Increased cerebrospinal fluid protein tau concentration in neuro-AIDS

doi:10.1016/S0022-510X(99)00253-1

Journal of the Neurological Sciences

Volume 171, Issue 2, 15 December 1999, Pages 92-96

https://doi.org/10.1016/S0022-510X(99)00253-1 Get rights and content

Abstract

Objectives: Assessment of cerebrospinal fluid (CSF) levels of protein tau in human immunodeficiency virus type 1 (HIV-1) infection. Material and methods: CSF tau levels were analyzed in 52 HIV-1-infected patients, 37 of whom had no neurological symptoms, eight had aquired immunodeficiency syndrome (AIDS) dementia complex (ADC), and seven had AIDS with other neurological complications. Results: A significantly higher mean CSF tau concentration was found in patients with ADC (380 pg/ml) compared with patients with neuroasymptomatic HIV-1 infection (120 pg/ml, P<0.01) and HIV-negative controls (150 pg/ml, P<0.05). No difference in CSF tau levels was found between patients with ADC and patients with AIDS with other neurological complications. Conclusion: CSF tau might be used as a biochemical marker for axonal degeneration and might be of use to identify HIV-1-infected patients with ADC and other neurological complications, but it cannot discriminate between ADC and other neurological complications in HIV-1-infection.

Introduction

Neurological complications are common in human immunodeficiency virus type 1 (HIV-1) infection, and approximately 15% of patients with acquired immunodeficiency syndrome (AIDS) without antiretroviral treatment develop a subcortical dementia, the AIDS dementia complex (ADC) [1], [2]. Biochemical markers in the cerebrospinal fluid (CSF) are sought to predict or support the diagnosis of ADC. Elevated CSF levels of beta-2-microglobulin, neopterin, ganglioside GM1 and GD3 [3], [4], [5], [6] have been found in HIV-1-infected patients, but none of these specifically indicates the onset or development of ADC. Recently, several groups have shown a significant correlation between CSF HIV RNA load and ADC, although patients with ADC and low CSF viral load, as well as patients without ADC and high CSF viral load, have been reported [7], [8], [9]. A more distinct CSF biochemical marker that predicts or distinguishes ADC from other CNS-related disease in HIV-1-infection would be of considerable clinical importance.

Protein tau (tau) is a microtubuli-associated protein that promotes microtubuli assembly and stability [10]. A hyperphosphorylated form of tau (PHF-tau) is found in brains from patients with Alzheimer’s disease where it constitutes the principal component of paired helical filaments, neuropil threads, and senile plaque neurites. Elevated CSF levels of normal and PHF-tau have been found in Alzheimer’s disease and to a lesser extent in vascular dementia and other degenerative neurological disorders [11]. It has been proposed that elevated CSF protein tau concentrations are associated with axonal degeneration and reflect a common pathological pathway in neurodegenerative disorders [11], [12].

HIV-1 encephalitis is the neuropathological correlate to ADC, and neuronal loss [13] with axonal degeneration [14], [15] is frequently found on neuropathological examination. Furthermore, HIV-1 encephalitis is characterized by signs of productive brain infection, myelin pallor, microglial activation, and reactive astrogliosis [16], [17].

In this study, CSF levels of tau were analysed and compared with CSF neopterin concentrations and CSF HIV-1 RNA load in 52 HIV-1-infected patients, 15 with and 37 without neurological complications. Forty-two HIV-1-negative healthy age-matched individuals were included for comparison.

Section snippets

Materials and methods

The study was approved by the Research Ethics Committee at Göteborg University.

Results

The CSF tau concentration was significantly higher in patients with ADC (mean 380, range 30–900 pg/ml) than in HIV-negative controls (mean 150, range 70–380 pg/ml, P<0.05) and in HIV-1-infected individuals without neurological complications (mean 120, range 30–320 pg/ml, P<0.01). No difference in CSF tau levels was found between patients with ADC and HIV-1-infected patients with other neurological complications (mean 720, range 90–1620 pg/ml). The latter group also had significantly higher mean

Discussion

We found a significantly higher mean CSF concentration of tau in patients with ADC compared with HIV-1-infected patients without neurological complications and with HIV-negative controls. HIV-1-infected patients with other neurological complications also had increased CSF concentrations of tau, which did not differ from those in patients with ADC.

Increased CSF levels of normal and PHF-tau are associated with axonal degeneration and have been found in Alzheimer’s disease and to a lesser extent

Acknowledgements

This study was supported by grants from the Swedish Medical Research Council (projects #11560 and #12103), from the Medical Faculty, Göteborg University, from the research foundation Swedish Physicians against AIDS, from the Swedish Society of Medicine and from the Göteborg Society of Medicine.

