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Symptomatic herpes viruses were linked with several neurologic and cognitive features, but not with Alzheimer's disease processes, a longitudinal cohort study showed.

Among older adults who mainly were cognitively normal, herpes virus infection was associated with accelerated tissue loss in brain white matter over time, particularly in the temporal lobe, according to Keenan Walker, PhD, of the NIH National Institute on Aging in Baltimore, and colleagues.

However, there was no association between herpes virus infection and changes in volumes of total brain, total gray matter, or in areas associated with Alzheimer's disease, they reported in

Infection was tied to accelerated longitudinal declines in attention and elevated plasma levels of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytes and neuroinflammation. It was not associated with plasma amyloid-beta 42/40 ratios or neurofilament light (NfL) levels.

"We did not find evidence that herpetic infection is associated with measures of Alzheimer's-specific disease processes, including brain volumes vulnerable to atrophy in Alzheimer's disease, verbal memory performance, and a measure of amyloid plaque burden," Walker told MedPage Today.

Whether infections can trigger Alzheimer's disease has been debated for years, and new research about herpes has fueled the controversy.

"An infectious origin of Alzheimer's disease has received renewed attention, with a particular focus on human herpes viruses and other inflammatory factors," Walker noted. "However, the effects of these viruses on brain structure and cognition over time remain poorly understood, as do their effects on Alzheimer's and neurodegeneration biomarkers."

Earlier studies have identified human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in postmortem Alzheimer's brain tissue samples at levels up to twice as high as non-Alzheimer's samples, leading researchers to speculate whether HHV-6A and HHV-7 DNA could regulate the expression of genes linked to Alzheimer's.

Other investigators have proposed that a combination of herpes simplex virus 1 (HSV-1) and the APOE4 gene may increase Alzheimer's risk. And earlier this month, a lab study suggested could play a role in Alzheimer's by reactivating HSV-1.

Walker and colleagues evaluated 1,009 participants in the Baltimore Longitudinal Study of Aging , 98% of whom were cognitively normal at baseline MRI. Mean baseline age was about 66 and 54.8% were women. Comprehensive cognitive assessments started between 1984 and 1993 and 3T MRIs were initiated in 2009 and 2010. Plasma biomarkers were measured at the time of the initial MRI.

Study visits occurred biannually until 2005, then every 1 to 4 years depending on age. Participants entered the study at different times and had different follow-up periods. Serial brain MRIs occurred over 3.4 years and cognitive exams over 8.6 years, on average.

Medical history reports were used to identify herpes diagnoses. Participants with diagnostic codes that corresponded to chicken pox were not classified as having symptomatic herpes viruses in the study. There was no serological testing for human herpesviruses in the BLSA and the specificity of virus documentation could not be independently verified.

Overall, 119 participants had a record of symptomatic herpes infection. Having an infection was associated with longitudinal reductions in white matter volume (annual additional rate of change -0.34 cm³/year, P=0.035), notably in the temporal lobe. Exposure to antiviral treatment attenuated declines in occipital white matter (P=0.04).

Although participants with a herpes diagnosis had higher cognitive scores at baseline, they showed greater longitudinal reductions in attention performance (annual additional rate of change -0.01 Z-score/year, P=0.008). Infected participants maintained elevated plasma levels of GFAP, an indicator of reactive astrogliosis.

The study had several limitations, the researchers acknowledged. Inaccurate reporting or undiagnosed herpes virus infection may have led to misclassifications. The observational time window to assess relationships with Alzheimer's processes could have been too short, and unmeasured variables may have influenced results.

Despite its limitations, the study indicates that herpes virus is associated with steeper declines in white matter volume and in attention, a cognitive domain particularly vulnerable to disruptions in white matter integrity, Walker and colleagues noted. The results also provide evidence for a link between herpes infection and GFAP.

"These findings highlight the neurobiological correlates of herpetic infection in older adults and suggest potential pathways by which herpetic infection may influence dementia risk," they wrote.

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