Translational Neurodegeneration | 2021
Cerebral spinal fluid biomarker profiles in CNS infection associated with HSV and VZV mimic patterns in Alzheimer’s disease
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. Although AD was initially considered to be a cell autonomous neurodegenerative disorder, marked neuroinflammation has been observed in brains of AD patients. Genetic and molecular biological findings have suggested the central nervous system (CNS) inflammatory processes to be involved in the etiopathogenesis of AD, in which the activated microglia play a key role. This has also been supported by epidemiological observation that CNS infections are associated with the development of AD, and the relationship between herpes simplex virus (HSV)-1 and AD has been particularly well investigated [1]. For example, the presence of anti-HSV antibody is associated with an elevated risk of AD [2]. Anti-herpetic medication is associated with a reduced risk of dementia in a population-based study [1]. Similar results have also been observed in varicella zoster virus (VZV) infections [3]. In this study, we enrolled 9 patients with HSV infection of the CNS, 8 patients with herpes zoster complicated by CNS involvement, and 18 agematched control patients presenting with neither CNS infection nor dementia, and measured cerebral spinal fluid (CSF) levels of Aβ1–42, Aβ1–40, total-tau (t-tau), and phosphorylated tau at threonine 181 (p-tau) as the AD signature; neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (p-NfH) as indicators of axonal injury; soluble triggering receptor expressed on myeloid cells 2 (sTREM2) as a potential biomarker for microglial activity; and glial fibrillary acidic protein (GFAP) as a biomarker for astrocytic damage. We also measured serum levels of NfL as a bloodbased biomarker for axonal injury. Detailed methods are provided in Supplementary Methods. There was no significant difference in age or sex among the HSV, VZV, and control groups (Table S1). The raw data on biomarkers are presented in Table S2. We found that the levels of CSF Aβ1–42, Aβ1–40, and the Aβ1–42/Aβ1–40 ratio were significantly lower in the HSV + VZV combined group (HSV/VZV) compared with the control group (p = 0.01836, 0.0380, and 0.0262, respectively) (Fig. 1a–c). The CSF t-tau, p-tau, sTREM2, and GFAP levels were significantly elevated in the HSV/VZV group compared with the control group (p = 0.0043, 0.0007, 0.0030, and 0.0139, respectively) (Fig. 1d, e, i, and j). These results correspond to previous reports showing significantly decreased Aβ1–42, increased t-tau, and increased p-tau in CSF of patients with HSV encephalitis [4, 5]. The CSF p-tau/t-tau, CSF NfL, CSF p-NfH and serum NfL levels did not significantly differ between the HSV/ VZV and control groups (Fig. 1f, g, h, and k). Comparison among the HSV, VZV and control groups showed that the elevation of CSF p-tau was significant in the VZV group while the level of CSF t-tau was elevated specifically in the HSV group (Supplementary Fig. S1). The other biomarkers showed similar trends to those in comparison between HSV/VZV and the control groups. Results of uniand multivariate regression analyses between those biomarker values and clinical severity are summarized in Supplementary Table S3. The negative correlations between Glasgow coma scale and NfL in