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Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection.

ABSTRACT: BACKGROUND:Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about the mechanisms driving milder forms that are prevalent despite combination antiretroviral therapy (cART). To examine relationships of monocyte activation markers to HAND of varying severity, we compared plasma and cerebrospinal fluid (CSF) biomarker levels with neurocognitive test scores in HIV+ subjects. METHODS:Plasma and CSF soluble CD14 (sCD14), CCL2, and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay in 67 HIV+ subjects with nadir CD4 <300, and CSF inflammatory biomarkers were measured by multiplex assay in 14 subjects on suppressive cART. RESULTS:Eighty-two percent were on cART, with 31% having undetectable plasma viral load (VL). CSF sCD14 was increased in subjects with impaired neurocognitive testing (P = 0.02), correlated inversely with global T scores in subjects with detectable but not undetectable plasma VL (P = 0.02), and yielded higher area under the receiver operating characteristic curve values for predicting impaired T scores (0.659) than plasma or CSF VL and current or nadir CD4 counts in single-marker and multivariate models. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and interferon (IFN) gamma were increased in subjects on suppressive cART regardless of cognitive status and predicted patient class in unsupervised analyses, with IL-8, CCL2, and IFN? explaining most of the variance. CONCLUSIONS:CSF sCD14 is associated with impaired neurocognitive testing in patients with HIV on nonsuppressive cART, suggesting potential utility as a biomarker to monitor HAND progression. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and IFN? remain elevated in patients on suppressive cART regardless of cognitive status, implying ongoing intrathecal inflammation even in the absence of clinical manifestations.

SUBMITTER: Kamat A

PROVIDER: S-EPMC3383928 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection.

Kamat Anupa A Lyons Jennifer L JL Misra Vikas V Uno Hajime H Morgello Susan S Singer Elyse J EJ Gabuzda Dana D

Journal of acquired immune deficiency syndromes (1999) 20120701 3

<h4>Background</h4>Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about the mechanisms driving milder forms that are prevalent despite combination antiretroviral therapy (cART). To examine relationships of monocyte activation markers to HAND of varying severity, we compared plasma and cerebrospinal fluid (CSF) biomarker levels with neurocognitive test scores in HIV+ subjects.<h4>Methods</h4>Plasma and CSF soluble ...[more]

PMID: 22569268

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Project description:In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351-500 cells/μL (N = 40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

Project description:BackgroundBrain metastases (BM), including brain parenchyma metastases (BPM) and leptomeningeal metastases (LM), are devastating metastatic complications in advanced cancer patients. Next-generation sequencing (NGS) is emerging as a new promising tool for profiling cancer mutation, which could facilitate the diagnosis of cancer. This retrospective study aimed to investigate the molecular genetic characteristics of non-small cell lung cancer (NSCLC) patients with BPM and LM using NGS.MethodsCerebrospinal fluid (CSF) samples and paired plasma samples were collected from 37 patients of NSCLC-BM. We profiled genetic mutation characteristics using NGS from NSCLC-BM by comparing CSF circulating tumour DNA (ctDNA) with plasma ctDNA and primary tumour tissues.ResultsAmong the 37 patients with NSCLC-BM, 28 patients had LM with or without BPM, while 9 patients only had BPM. Driver and drug-resistant mutations in primary tumours with LM included: EGFR L858R (10, 35.7%), EGFR 19del (6, 21.4%), EGFR L858R+MET (1, 3.6%), EGFR L858R+S768I (1, 3.6%), ALK (2, 7.1%), ROS1 (1, 3.6%), negative (5, 17.9%), and unknown (2, 7.1%). In patients with NSCLC-LM, the detection rate and abundance of ctDNA in the CSF were significantly higher than those in paired plasma. The main driver mutations of NSCLC-LM remained highly consistent with those of the primary tumours, along with other unique mutations. Circulating tumour DNA was negative in the CSF samples of BPM patients. Patients with BMP had a higher ratio of EGFR 19del than L858R mutation (55.6% vs 11.1.%), whereas NSCLC patients with LM had a higher ratio of EGFR L858R than 19del mutation (50.0% vs 25.0%). Most patients with positive plasma ctDNA results were male (p = 0.058) and in an unstable state (p = 0.003).ConclusionOur study indicated that the CSF ctDNA detected by NGS may reflect the molecular characteristics and heterogeneity of NSCLC-LM. Timely screening of patients with NSCLC for CSF ctDNA, especially for patients with positive plasma ctDNA, may facilitate the early detection of LM. Furthermore, patients with the EGFR 19del may have a higher risk of developing BPM.

Dataset Information

Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection.

Publications

Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection.

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