Increased cerebrospinal fluid protein tau concentration in neuro-AIDS
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.
References (32)
- et al.
Human Immunodeficiency Virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains
Hum Pathol
(1991) - et al.
Cerebrospinal fluid tau protein is not elevated in HIV-associated neurologic disease in humans. HIV Neurobehavioral Research Center group (HNRC)
Neurosci Lett
(1998) - et al.
A neuronal fibrillary inclusion shares the epitope of p24 of Human Immunodeficiency Virus
Neurosci Lett
(1995) - et al.
Declining incidence of AIDS dementia complex after introduction of zidovudine treatment
BMJ
(1989) - et al.
Neurologic manifestations of AIDS: a comparative study of two populations from Mexico and the United States
J Acquired Immune Defic Syndr Hum Retrovirol
(1995) - et al.
Markers of immune stimulation in the cerebrospinal fluid during HIV infection: a longitudinal study
Scand J Infect Dis
(1994) - et al.
Increased cerebrospinal fluid ganglioside GM1 concentrations indicating neuronal involvement in all stages of HIV-1 infection
J Neurovirol
(1997) - et al.
Elevated neopterin and beta 2-microglobulin levels in blood and cerebrospinal fluid occur early in HIV-1 infection
AIDS
(1989) - et al.
Increased cerebrospinal fluid ganglioside GD3 concentrations as a marker of microglial activation in HIV type 1 infection
AIDS Res Hum Retroviruses
(1998) - et al.
Cerebrospinal fluid HIV-1 RNA levels: correlation with HIV encephalitis
AIDS
(1998)
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
Cited by (39)
HIV, prospective memory, and cerebrospinal fluid concentrations of quinolinic acid and phosphorylated Tau
2018, Journal of NeuroimmunologyCitation Excerpt :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.
Increased total-Tau levels in cerebrospinal fluid of pediatric hydrocephalus and brain tumor patients
2008, European Journal of Paediatric NeurologyCitation Excerpt :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.
Cerebrospinal fluid markers in central nervous system HIV infection and AIDS dementia complex
2007, Handbook of Clinical NeurologyCitation 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.
Cerebrospinal fluid levels of markers of brain parenchymal damage in Vietnamese adults with severe malaria
2005, Transactions of the Royal Society of Tropical Medicine and HygieneAxonal Degeneration as a Predictor of Outcome in Neurological Disorders
2005, Multiple Sclerosis As A Neuronal Disease