Glymphatic system impairment in Alzheimer’s disease: associations with perivascular space volume and cognitive function

Objectives: To investigate glymphatic function in Alzheimer's disease (AD) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations between DTI-ALPS index and perivascular space (PVS) volume, as well as between DTI-ALPS index and cognitive function.

Methods: Thirty patients with PET-CT-confirmed AD (15 AD dementia; 15 mild cognitive impairment due to AD) and 26 age- and sex-matched cognitively normal controls (NCs) were included in this study. All participants underwent neurological MRI and cognitive assessments. Bilateral DTI-ALPS indices were calculated. PVS volume fractions were quantitatively measured at three locations: basal ganglia (BG), centrum semiovale, and lateral ventricle body level. DTI-ALPS index and PVS volume fractions were compared among three groups; correlations among the DTI-ALPS index, PVS volume fraction, and cognitive scales were analyzed.

Results: Patients with AD dementia showed a significantly lower DTI-ALPS index in the whole brain (p = 0.009) and in the left hemisphere (p = 0.012) compared with NCs. The BG-PVS volume fraction in patients with AD was significantly larger than the fraction in NCs (p = 0.045); it was also negatively correlated with the DTI-ALPS index (r = - 0.433, p = 0.021). Lower DTI-ALPS index was correlated with worse performance in the Boston Naming Test (β = 0.515, p = 0.008), Trail Making Test A (β = - 0.391, p = 0.048), and Digit Span Test (β = 0.408, p = 0.038).

Conclusions: The lower DTI-ALPS index was found in patients with AD dementia, which may suggest impaired glymphatic system function. DTI-ALPS index was correlated with BG-PVS enlargement and worse cognitive performance in certain cognitive domains.

Clinical relevance statement: Diffusion tensor image analysis along the perivascular space index may be applied as a useful indicator to evaluate the glymphatic system function. The impaired glymphatic system in patients with Alzheimer's disease (AD) dementia may provide a new perspective for understanding the pathophysiology of AD.

Key points: • Patients with Alzheimer's disease dementia displayed a lower diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, possibly indicating glymphatic impairment. • A lower DTI-ALPS index was associated with the enlargement of perivascular space and cognitive impairment. • DTI-ALPS index could be a promising biomarker of the glymphatic system in Alzheimer's disease dementia.