White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease
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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.
Glossary
- Aβ1–42=
- β-amyloid 1–42;
- AD=
- Alzheimer disease;
- CDR=
- Clinical Dementia Rating;
- CI=
- confidence interval;
- FLAIR=
- fluid-attenuated inversion recovery;
- GPB=
- Geriatric Psychiatry Branch;
- HR=
- hazard ratio;
- JHU=
- Johns Hopkins University;
- MCI=
- mild cognitive impairment;
- NIA=
- National Institute on Aging;
- p-tau=
- phosphorylated tau;
- t-tau=
- total tau;
- WMH=
- white matter hyperintensities
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
BIOCARD Research Team coinvestigators are listed in the appendix at the end of the article.
- Received January 15, 2019.
- Accepted in final form August 30, 2019.
- © 2019 American Academy of Neurology
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Letters: Rapid online correspondence
- Reader response: White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease
- Vinod K. Gupta, Physician-Medical Director, Migraine-Headache Institute, Gupta Medical Center (New Delhi, India)
Submitted January 08, 2020
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