Cerebral spinal fluid biomarker profiles in CNS infection associated with HSV and VZV mimic patterns in Alzheimer’s disease

Shinomoto, Makiko; Kasai, Takashi; Tatebe, Harutsugu; Kitani-Morii, Fukiko; Ohmichi, Takuma; Fujino, Yuzo; Mizuno, Toshiki; Tokuda, Takahiko

doi:10.1186/s40035-020-00227-w

Cited by 10 publications

(11 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…46 Increased GFAP in CSF has been associated with nonencephalitic sHHV diagnoses. 47,48 In this study, we show that increased plasma GFAP is also associated with herpetic infections. Elevations in this marker of reactive astrogliosis may be attributed to astrocytemediated neuroinflammation precipitated by sHHV infection.…”

Section: Discussionsupporting

confidence: 53%

Herpes Viruses in the Baltimore Longitudinal Study of Aging

Duggan

Peng

et al. 2022

Neurology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 53%

Herpes Viruses in the Baltimore Longitudinal Study of Aging

Duggan

Peng

et al. 2022

Neurology

View full text Add to dashboard Cite

show abstract

“…Notably, there is growing epidemiological and experimental evidence suggest that recurrent HSV infection is a risk factor for Alzheimer’s disease (AD) ( Shinomoto et al., 2021 ; Protto et al., 2022 ), although the underlying molecular and functional mechanisms have not been fully elucidated. Herpes simplex virus is a neurotropic double-stranded DNA virus that primarily infects the epithelial cells of the oral cavity, nasal mucosa, and vagina.…”

Section: Discussionmentioning

confidence: 99%

Understanding global changes of the mouse brain proteome after vaginal infection with HSV-2 using a label-free shotgun approach

Cheng

Wang

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Herpes simplex virus type 2 (HSV-2) is a common human pathogen that establishes lifelong latency in neurons of the nervous system. The number of severe central nervous system infections caused by the virus has increased recently. However, the pathogenesis of HSV-2 infection in the nervous system is not fully understood. Here, we demonstrated global proteomic changes in the brain tissue in BALB/c mice vaginally infected with HSV-2. Data are available via ProteomeXchange with identifier PXD034186. A total of 249 differentially expressed proteins were identified in infected brain tissue. The GO and KEGG enrichment analysis of these proteins indicated that they were mainly involved in the regulation of synapse formation and synaptic excitability. In addition, genes affecting autophagy, the development of other neurodegenerative diseases, and signaling pathways relevant to other neurologic diseases were identified. Additional experiments, comparing the brain tissue of asymptomatic and symptomatic mice showed a differential expression of proteins involved in synapse formation and synaptic transmission. Others were involved in autophagy, addiction, and signaling pathways of other neurologic diseases. These results suggest that changes in synaptic structure and function, as well as autophagy, may be related to the development of neurologic abnormalities that follow HSV-2 infection. We also identified a protein GluN2A encoded by Grin2a was continuously expressed at high levels after infection. We propose that GluN2A may be a key molecule in the pathogenesis of HSV-2-induced neurologic diseases.

show abstract

“…Previous studies suggested that viral encephalitis was an important exception of CSF p-tau181 elevation. 28,29 Krut et al reported that patients with herpes-simplex virus type 1 (HSV-1) encephalitis showed increased CSF p-tau181 and t-tau along with decreased CSF Aβ42. 28 As previous in vitro studies showed that the HSV-1 virus could induce hyperphosphorylation of tau, 41,42 possibly through the activation of phosphokinases such as GSK3β, 42 the authors suggested that an increase of CSF p-tau181 could be due to the direct effect of HSV-1.…”

Section: Discussionmentioning

confidence: 99%

“…Although encephalitis is known to cause transient CSF p-tau181 elevation 28,29 and the subsets of NIID patients are known to experience encephalitic/stroke-like attacks, 10,11 CSF p-tau181 levels of patients with or without a history of encephalitic/stroke-like attacks were also comparable (74.1 ± 20.1 vs 72.3 ± 27.3 pg/mL). In patient 7, CSF was available at baseline, during the remission phase, and one day after an encephalitic attack four years later as a followup.…”

Section: Csf Follow-up In One Niid Patient After Encephalitic Episode...mentioning

confidence: 95%

CSF p-tau181 Increases in Patients with Neuronal Intranuclear Inclusion Disease without Amyloid Burden

Kurihara

Komatsu

Sengoku

et al. 2022

Preprint

View full text Add to dashboard Cite

Background and Objectives: CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer's disease (AD) and has recently been regarded to reflect amyloid-beta (Aβ) and/or p-tau deposition in the AD brain. Although it is important to know how this biomarker reacts in other neurocognitive diseases, CSF p-tau181 in patients with neuronal intranuclear inclusion disease (NIID) has not been studied. Methods: CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with symptomatic AD biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in six NIID patients. Results: CSF p-tau181 concentration was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared to DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 NIID patients (91.7%). Within these patients, only two patients showed decreased CSF Aβ42. PiB PET scans were negative in all 6 patients tested including 2 patients showing decreased CSF Aβ42. CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared to disease controls. Discussion: CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

show abstract

Cerebral spinal fluid biomarker profiles in CNS infection associated with HSV and VZV mimic patterns in Alzheimer’s disease

Cited by 10 publications

References 10 publications

Herpes Viruses in the Baltimore Longitudinal Study of Aging

Herpes Viruses in the Baltimore Longitudinal Study of Aging

Understanding global changes of the mouse brain proteome after vaginal infection with HSV-2 using a label-free shotgun approach

CSF p-tau181 Increases in Patients with Neuronal Intranuclear Inclusion Disease without Amyloid Burden

Contact Info

Product

Resources

About