Alteration of the glymphatic system in Alzheimer disease compared to non-Alzheimer dementia: a single center PET/MRI study

Background: The glymphatic system clears brain waste via cerebrospinal fluid (CSF) perivascular routes, maintaining homeostasis, but its function is disrupted in neurological disorders such as Alzheimer disease (AD). The diffusion Tensor Imaging along the perivascular spaces (DTI-ALPS, Taoka et al. 2017) index serves as a non-invasive proxy for glymphatic functioning. Aim: This study investigates the association between DTI-ALPS index and structural network alterations in people with dementia depending on amyloid positivity. Methods: 104 subjects underwent brain DWI and amyloid PET scans in a PET/MR integrated system (3T, Siemens Biograph). Eighty-six of them had complete MRI data of enough quality. Of these, one patient was excluded for a diagnosis prone of interpretative bias. The resulting 85 patients were selected for further analyses. Subjects were divided into two groups based on qualitatively evaluated amyloid positivity on PET: 42 AMY+ (sex: 16F, age: 68.16 ± 7.07 years) and 43 AMY- (sex: 15 F, age: 67 ± 9 years). The AMY+ group was represented by AD (57%), PD/PDD/DLB (38%) and CAA (5%). The AMY- group was represented by patients with non-AD-related neurodegenerative diseases and was more heterogeneous. Diffusivity was evaluated at the level of the lateral ventricle body in spherical ROIs placed in projection and associative fibers to obtain the DTI-ALPS index. The ROIs were warped from standard space to DWI space passing through the high-resolution T1w. Whole-brain tractograms were generated through anatomically constrained probabilistic tractography as implemented in MRtrix3. We evaluated information transfer across the structural connectome using the characteristic path length (CPL) index. Results: The AMY+ group exhibited a lower DTI-ALPS index as compared to AMY- group (t = +2,78, p = 0.005). The DTI-ALPS index did not correlate with disease severity and showed a direct correlation with age (younger aged had lower DTI-ALPS index). The CPL was significantly higher in the AMY+ group as compared to the AMY- (t = -2.71, p = 0.006). DTI-ALPS and CPL showed a significant negative association (Spearman’s ρ = -0.37, p = 0.023). Conclusions: The glymphatic system is impaired in people with cognitive decline and positive amyloid PET compared to people with non-AD cognitive decline. The degree of glymphatic dysfunction is associated with impaired global information transfer along the structural connectome.