Herpes Viruses in the Baltimore Longitudinal Study of Aging: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers

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 Aβ_42/40 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.

Figure 1. Study Design and Participant Selection

BLSA = Baltimore Longitudinal Study of Aging; ICD-9 = International Classification of Diseases, Ninth Revision; sHHV = symptomatic human herpes virus.

Figure 2. Estimated Changes in Total Brain, AD Signature Region, White Matter and Temporal White Matter Volumes (cm³) Associated With sHHV Diagnoses

Estimated volumes derived from linear mixed-effects models were adjusted for baseline intracranial volume, age, sex, race, education, APOEε4, comorbidity index (i.e., obesity, hypertension, diabetes, cancer, ischemic heart disease, chronic heart failure, chronic kidney disease, and chronic obstructive pulmonary disease), and 2-way interactions of age, sex, race, education, APOEε4, and comorbidity index with time. βs and corresponding p values represent adjusted differences in estimated annual brain volume changes between groups (sHHV+/−). AD = Alzheimer disease; sHHV = symptomatic human herpes virus.

Figure 3. Estimated Changes in Attention, Executive Function, Verbal Memory, and Attention (as a Function of Age) Composite Scores Associated With sHHV Diagnoses

Estimated scores from linear mixed-effects models were adjusted for age, sex, race, education, APOEε4, comorbidity index (i.e., obesity, hypertension, diabetes, cancer, ischemic heart disease, chronic heart failure, chronic kidney disease, and chronic obstructive pulmonary disease), and 2-way interactions of age, sex, race, education, APOEε4, and comorbidity index with time. βs and corresponding p values represent adjusted differences in estimated annual composite score changes between groups (sHHV+/−). sHHV = symptomatic human herpes virus.

Figure 4. Plasma Biomarkers (Standardized Values) Associated With sHHV Diagnoses

Results derived from independent samples t tests. Aβ_42/40 = amyloid-β_42/40 ratio; GFAP = glial fibrillary acidic protein; NfL = neurofilament light; sHHV = symptomatic human herpes virus.