Cortisol Diurnal Variation, IL-6 and TNF-alpha as Potential Diagnostic Markers in Autism

Cortisol Diurnal Variation IL-6 TNF Marker Autism
Cortisol Diurnal Variation, IL-6 and TNF-α – Markers in Autism

Update at BrainImmuneA study published in the Research in Autism Spectrum Disorders Journal indicates that cortisol, IL-6 and TNF-α may become useful markers for autism spectrum disorder (ASD).

At present, 1 in 68 children in the US, and 1 in 100, in the UK, develop ASD. This is approximately a 30% increase versus the previous estimates reported in 2012.

In spite of this significant increase of ASD, there is no reliable diagnostic test available for these serious neurodevelopmental conditions.

Previous research indicates a sluggish and dysfunctional hypothalamic–pituitary–adrenal (HPA) axis, with altered circadian patterns of the stress hormone cortisol, and several cytokines abnormalities.

These include increased levels and/or expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in plasma, the cerebrospinal fluid, or in postmortem brain specimens; and a neuroinflammatory process in the cerebral cortex, white matter, and the cerebellum of autistic patients.

In the Research in Autism Spectrum Disorders study, Chang-Jiang Yang and colleagues from the East China Normal University and Fudan University, Shanghai, China, demonstrate that children with autism have a lower level of cortisol diurnal variation, but higher levels of plasma IL-6 and TNF-α as compared to healthy controls. These changes correlated with the severity of ASD.

Of note, this is perhaps the first study where the authors have used receiver operating characteristics (ROC) analysis to test the specificity and sensitivity of biological markers such as cortisol, IL-6 and TNF-α to detect autism.

Importantly, the results of ROC analysis indicated that the cortisol variation, IL-6 and TNF-α may represent potential biomarkers for ASD. As the combination of the three measurements gave the best sensitivity and specificity values, the authors suggest that this validates their usefulness and reliability as biomarkers.

This may provide a relative simple diagnostic tool in autism, if the findings can be replicated in a larger group of individuals with ASD.

Source: Research in Autism Spectrum Disorders, 2015, 9:174-181.
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A 2016 study characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD, developmental delay (DD) without ASD, and general population (GP) controls using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID) and those without (composite score⩾70).

Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

A 2017 study provided further support for the potential use of immunological measures as autism spectrum disorder (ASD) biomarkers. In this study, TNF-α concentrations were positively correlated with severity of autistic symptoms.

The authors used Milliplex cytokine kits to determine serum concentrations of 11 Th1, Th2 and Th17 related cytokines. Of the 11 cytokines measured only concentrations of TNF-α, IL-1β and IL-17a were significantly increased in ASD children. But only TNF-α concentrations were positively correlated with severity of ASD symptoms on all 5 different ABC sub-scales and were predictive of an ASD phenotype.

The increase of IL-17A level in ASD children correlates with other recent studies. Thus, a recent study using a mouse model has reported that maternal infection caused Th17 over-activation and autistic-like symptoms.

Another 2017 study examined neonatal blood spots from children with ASD, children with typical development, and children with developmental delay as control subjects. Levels of 17 cytokines and chemokines were compared across groups. The study demonstrated that peripheral cytokine profiles at birth are associated with ASD later in childhood and that cytokine profiles vary depending on ASD severity.

Interleukin (IL)-1β and IL-4 were independently associated with ASD compared with typical development, although these relationships varied by ASD symptom intensity. Elevated IL-4 was associated with increased odds of severe ASD, whereas IL-1β was associated with increased odds of mild/moderate ASD.

A 2022 current opinion article concluded that the biomarker development for ASD is only in the early stages. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups.

A common theme for the future is further investigation of biomarkers in subgroupings of ASD, as ASD is a very heterogeneous condition that will most likely require optimized individualized treatment. In conclusion, the current state of biomarker research is still preliminary but promising.

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