MRI free water mediates the association between diffusion tensor image analysis along the perivascular space and executive function in four independent middle to aged cohorts

Abstract

Introduction: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was proposed for assessing glymphatic clearance function. This study evaluated DTI-ALPS as a biomarker for cerebral small vessel disease (cSVD) related vascular cognitive impairment and dementia (VCID).

Methods: Four independent cohorts were examined. A composite score of executive function (UDS3-EF) was used to evaluate EF status. The association between the ALPS index and UDS3-EF scores and the mediator effect of free water in white matter (WM-FW) on such association was analyzed.

Results: The ALPS index was significantly associated with UDS3-EF scores in all cohorts. Additionally, WM-FW mediates the relationship between the ALPS index and UDS3-EF scores.

Discussion: Lower ALPS index may be a surrogate marker of glymphatic dysfunction, which is associated with impaired EF, and this association is mediated by the interstitial fluid (ISF) drainage ISF in WM, providing a clinical rationale for using ALPS index as a biomarker for cSVD-related VCID.

Highlights: This is the first study to investigate the mediation role of interstitial FW fraction (WM-FW) on the relationship between glymphatic clearance (ALPS index) and EF (UDS3-EF scores) in four independent middle to aged cohorts at risk for cSVD. This study identified that ALPS index was independently associated with UDS3-EF scores after adjusting for demographics, VRFs, and WM hyperintensity burden and that WM-FW mediated this association in all middle to aged cohorts. Our findings suggest that in middle to aged individuals, glymphatic dysfunction (reflected by ALPS index) is strongly associated with EF and that this association is mediated by the ISF drainage in WM. This study provides a strong clinical rationale for the use of the ALPS index as a marker of cognitive function in multi-site observational studies and clinical trials to monitor and prevent VCID.

Keywords: cerebral small vessel disease (cSVD); diffusion tensor image analysis along the perivascular space index (DTI‐ALPS); free water (FW); glymphatic system (GS); vascular cognitive impairment and dementia (VCID).

FIGURE 1

Cross‐sectional association between the diffusion analysis along PVS (ALPS) index and the validated UDS3‐EF in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). Scatter plots show a significantly positive correlation between the ALPS index and residualized UDS3‐EF scores for multiple linear regression Model 1, adjusted by demographics, that is, age, gender, and education in all four cohorts (MarkVCID, p < 0.01; UCD_ADRC, p < 0.05; UCSF_MAC, p < 0.001; FHS, p < 0.001). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; PVS, perivascular space; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; VRFs, vascular risk factors; WMHV, white matter hyperintensity volume.

FIGURE 2

Cross‐sectional association between the diffusion analysis along PVS (ALPS) index and the validated UDS3‐EF in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). Scatter plots show a significantly positive correlation between the ALPS index and residualized UDS3‐EF scores for multiple linear regression Model 2, adjusted by additional VRFs that is, the presence of diabetes, hypertension, and smoking to Model 1 in all four cohorts (MarkVCID, p < 0.05; UCD_ADRC, p < 0.05; UCSF_MAC, p < 0.001; FHS, p < 0.001). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; PVS, perivascular space; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; VRFs, vascular risk factors; WMHV, white matter hyperintensity volume.

FIGURE 3

Cross‐sectional association between the diffusion analysis along PVS (ALPS) index and the validated UDS3‐EF in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). Scatter plots show a significantly positive correlation between the ALPS index and residualized UDS3‐EF scores for multiple linear regression Model 3, adjusted by additional WMHV to Model 2 in all four cohorts (MarkVCID, p < 0.05; UCD_ADRC, p = 0.054; UCSF_MAC, p < 0.001; FHS, p < 0.001). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; PVS, perivascular space; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; VRFs, vascular risk factors; WMHV, white matter hyperintensity volume.

FIGURE 4

Mediation analysis between diffusion analysis along PVS (ALPS) index and the validated UDS3‐EF with WM‐FW as a mediator in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). The analysis was performed with covariates of demographics, that is, age, sex, and education (Model 1). The mediation analysis diagrams show a significant indirect effect of WM‐FW on mediating the relationship between ALPS index and UDS3‐EF scores in all four cohorts (MarkVCID cohort, indirect effect β = 0.06, p < 0.001, mediation effect 42.6%; UCD_ADRC cohort, indirect effect β = 0.03, p < 0.05, mediation effect 30.5%; UCSF_MAC cohort, indirect effect β = 0.08, p < 0.01, mediation effect 29.4%; FHS cohort, indirect effect β = 0.03, p < 0.05, mediation effect 41.4%). There's a significant direct effect of the ALPS index on UDS3‐EF scores in the UCSF_MAC cohort (direct effect β = 0.15, p < 0.05) and FHS cohort (direct effect β = 0.04, p < 0.05). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; PVS, perivascular space; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; WM‐FW, mean free water in the white matter.

FIGURE 5

Mediation analysis between diffusion analysis along PVS (ALPS) index and the validated UDS3‐EF with WM‐FW as a mediator in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). The analysis was performed with covariates of additional VRFs that is, the presence of diabetes, hypertension, and smoking to Model 1 (Model 2). The mediation analysis diagrams show a significant indirect effect of WM‐FW on mediating the relationship between ALPS index and UDS3‐EF scores in all four cohorts (MarkVCID cohort, indirect effect β = 0.05, p < 0.001, mediation effect 42.4%; UCD_ADRC cohort, indirect effect β = 0.03, p < 0.05, mediation effect 29.4%; UCSF_MAC cohort, indirect effect β = 0.08, p < 0.05, mediation effect 29.4%; FHS cohort, indirect effect β = 0.03, p < 0.001, mediation effect 39.5%). There's a significant direct effect of the ALPS index on UDS3‐EF scores in the FHS cohort (direct effect β = 0.04, p < 0.05). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; PVS, perivascular space; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; VRFs, vascular risk factors; WM‐FW, mean free water in the white matter.

FIGURE 6

Mediation analysis between diffusion analysis along PVS (ALPS) index and the validatedUDS3‐EF with WM‐FW as mediator in MarkVCID cohort (A), UCD_ADRC cohort (B), UCSF_MAC cohort (C), and FHS cohort (D). The analysis was performed with covariates of additional WMHV to Model 2 (Model 3). The mediation analysis diagrams show a significant indirect effect of WM‐FW on mediating the relationship between ALPS index and UDS3‐EF scores in all four cohorts (MarkVCID cohort, indirect effect β = 0.05, p < 0.01, mediation effect 41.4%; UCD_ADRC cohort, indirect effect β = 0.02, p < 0.001, mediation effect 26.1%; UCSF_MAC cohort, indirect effect β = 0.07, p < 0.05, mediation effect 32.0%; FHS cohort, indirect effect β = 0.03, p < 0.001, mediation effect 38.6%). There's a significant direct effect of the ALPS index on UDS3‐EF scores in the FHS cohort (direct effect β = 0.04, p < 0.05). ALPS, diffusion analysis along the perivascular space; FHS, Framingham Heart Study; UCD_ADRC, University of California Davis Alzheimer's Disease Research Center; UCSF_MAC, University of California San Francisco Memory and Aging Center; UDS3‐EF, composite scores of executive functions derived from the Uniform Data Set (v3.0); VCID, vascular cognitive impairment and dementia; WM‐FW, mean free water in the white matter; WMHV, white matter hyperintensity volume.