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Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients.

Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslén M - PLoS ONE (2014)

Bottom Line: Whether this is a result of active HIV-related neurodegeneration is unclear.While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL.NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT

Background: Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method.

Methods: With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation.

Results: While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups.

Conclusions: Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

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Correlations with CD4 T-cell counts and CSF NFL.A loess regression (dotted line) suggested an inverse transformation of CD4+ T-cell counts. Visual inspection reveals a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. The relationship between log10 CSF NFL levels and CD4+ cell counts were fitted with non-linear regression using the function Log CSF NFL  =  b1 + b2/(CD4 + b3) (filled line). CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in the figure were significantly elevated also compared to untreated neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001.
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pone-0088591-g002: Correlations with CD4 T-cell counts and CSF NFL.A loess regression (dotted line) suggested an inverse transformation of CD4+ T-cell counts. Visual inspection reveals a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. The relationship between log10 CSF NFL levels and CD4+ cell counts were fitted with non-linear regression using the function Log CSF NFL  =  b1 + b2/(CD4 + b3) (filled line). CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in the figure were significantly elevated also compared to untreated neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001.

Mentions: The influence of disease progression was more directly shown as a strong correlation of CSF NFL with the blood CD4+ T-cell counts in neuroasymptomatic untreated patients, p = <0.001. A loess regression suggested an inverse transformation of CD4+ T-cell counts (Figure 2). Visual inspection revealed a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in figure 2, were significantly higher also compared to neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001, suggesting additional factors contributing to this more severe and clinically overt disease.


Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients.

Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslén M - PLoS ONE (2014)

Correlations with CD4 T-cell counts and CSF NFL.A loess regression (dotted line) suggested an inverse transformation of CD4+ T-cell counts. Visual inspection reveals a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. The relationship between log10 CSF NFL levels and CD4+ cell counts were fitted with non-linear regression using the function Log CSF NFL  =  b1 + b2/(CD4 + b3) (filled line). CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in the figure were significantly elevated also compared to untreated neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921217&req=5

pone-0088591-g002: Correlations with CD4 T-cell counts and CSF NFL.A loess regression (dotted line) suggested an inverse transformation of CD4+ T-cell counts. Visual inspection reveals a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. The relationship between log10 CSF NFL levels and CD4+ cell counts were fitted with non-linear regression using the function Log CSF NFL  =  b1 + b2/(CD4 + b3) (filled line). CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in the figure were significantly elevated also compared to untreated neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001.
Mentions: The influence of disease progression was more directly shown as a strong correlation of CSF NFL with the blood CD4+ T-cell counts in neuroasymptomatic untreated patients, p = <0.001. A loess regression suggested an inverse transformation of CD4+ T-cell counts (Figure 2). Visual inspection revealed a rapid decline with increasing CD4+ T-cell counts that flattens out at around 250 cells/mL. CSF NFL concentrations in patients with HIV-associated dementia (HAD) diagnosis, marked with red color in figure 2, were significantly higher also compared to neuroasymptomatic patients with equivalently low CD4+ T-cell counts, p<0.001, suggesting additional factors contributing to this more severe and clinically overt disease.

Bottom Line: Whether this is a result of active HIV-related neurodegeneration is unclear.While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL.NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT

Background: Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method.

Methods: With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation.

Results: While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups.

Conclusions: Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

Show MeSH
Related in: MedlinePlus