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Abstract
Background and Objectives Although an infectious etiology of Alzheimer disease (AD) has received renewed attention with a particular focus on herpes viruses, the longitudinal effects of symptomatic herpes virus (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers.
Methods We used a longitudinal, community-based cohort to characterize the association of sHHV diagnoses with changes in 3 T MRI brain volume and cognitive performance. In addition, we related sHHV to cross-sectional differences in plasma biomarkers of AD (β-amyloid [Aβ]42/40), astrogliosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light [NfL]). Baltimore Longitudinal Study of Aging participants were recruited from the community and assessed with serial brain MRIs and cognitive examinations over an average of 3.4 (SD = 3.2) and 8.6 (SD = 7.7) years, respectively. sHHV classification used International Classification of Diseases, Ninth Revision codes documented at comprehensive health and functional screening evaluations at each study visit. Linear mixed-effects and multivariable linear regression models were used in analyses.
Results A total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI (mean age = 65.7 years; 54.8% female). Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change −0.34 cm3/y; p = 0.035), particularly in the temporal lobe. However, there was no association between sHHV and changes in total brain, total gray matter, or AD signature region volumes. Among the 119 participants with sHHV, exposure to antiviral treatment attenuated declines in occipital white matter (p = 0.04). Although the sHHV group had higher cognitive scores at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change −0.01 Z-score/year; p = 0.008). In addition, sHHV diagnosis was associated with elevated plasma GFAP, but not related to Aβ42/40 and NfL levels.
Discussion These findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD-specific disease processes.
Glossary
- AD=
- Alzheimer disease;
- Aβ=
- β-amyloid;
- BLSA=
- Baltimore Longitudinal Study of Aging;
- CDT=
- clock-drawing test;
- eGFR=
- estimated glomerular filtration rate;
- GFAP=
- glial fibrillary acidic protein;
- HHV=
- human herpes virus;
- HSV=
- herpes simplex virus;
- ICD-9=
- International Classification of Diseases, Ninth Revision;
- IQR=
- interquartile range;
- MCI=
- mild cognitive impairment;
- MUSE=
- multiatlas region segmentation utilizing ensembles;
- NfL=
- neurofilament light;
- ROI=
- region of interest;
- sHHV=
- symptomatic HHV;
- VZV=
- varicella-zoster virus
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.
Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD, FAAN.
- Received February 11, 2022.
- Accepted in final form June 15, 2022.
- © 2022 American Academy of Neurology
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