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Several studies have attempted to determine whether HIV is also associated with abnormal Tau levels and might represent a “Tauopathy”. Studies in the pre-cART era focusing on total Tau (t-Tau) were small, and the results were conflicting (Andersson et al., 1999; Green et al., 2000). More recent studies have focused on phosphorylated Tau (pTau), which is more specific for Tauopathy-associated dementias.
There is mounting evidence that prospective memory (PM) is impaired during HIV infection despite treatment. In this prospective study, 66 adults (43 HIV+ and 23 HIV negative) underwent PM assessment and cerebrospinal fluid (CSF) examination. HIV+ participants had significantly lower PM but significantly higher CSF concentrations of CXCL10 and quinolinic acid (QUIN). Higher CSF phosphorylated Tau (pTau) was associated with worse PM. In a secondary analysis excluding outliers, higher QUIN correlated with higher pTau. CSF QUIN is thus elevated during HIV infection despite antiretroviral therapy and could indirectly contribute to impaired PM by influencing the formation of pTau.
Increased total-Tau levels in cerebrospinal fluid of pediatric hydrocephalus and brain tumor patients
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Changes in CSF t-Tau levels and β-amyloid(1–42) levels were first thought to be specific for Alzheimer's disease.1–9 However, CSF t-Tau, p-Tau(181P) and β-amyloid(1–42) levels were also demonstrated to be of importance in various other diseases, such as frontotemporal10–13 and Lewy body10,14 dementia, multiple sclerosis,15–17 Creutzfeldt–Jakob disease,18–22 amytrophic lateral sclerosis,23 stroke,24 acute brain injury,25 neuro-AIDS,26 normal pressure hydrocephalus27,28 and in hematologic malignancies.29,30 Highest levels of t-Tau were found in disorders with the most intense neuronal degeneration, such as Creutzfeldt–Jakob disease,18 suggesting that t-Tau is an indicator of the extent of neuronal damage, but is not disease-specific.
Total Tau (t-Tau), hyperphosphorylated Tau (p-Tau_(181P)) and β-amyloid_(1–42) in cerebrospinal fluid (CSF) have shown to be markers of neuronal and axonal degeneration in various neurological and neurodegenerative diseases. The aim of this study was to evaluate the influence of the presence of a brain tumor and hydrocephalus on t-Tau, p-Tau_(181P) and β-amyloid_(1–42) levels in CSF of pediatric patients.
t-Tau, p-Tau_(181P) and β-amyloid_(1–42) levels were simultaneously quantified by xMAP^® technology in 22 lumbar and 15 ventricular CSF samples from newly diagnosed pediatric brain tumor patients and 39 lumbar and 12 ventricular CSF samples from pediatric patients without a brain tumor.
t-Tau, p-Tau_(181P) and β-amyloid_(1–42) levels in both lumbar and ventricular CSF were not significantly correlated with age. t-Tau levels in lumbar CSF were elevated in brain tumor patients, being especially high in medulloblastoma patients. Lumbar CSF p-Tau_(181P) levels were lower in brain tumor patients compared to normal controls. Ventricular levels of t-Tau, p-Tau_(181P) and β-amyloid_(1–42) were not significantly different between the brain tumor patients and non-tumor patients, but t-Tau levels were significantly increased in patients with radiological signs of hydrocephalus. Two patients with an infected ventriculo-peritoneal drain also had high CSF t-Tau levels.
In conclusion, high t-Tau levels in CSF are found in pediatric patients with a brain tumor, patients with hydrocephalus and patients with a serious CNS infection, reflecting neuronal and axonal damage. Ongoing studies should determine whether these neurodegenerative markers in CSF can be used to monitor neuronal and axonal degeneration in these patients during therapy and long-term follow up.
Cerebrospinal fluid markers in central nervous system HIV infection and AIDS dementia complex
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Citation Excerpt :
A few studies have addressed the significance of CSF tau protein level in HIV infection (Ellis et al., 1998; Andersson et al., 1999; Brew et al., 2005). Although these reached somewhat different conclusions, most agreed that both t‐tau and p‐tau are elevated in patients with ADC compared to neurologically asymptomatic patients, and that the latter have levels similar to HIV negative healthy controls (Andersson et al., 1999; Brew et al., 2005). Of note, t‐tau and p‐tau concentrations in ADC were similar to those observed in patients with Alzheimer's disease, whereas CSF Aβ1–42 was decreased in both conditions.
This chapter discusses the individual cerebrospinal fluid (CSF) markers, with focus on both their implications for AIDS dementia complex (ADC) pathogenesis and their current or potential future use for clinical management, including diagnosis, assessment of disease activity, prognosis, and response to anti-HIV treatments. The analysis of CSF is among the most important procedures in the diagnosis of central nervous system (CNS) infections. CSF analysis can directly identify the underlying etiological agent, and it can also characterize specific local immune responses that establish etiology and predict prognosis. CSF markers are divided into three groups related to the three major components of the process ultimately leading to ADC: (1) viral markers, (2) host-response markers, and (3) the indicators of CNS tissue damage. The host-response markers are further divided according to their main role in the pathogenesis of ADC: immune-activation markers, neurotoxic molecules, and markers of apoptosis. A number of techniques available for HIV detection in CSF—including virus culture, antigen detection, and nucleic-acid measurement—are discussed in the chapter.
Cerebrospinal fluid levels of markers of brain parenchymal damage in Vietnamese adults with severe malaria
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A retrospective study of cerebrospinal fluid (CSF) markers of brain parenchymal damage was conducted in Vietnamese adults with severe malaria. Three markers were analysed by immunoassays: the microtubule-associated protein tau, for degenerated axons; neuron-specific enolase (NSE), for neurons; and S100B for astrocytes. The mean concentration of tau proteins in the CSF was significantly raised in patients with severe malaria compared with controls (P = 0.0003) as reported for other central nervous system diseases. By contrast, the mean concentration of NSE and S100B remained within the normal range. Tau levels were associated with duration of coma (P = 0.004) and S100B was associated with convulsions (P = 0.006). Concentrations of axonal and astrocyte degeneration markers also were associated with vital organ dysfunction. No association was found between the level of markers of brain parenchymal damage on admission and a fatal outcome. On admission to hospital, patients with severe malaria had biochemical evidence of brain parenchymal damage predominantly affecting axons.
Axonal Degeneration as a Predictor of Outcome in Neurological Disorders
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Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection
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Increased levels of the light-chain neurofilament protein (NFL) in CSF provide a marker of CNS injury in several neurodegenerative disorders and have been reported in the AIDS dementia complex (ADC). We examined the effects of highly active antiretroviral treatment (HAART) on CSF NFL in HIV-1–infected subjects with and without ADC who underwent repeated lumbar punctures (LPs).
NFL was measured by ELISA (normal reference value < 250 ng/L) in archived CSF samples from 53 patients who had undergone LPs before and after initiation of HAART.
Twenty-one of the subjects had increased CSF NFL at baseline, with a median level of 780 ng/L and an intraquartile range (IQR) of 480 to 7300. After 3 months of treatment, NFL concentrations had fallen to normal in 48% (10/21), and the median decreased to 340 ng/L (IQR < 250 to 4070) (p < 0.001), whereas at 1 year, only 4 of 16 of the 21 subjects observed for this length still had elevated NFL levels. Thirty-two subjects had normal NFL at baseline, and all but one remained normal at follow-up. These effects on CSF NFL were seen in association with clinical improvement in ADC patients, decreases in plasma and CSF HIV-1 RNA and CSF neopterin, and increases in blood CD4 T cell counts.
HAART seems to halt the neurodegenerative process(es) caused by HIV-1, as shown by the significant decrease in CSF NFL after treatment initiation. CSF NFL may serve as a useful marker in monitoring CNS injury in HIV-1 infection and in evaluating CNS efficacy of antiretroviral therapy.

