Abstract
HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer’s disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND.
Highlights
HIV-associated neurocognitive disorders (HAND) can affect up to 50% of people living with HIV1–3
We further explored whether cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels in HAND were influenced by viral load and altered levels of key CSF cytokines linked to innate immunity or T-cell-related pathways, including interferon-γ-inducible protein 10 (CXCL10/IP10), interleukin 8 (CXCL8/IL-8), fractalkine (CX3CL1), tumor necrosis factor alpha (TNF-α), macrophage-derived chemokine (MDC), and interleukin 10 (IL-10)
We analyzed CSF AD biomarkers and cytokines in a group of HIV-infected and HIV-negative subjects to simultaneously examine two pathways previously implicated in HAND
Summary
HIV-associated neurocognitive disorders (HAND) can affect up to 50% of people living with HIV1–3. Biofluid or imaging markers have the potential of enhancing early and accurate detection of mild HAND. Such biomarkers will be especially important in drug development if they reflect known disease mechanisms or provide new pathophysiologic insight. Whereas post-mortem studies commonly associated viral infection as a key mechanism in HIV-associated dementia[13], no neuropathologic process has been consistently identified in HAND14. We further explored whether CSF AD biomarker levels in HAND were influenced by viral load and altered levels of key CSF cytokines linked to innate immunity or T-cell-related pathways (selected for biological function and reproducibility in CSF assays), including interferon-γ-inducible protein 10 (CXCL10/IP10), interleukin 8 (CXCL8/IL-8), fractalkine (CX3CL1), tumor necrosis factor alpha (TNF-α), macrophage-derived chemokine (MDC), and interleukin 10 (IL-10). To lend support for a mechanistic link between AD biomarkers and inflammation, we examined in a group of HIV subjects with serial CSF collection whether the two biomarker sets underwent parallel changes over time
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