 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 d = 1.15-1.48; p < 0.001) and FW-WM (Cohen d = 0.73; p < 0.05) and a lower ALPS index (Cohen d = 0.63; p < 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen d = 0.99; p < 0.05) and WM (Cohen d = 0.91; p < 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 (r s = 0.41, p fdr = 0.026), FDG-PET uptake (r s = 0.54, p fdr < 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 (r s = -0.47, p fdr = 0.021) and worse cognitive performances.

Discussion: 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.

MeSH terms

  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Biomarkers
  • Cognition
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / pathology
  • Glymphatic System* / diagnostic imaging
  • Glymphatic System* / pathology
  • Humans
  • Magnetic Resonance Imaging / methods
  • Positron-Emission Tomography / methods


  • Amyloid beta-Peptides
  • Biomarkers