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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 levels before-after combination antiretroviral treatment (cART) initiation.Overall CSF NFL levels decreased in 63% of the patients after initiation of cART (p<0.01), demonstrated as a lower CSF NFL geometric mean (dotted line) after initiation of cART. 33% of the patents had elevated levels of CSF NFL at baseline and 81% of those exhibited reduction in their CSF NFL levels after treatment (p<0.01). 35% of patients with pathological CSF NFL at baseline normalized their levels (green colored). Those with normal CSF NFL at baseline exhibited no significant reduction in CSF NFL (blue colored). Three patients with normal baseline CSF NFL exhibited elevated levels of CSF NFL after cART initiation (red colored).
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pone-0088591-g004: CSF NFL levels before-after combination antiretroviral treatment (cART) initiation.Overall CSF NFL levels decreased in 63% of the patients after initiation of cART (p<0.01), demonstrated as a lower CSF NFL geometric mean (dotted line) after initiation of cART. 33% of the patents had elevated levels of CSF NFL at baseline and 81% of those exhibited reduction in their CSF NFL levels after treatment (p<0.01). 35% of patients with pathological CSF NFL at baseline normalized their levels (green colored). Those with normal CSF NFL at baseline exhibited no significant reduction in CSF NFL (blue colored). Three patients with normal baseline CSF NFL exhibited elevated levels of CSF NFL after cART initiation (red colored).

Mentions: Overall, CSF NFL levels decreased in 63% of the patients (n = 49) from a pre-treatment CSF NFL median level of 520 ng/L (IQR 310–1070) to 475 ng/L (IQR 315–782.5) after initiation of cART (p<0.01) (Figure 4). Of the 26 (33%) subjects with elevated levels of CSF NFL at baseline, 21 (81%) exhibited a reduction in their CSF NFL levels after treatment, from a pre-treatment median level of 1415 ng/L (IQR 1023–2715) to a posttreatment level of 825 ng/L (IQR 662.5–1220) after a median of 15 weeks of treatment (p<0.01), figure 4. Nine (35%) had normalized by the posttreatment assessment. In one patient, an unexpected increase from 2350 ng/L to 17310 ng/L was observed. This patient had systemic Mycobacterium Avium Complex infection and developed systemic immune reconstitution inflammatory syndrome (IRIS) after starting cART which may have also involved the CNS.


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 levels before-after combination antiretroviral treatment (cART) initiation.Overall CSF NFL levels decreased in 63% of the patients after initiation of cART (p<0.01), demonstrated as a lower CSF NFL geometric mean (dotted line) after initiation of cART. 33% of the patents had elevated levels of CSF NFL at baseline and 81% of those exhibited reduction in their CSF NFL levels after treatment (p<0.01). 35% of patients with pathological CSF NFL at baseline normalized their levels (green colored). Those with normal CSF NFL at baseline exhibited no significant reduction in CSF NFL (blue colored). Three patients with normal baseline CSF NFL exhibited elevated levels of CSF NFL after cART initiation (red colored).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088591-g004: CSF NFL levels before-after combination antiretroviral treatment (cART) initiation.Overall CSF NFL levels decreased in 63% of the patients after initiation of cART (p<0.01), demonstrated as a lower CSF NFL geometric mean (dotted line) after initiation of cART. 33% of the patents had elevated levels of CSF NFL at baseline and 81% of those exhibited reduction in their CSF NFL levels after treatment (p<0.01). 35% of patients with pathological CSF NFL at baseline normalized their levels (green colored). Those with normal CSF NFL at baseline exhibited no significant reduction in CSF NFL (blue colored). Three patients with normal baseline CSF NFL exhibited elevated levels of CSF NFL after cART initiation (red colored).
Mentions: Overall, CSF NFL levels decreased in 63% of the patients (n = 49) from a pre-treatment CSF NFL median level of 520 ng/L (IQR 310–1070) to 475 ng/L (IQR 315–782.5) after initiation of cART (p<0.01) (Figure 4). Of the 26 (33%) subjects with elevated levels of CSF NFL at baseline, 21 (81%) exhibited a reduction in their CSF NFL levels after treatment, from a pre-treatment median level of 1415 ng/L (IQR 1023–2715) to a posttreatment level of 825 ng/L (IQR 662.5–1220) after a median of 15 weeks of treatment (p<0.01), figure 4. Nine (35%) had normalized by the posttreatment assessment. In one patient, an unexpected increase from 2350 ng/L to 17310 ng/L was observed. This patient had systemic Mycobacterium Avium Complex infection and developed systemic immune reconstitution inflammatory syndrome (IRIS) after starting cART which may have also involved the CNS.

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