White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease

Abstract

Objective: Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).

Methods: Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.

Results: Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.

Conclusion: These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

Figure 1. Timeline shows the design of the BIOCARD study

Symbols indicate the types of data collected for the BIOCARD study each year (from 1995 to 2017). PiB = Pittsburgh compound B.

Figure 2. Kaplan-Meier plot shows the proportion of participants who remain symptom-free as a function of baseline level of CSF total tau (t-tau) and white matter hyperintensity (WMH) load

The survival plot shows the interaction between baseline CSF t-tau and WMH load with respect to the time to symptom onset. The x-axis shows time since baseline and the y-axis represents the proportion of participants remaining without symptoms. There was no significant difference in survival time between participants with high t-tau and high WMH load (red line) compared with those with high t-tau and low WMH load (green line). However, among participants with low CSF t-tau, those with high WMH load (blue line) were more likely to become symptomatic than those with low WMH load (purple line); see Results for details. Note that the survival curves are not adjusted for age, sex, or education.