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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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Related in: MedlinePlus

CSF NFL related to age and treatment effect.Since CSF NFL increases with age, we analyzed the group differences with a linear mixed effects model with age as covariate. This implies a model with three parallel regression lines where the group differences correspond to the vertical distances between the regression lines. The group differences can be expressed as the corresponding age increase needed for an equivalent difference. The 95% prediction interval of CSF NFL levels of HIV-negative controls is demonstrated as dotted lines (Neg 95% PI). Concentrations of CSF NFL in neuroasymptomatic untreated HIV-infected subjects (No ART) were equivalent to those of HIV-negative subjects (negative) who were 18.5 years older (p<0.001). CSF NFL concentrations in the treated group (ART) were equivalent to those of HIV-negative subjects who were 3.9 years older (p<0.01).
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pone-0088591-g003: CSF NFL related to age and treatment effect.Since CSF NFL increases with age, we analyzed the group differences with a linear mixed effects model with age as covariate. This implies a model with three parallel regression lines where the group differences correspond to the vertical distances between the regression lines. The group differences can be expressed as the corresponding age increase needed for an equivalent difference. The 95% prediction interval of CSF NFL levels of HIV-negative controls is demonstrated as dotted lines (Neg 95% PI). Concentrations of CSF NFL in neuroasymptomatic untreated HIV-infected subjects (No ART) were equivalent to those of HIV-negative subjects (negative) who were 18.5 years older (p<0.001). CSF NFL concentrations in the treated group (ART) were equivalent to those of HIV-negative subjects who were 3.9 years older (p<0.01).

Mentions: Since CSF NFL increases with age in uninfected populations, we analyzed the differences between treated and untreated subjects and HIV negatives with age as covariate. This resulted in a model of three parallel regression lines (Figure 3). The group differences can be expressed as the corresponding age increase needed for an equivalent difference in the two HIV-infected groups compared to the controls.. We found that the CSF concentration of NFL in the untreated group, despite their lack of symptoms, was equivalent to subjects 18.5 years older than the HIV negative controls (p<0.001). While treatment reduced these concentrations, CSF NFL concentration in the population on cART was equivalent to HIV-negatives 3.9 years older (p<0.01), figure 3. The 95% prediction interval for CSF NFL levels in HIV-negative controls corresponded well to the age-related cut-offs provided by the laboratory.


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)

CSF NFL related to age and treatment effect.Since CSF NFL increases with age, we analyzed the group differences with a linear mixed effects model with age as covariate. This implies a model with three parallel regression lines where the group differences correspond to the vertical distances between the regression lines. The group differences can be expressed as the corresponding age increase needed for an equivalent difference. The 95% prediction interval of CSF NFL levels of HIV-negative controls is demonstrated as dotted lines (Neg 95% PI). Concentrations of CSF NFL in neuroasymptomatic untreated HIV-infected subjects (No ART) were equivalent to those of HIV-negative subjects (negative) who were 18.5 years older (p<0.001). CSF NFL concentrations in the treated group (ART) were equivalent to those of HIV-negative subjects who were 3.9 years older (p<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088591-g003: CSF NFL related to age and treatment effect.Since CSF NFL increases with age, we analyzed the group differences with a linear mixed effects model with age as covariate. This implies a model with three parallel regression lines where the group differences correspond to the vertical distances between the regression lines. The group differences can be expressed as the corresponding age increase needed for an equivalent difference. The 95% prediction interval of CSF NFL levels of HIV-negative controls is demonstrated as dotted lines (Neg 95% PI). Concentrations of CSF NFL in neuroasymptomatic untreated HIV-infected subjects (No ART) were equivalent to those of HIV-negative subjects (negative) who were 18.5 years older (p<0.001). CSF NFL concentrations in the treated group (ART) were equivalent to those of HIV-negative subjects who were 3.9 years older (p<0.01).
Mentions: Since CSF NFL increases with age in uninfected populations, we analyzed the differences between treated and untreated subjects and HIV negatives with age as covariate. This resulted in a model of three parallel regression lines (Figure 3). The group differences can be expressed as the corresponding age increase needed for an equivalent difference in the two HIV-infected groups compared to the controls.. We found that the CSF concentration of NFL in the untreated group, despite their lack of symptoms, was equivalent to subjects 18.5 years older than the HIV negative controls (p<0.001). While treatment reduced these concentrations, CSF NFL concentration in the population on cART was equivalent to HIV-negatives 3.9 years older (p<0.01), figure 3. The 95% prediction interval for CSF NFL levels in HIV-negative controls corresponded well to the age-related cut-offs provided by the laboratory.

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