Cerebrospinal fluid biomarkers in patients with central nervous system infections: a retrospective study

Stefano, Alessandro Di; Alcantarini, Chiara; Atzori, Cristiana; Lipani, Filippo; Imperiale, Daniele; Burdino, Elisa; Audagnotto, Sabrina; Mighetto, Lorenzo; Milia, Maria Grazia; Perri, Giovanni Di; Calcagno, Andrea

doi:10.1017/s1092852919000981

Cited by 22 publications

(23 citation statements)

References 15 publications

(17 reference statements)

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“…On comparing HSV and VZV groups, elevation of p-tau was marked in the VZV group and, while the levels of CSF t-tau were elevated speci cally in the HSV group. These results correspond to previous reports showing signi cantly decreased Aβ1-42, increased t-tau, and increased p-tau in CSF of patients with HSV encephalitis [4,5]. To our best knowledge, this is the rst report of CSF p-tau elevation in patients with CNS VZV infection.…”

Section: Results Of Uni-and Multivariate Regression Analyses Between supporting

confidence: 91%

CSF Biomarker Profiles in CNS Infection Associated with HSV and VZV Mimic Pattern in Alzheimer’s Disease.

Shinomoto¹,

Kasai²,

Tatebe³

et al. 2020

Preprint

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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 is observed in the brains of patients with AD, alongside Aβ and tau pathology. Based on genetic and molecular biological findings, central nervous system (CNS) inflammatory processes have been postulated to be involved in the etiopathogenesis of AD, in which activated microglia play a key role. This has also been supported by the epidemiological observation that CNS infections were associated with the development of AD, and in particular the relationship between herpetic virus and AD has been well-investigated. For example, the presence of anti-herpes simplex virus (HSV) antibody was associated with an elevated risk of developing AD [1]. Moreover, anti-herpetic medication was associated with a reduced risk of dementia in a population-based study [2]. Similar results were also observed in the case of varicella zoster virus (VZV) infections [3]. Taking into consideration the reports above, we hypothesized that the biomarker signature representing AD might be observed in patients with herpetic viral CNS infections as a prognostic biomarker of AD development. In the current study, we aimed to determine whether or not the biomarkers related to AD and neurodegeneration were changed in patients with CNS infection by HSV and VZV compared with controls. This study focused on CSF levels of Aβ1-42, Aβ1-40, total-tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) as molecules representing 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 microglia activity; and glial fibrillary acidic protein (GFAP) as a biomarker for astrocytic damage. We also measured serum levels of NfL as a blood based biomarker for axonal injury. (For detailed methods, see Supplementary methods) The demographic characteristics, diagnosis, CSF profiles, results of viral detection, magnetic resonance imaging (MRI) findings, lowest score of the Glasgow coma scale (GCS) during the hospitalization period, and modified Rankin Scale (mRS) at discharge are summarized in Supplementary Table 1 and 2. There was no significant difference in age or sex among the HSV, VZV, and control groups.

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Section: Results Of Uni-and Multivariate Regression Analyses Between supporting

confidence: 91%

CSF Biomarker Profiles in CNS Infection Associated with HSV and VZV Mimic Pattern in Alzheimer’s Disease.

Shinomoto¹,

Kasai²,

Tatebe³

et al. 2020

Preprint

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“…These results correspond to previous reports showing signi cantly decreased Aβ1-42 [16], increased t-tau, and increased p-tau in CSF of patients with HSV encephalitis [16,17]. CSF t-tau elevation is also consistent with changes in CSF t-tau of patients with human herpes virus 6 encephalitis [18] and, therefore, can be considered to re ect neuronal damage due to viral infection [17]. To our best knowledge, this is the rst report of CSF p-tau elevation in patients with CNS VZV infection.…”

Section: Discussionsupporting

confidence: 92%

CSF biomarker profiles in CNS infection associated with HSV and VZV mimic pattern in Alzheimer’s disease.

