Magnetic Resonance Images Implicate That Glymphatic Alterations Mediate Cognitive Dysfunction in Alzheimer Disease

Abstract

Objective: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans.

Methods: Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS).

Results: ALPS-indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, and APOE4 genotype covariates in multiple AD-related brain regions (all p < 0.05). Mediation analysis showed that ALPS-index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD-related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation.

Interpretation: Glymphatic system activity may act as a significant mediator in AD-related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS-index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. ANN NEUROL 2023;93:164-174.

FIGURE 1

Schema shows the analysis process and data from two representative participants. (A) Analysis process from initial diffusion‐weighted imaging (DWI) images to calculate analysis along the perivascular space (ALPS) indexes and evaluate the associations with standardized uptake value ratios of amyloid (¹⁸F‐AV‐45) position emission tomography (PET) images and tau (¹⁸F‐APN 1607) PET images. (B) Images and data from 2 representative participants show the ¹⁸F‐AV‐45 PET images, ¹⁸F‐APN 1607 PET images, diffusion tensor imaging (DTI) images, and ALPS‐indexes. AD = Alzheimer disease; ICBM = International Consortium of Brain Mapping; MMSE = Mini‐Mental State Examination; MNI = Montreal Neurological Institute; NC = normal control; y/o = years old.

FIGURE 2

Diffusion tensor image analysis along the perivascular space (ALPS) indexes are correlated with the mean standardized uptake value ratios (SUVRs) of ¹⁸F‐AV‐45 PET images and ¹⁸F‐APN 1607 position emission tomography (PET) images and Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD‐NAB) total scores. (A) ALPS‐indexes showed a significant correlation with CERAD‐NAB total scores after adjusting for age, sex, years of education, and APOE4 genotype (R ² = 0.35, p < 0.01). (B) ALPS‐indexes showed a significant correlation with the mean SUVRs of ¹⁸F‐AV‐45 PET images after adjusting for age, sex, years of education, and APOE4 genotype (R ² = 0.12, p = 0.02). (C) ALPS‐indexes showed a significant correlation with the mean SUVRs of ¹⁸F‐APN 1607 PET images after adjusting for age, sex, years of education, and APOE4 genotype (R ² = 0.27, p < 0.01). Dotted lines indicate the 95% confidence intervals. (D) Combined fitting curves from the SUVRs of the ¹⁸F‐AV‐45 PET image, SUVRs of the ¹⁸F‐APN1607 PET image, ALPS‐indexes, and gray matter volume (GMV) ratios in the precuneus region. The values of regional SUVRs in the ¹⁸F‐AV‐45 PET images and ¹⁸F‐APN1607 PET images were scaled to 0–100%, with 0% representing the minimal value and 100% representing the maximal value. The original ALPS‐indexes and regional GM ratios were reversed, with 100% representing the minimal value and 0% representing the maximal value. This normalization procedure made the higher values of abnormalities in regional SUVRs, GMV ratios, and ALPS‐indexes represent the more severe disease state. AD = Alzheimer disease; NC = normal control.

FIGURE 3

The schema of mediation analysis in the precuneus region and the topographical distribution of diffusion tensor image analysis along the perivascular space (ALPS) indexes as significant mediators after correction for age, sex, years of education and APOE4 genotype. (A). ALPS‐indexes are statistically significant mediators of the relationship between amyloid position emission tomography (PET), tau PET, and cognitive dysfunction in the precuneus. (B, C) The ALPS‐index significantly mediates the relationship between amyloid (A) and tau (B) deposition and cognitive dysfunction. A = anterior; P = posterior; R = right; S = superior. (D) The percent of mediation (Pm) analysis of ALPS‐indexes between regional amyloid and tau deposition and cognition from the indirect mediation analysis. (E) The Pm of ALPS‐indexes between regional amyloid and tau and gray matter volume (GMV) ratios. The significant regions are plotted on the different color bars. Nonsignificant (ns) regions are in white. Background regions are in gray. ACC = anterior cingulate cortex; CERAD‐NAB = Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery; F = frontal; O = occipital; P = parietal; PCC = posterior cingulate cortex; pHP = parahippocampus; PreCu = precuneus; S‐M = sensory–motor cortex; T = temporal.

FIGURE 4

Topographical distribution of diffusion tensor image analysis along the perivascular space (ALPS) indexes as significant mediators after correction for age, sex, years of education, APOE4 genotype, and regional gray matter volume (GMV) ratios. (A, B) The ALPS‐index significantly mediates the relationship between amyloid (A) and tau (B) deposition and cognitive dysfunction after correction for multiple covariates. A = anterior; P = posterior; R = right; S = superior. (C) The percent of mediation (Pm) of ALPS‐indexes between regional amyloid (A) and tau (T) deposition and cognition from the indirect mediation analysis. The significant regions are plotted on the different color bars. Nonsignificant (ns) regions are in white. Background regions are in gray. ACC = anterior cingulate cortex; CERAD‐NAB = Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery; F = frontal; O = occipital; P = parietal; PCC = posterior cingulate cortex; pHP = parahippocampus; PreCu = precuneus; S‐M = sensory–motor cortex; T = temporal.