Herpes Viruses in the Baltimore Longitudinal Study of Aging

Abstract

Background and Objectives.Although an infectious etiology of Alzheimer’s Disease (AD) has received renewed attention with a particular focus on herpes viruses, the longitudinal effects of symptomatic herpes viruses (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 3T MRI brain volume and cognitive performance. Additionally, we related sHHV to cross-sectional differences in plasma biomarkers of AD (Aβ42/40), astrogliosis (glial fibrillary acidic protein [GFAP]) and neurodegeneration (neurofilament light [NfL]). Baltimore Longitudinal Study of Aging (BLSA) participants were recruited from the community and assessed with serial brain MRIs and cognitive exams over an average of 3.4 (SD=3.2) and 8.6 (SD=7.7) years, respectively. sHHV classification used ICD9 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/year; p = 0.035), particularly in the temporal lobe. However, there was no association between sHHV and change in total brain, total gray matter, or AD signature region volume. 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). Additionally, 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.

Common infections and neuroimaging markers of dementia in three UK cohort studies

“… 41 In a study using data from the Baltimore Longitudinal Study of Aging, no associations were found between symptomatic herpesvirus infections and changes in brain volume or AD signature regions, although some associations were reported for other markers of dementia risk, including attentional decline and astrogliosis. 42 Null findings between HSV1 serostatus and whole brain atrophy were additionally reported in a cohort with parental history of early‐onset autosomal dominant AD. 43 In contrast, relationships between higher seroreactivity to HSV (either 1 or 2) and smaller hippocampal volume were reported in an analysis involving two small cohorts ( N = 349).…”

“…For example, serostatuses for C. pneumoniae , H. pylori , and CMV were not associated prospectively with dementia risk, whole brain volume, or white matter lesions in the Framingham cohort study 41 . In a study using data from the Baltimore Longitudinal Study of Aging, no associations were found between symptomatic herpesvirus infections and changes in brain volume or AD signature regions, although some associations were reported for other markers of dementia risk, including attentional decline and astrogliosis 42 . Null findings between HSV1 serostatus and whole brain atrophy were additionally reported in a cohort with parental history of early‐onset autosomal dominant AD 43 .…”

Common infections and neuroimaging markers of dementia in three UK cohort studies

“…41 In a study using data from the Baltimore Longitudinal Study of Aging, no associations were found between symptomatic herpesvirus infections and changes in brain volume or AD signature regions, although some associations were reported for other markers of dementia risk, including attentional decline and astrogliosis. 42 Null findings between HSV1 serostatus and whole brain atrophy were additionally reported in a cohort with parental history of earlyonset autosomal dominant AD. 43 In contrast, relationships between higher seroreactivity to HSV (either 1 or 2) and smaller hippocampal volume were reported in an analysis involving two small cohorts (N = 349).…”