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Increased cerebrospinal fluid protein tau concentration in neuro-AIDS

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Hum Pathol

Neurosci Lett

Neurosci Lett

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment

BMJ

Neurologic manifestations of AIDS: a comparative study of two populations from Mexico and the United States

J Acquired Immune Defic Syndr Hum Retrovirol

Markers of immune stimulation in the cerebrospinal fluid during HIV infection: a longitudinal study

Scand J Infect Dis

Increased cerebrospinal fluid ganglioside GM1 concentrations indicating neuronal involvement in all stages of HIV-1 infection

J Neurovirol

Elevated neopterin and beta 2-microglobulin levels in blood and cerebrospinal fluid occur early in HIV-1 infection

AIDS

Increased cerebrospinal fluid ganglioside GD3 concentrations as a marker of microglial activation in HIV type 1 infection

AIDS Res Hum Retroviruses

Cerebrospinal fluid HIV-1 RNA levels: correlation with HIV encephalitis

AIDS

CSF, plasma viral load and HIV associated dementia

J Neurovirol

Levels of Human Immunodeficiency Virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage

J Infect Dis

Role of microtubule-associated proteins in the control of microtubule assembly

Physiol Rev

Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease?

Mol Chem Neuropathol

The neurochemistry of Alzheimer’s disease

Acta Neurol Scand Suppl

Neocortical damage during HIV infection

Ann Neurol