Shinomoto

Kasai

Tatebe

et al. 2020

Preprint

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Background: Central nervous system (CNS) infections have been reported to have a certain etiological relevance to Alzheimer’s disease (AD). In particular, herpes simplex virus (HSV) and varicella zoster virus (VZV) infections has been reported as risk factors for AD. The aim of this study was to determine whether or not AD-related biomarkers were changed in patients with HSV or VZV CNS infections.Methods: Nine patients with HSV infection of the CNS, eight patients with VZV complicated by CNS involvement, and eighteen age-matched controls were enrolled. Amyloid β (Aβ)1-42, Aβ1-40, total-tau (t-tau), tau phosphorylated at threonine 181 (p-tau), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (p-NfH), glial fibrillary acidic protein (GFAP), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in were measured in cerebrospinal fluid (CSF), and NfL in serum.Results: Compared with the control group, CSF Aβ1-42, Aβ1-40, and the Aβ1-42/ Aβ1-40 ratio were significantly decreased, and CSF t-tau, p-tau, sTREM2, and GFAP were significantly increased in the HSV and VZV combined group, in which biomarker changes were similar to those reported in AD. CSF NfL levels measured on admission were significantly correlated with the disease severity and a poor outcome after age adjustment. Serum NfL on admission was also associated with disease severity after age adjustment.Conclusions: The fact that the biomarker profile in patients with CNS HSV and VZV infections mimicked that in AD patients should be paid attention to as a potential confounding factor in CSF biomarker-based diagnosis of AD, and it suggests an etiological similarity between herpetic virus infection and AD. The CSF NfL concentration on admission may be useful as a predictive marker of severity and prognosis in patients with CNS HSV and VZV infections.

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“…In this small case series we measured several cerebrospinal uid biomarkers in meningeal tuberculosis. We con rmed the presence of classical TBM CSF ndings such as BBB impairment, in ammation and report here, for the rst time, very low level of 1-42 Beta amyloid [1,2,3,21,28] Neuronal damage is a classical feature of TBM due to its devastating in ammation and disruptive process. 14.3.3 positivity was found in 5/13 (38,5%) of TBM; this cellular-cycle protein, previously associated with prionic disease, accumulates in the CSF after neuronal damage especially during bacterial involvement of CNS and it is cleared from the CFS after successful treatment [4].…”

Section: Discussionsupporting

confidence: 70%

Low Cerebrospinal Fluid Beta Amyloid1-42 in Patients with Tubercoulous Meningitis

Stroffolini¹,

Guastamacchia²,

Audagnotto³

et al. 2020

Preprint

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Introduction Tubercolous meningitis (TBM) is an important disease leading to morbidity, disability and mortality that primarily affects children and immune-depressed patients. Specific neuromarkers predicting outcomes, severity and inflammatory response are still lacking. In recent years an increasing number of evidences show a possible role for infective agents in developing neurodegenerative diseases. Methods We retrospectively included 13 HIV-negative patients presenting with meningeal tuberculosis. Lumbar punctures were performed for clinical reasons and CSF biomarkers were routinely available: we analyzed blood brain barrier permeability (CSF to serum albumin ratio, “CSAR”), intrathecal IgG synthesis, (CSF to serum IgG ratio), inflammation (neopterin), amyloid deposition (1-42 β-amyloid), neuronal damage (T-tau, P-tau, 14.3.3) and astrocytosis (S-100 β). Results Patients were 83% male and 67 % Caucasian with a median age of 51 years(24.5-63.5 IQR). Apart from altered CSAR (median value 18.4, 17.1-30.9 IQR), neopterin (14.3 ng/ml, 9.7-18.8) and IgG ratios (15.4, 7.9-24.9) patients showed very low levels of 1-42 β-amyloid in their CSF (348.5 pg/mL,125-532.2). Protein 14.3.3. tested altered in 38.5% cases. T-tau, ptau and S100Beta were in the range of normality. Altered low level of beta amyloid correlated over time with classical TBm findings and altered neuromarkers.Conclusion CSF Biomarkers from patients with TBM were compatible with inflammation, blood brain barrier damage and impairment in beta amyloid metabolism. Aβ1-42 could be tested as a prognostic markers, backing the routine use of available neuromarkers. To our knowledge this is the first case showing such low levels of Aβ1-42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases.

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Cerebrospinal fluid biomarkers in patients with central nervous system infections: a retrospective study

Cited by 22 publications

References 15 publications

CSF Biomarker Profiles in CNS Infection Associated with HSV and VZV Mimic Pattern in Alzheimer’s Disease.

CSF Biomarker Profiles in CNS Infection Associated with HSV and VZV Mimic Pattern in Alzheimer’s Disease.

CSF biomarker profiles in CNS infection associated with HSV and VZV mimic pattern in Alzheimer’s disease.

Low Cerebrospinal Fluid Beta Amyloid1-42 in Patients with Tubercoulous Meningitis

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