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Biomarkers, Hippocampal Volume Loss and Post-Traumatic Stress Disorder

biomarkers and hippocampus
Biomarkers and Post-Traumatic Stress Disorder

Update at BrainImmuneIn a recent review in Journal of Neurochemistry, James Andrews and Kameran Neises from the Naval Health Research Center, San Diego, California provide up to date information, and a brief but comprehensive overview on how peripheral blood mononuclear cells (PBMCs) and biomarkers may play a role in a putative mechanism and effective diagnosis of PTSD.

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that develops after exposure to traumatic life event(s).

This event may involve the threat of death to oneself or to someone else, or to one’s own or someone else’s physical, sexual, or psychological integrity, overwhelming the individual’s ability to cope.  Symptoms may include flashbacks, nightmares and severe anxiety, as well as uncontrollable thoughts about the event. PTSD can occur at any age.

It can follow a natural disaster such as a flood or fire, or events such as assault, domestic abuse, prison stay, rape, terrorism or war. PTSD is quite common in the general population, and its prevalence rate is between 3.5% and 8% in the United States, and from 0.3% to 6.1% in other countries.

Dysregulation of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-sympathetic nervous system (SNS), has been implicated in the pathophysiology of PTSD.

Over the last decade several studies have reported an altered activity of the HPA axis in PTSD, including differences in glucocorticoid receptor (GR) expression and function in peripheral blood mononuclear cells but these studies did not always report consistent findings.

Thus, contradictory results from peripheral measurements, exhibiting low 24 hours’ excretion of urinary free cortisol, low or normal circulating cortisol levels or even high plasma cortisol levels, have been reported. Peripheral biomarkers of the SNS activity are more consistent, showing increased 24h urinary or plasma catecholamines in PTSD patients compared to control individuals.

Since the neuroendocrine and the immune systems are closely intertwined, the traumatic or chronic stress may therefore have an effect on the regulation of both systems separately, as well as on their interaction. Despite what is known about the symptoms of PTSD, little progress has been made toward describing mechanisms or effective diagnostic biomarkers.

In the Journal of Neurochemistry review the authors look beyond the central nervous system (CNS), and propose a model or mechanism, which is initiated from a traumatic event and activated PBMCs, and terminates with hippocampal volume loss in patients with PTSD.

In this model, the traumatic event is linked to activation of PBMCs, and subsequent microglial activation and CNS inflammation. Both microglial activation and inflammation are associated with CNS cell death. This increased CNS cell death combined with decreased neurogenesis lead to hippocampal volume loss.

The authors also highlight the importance of several biomarkers that associate with PTSD symptoms and may provide some insight into the mechanism and an objective diagnosis. They also have the potential to differentiate PTSD from traumatic brain injury. The PTSD biomarkers reviewed include neuropeptide-Y, CD14, myeloid-related protein-8, p11 (S100A10), tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, Gs-alpha, and glucocorticoids.

The authors suggest that more work should focus on PBMCs and their role in neurodegenerative diseases such as PTSD. This approach may offer improved diagnoses and treatments for PTSD patients.

SOURCE:  J Neurochem 2012, 120:26-36. doi: 10.1111/j.1471-4159.2011.07545.x. Epub 2011 Nov 17

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Updates

A 2016 study indicates that the proinflammatory cytokine IL-12 is upregulated in the PBMCs of PTSD, thereby suggesting a role for IL-12 in the increase in interferon-γ (IFNG) seen in these patients. In a previous study, the same authors demonstrated that the protein level of IFNG was significantly increased in PBMCs from PTSD patients.

To determine whether the increased protein was due to the enhanced transcription, the investigators examined the expression of IFNG and its transcription factor TBX-21 by real time PCR. The expression of both TBX-21 and IFNG was significantly increased in PTSD samples compared with the control samples, suggesting that the transcription of IFNG might be enhanced in PTSD.

The authors also provide evidence that multiple epigenetic mechanisms and miRNAs can influence the expression of proinflammatory genes. As a proof, they demonstrate that the expression of IL-12 and IFNG could be influenced by multiple epigenetic mechanisms (histone methylation, DNA methylation) and by miRNAs.

In a 2018 review Suzanne Yang M.D., Gary H. Wynn, M.D., Robert J. Ursano, M.D wrote that The notable heterogeneity of the PTSD diagnosis suggests that biologically homogeneous groups – “biotypes” – might exist as PTSD subtypes and might respond to different treatments, as we are now finding with depression. However, no validated biological measures or laboratory tests currently exist to confirm the diagnosis of PTSD, to monitor disease progression, to assess treatment response, or to select appropriate treatments for particular individuals.

As per blood-based biomarkers the authors of this review summarize some biological markers identified in earlier investigations. This includes heart rate, electrodermal response (skin conductance), cortisol levels, and glucocorticoid receptor (GR) density in peripheral blood cells.

Thus, they list some of the most important along these lines: a) Decreased cortisol reactivity to an experimental stressor; b) High pre-exposure GR number in peripheral blood mononuclear cells and T-cell sensitivity to glucocorticoids for PTSD participants without depression; c) Elevation of cortisol and corticotropin-releasing hormone (CRH) concentrations in cerebrospinal fluid when compared with healthy controls; d) Some evidence suggesting that PTSD diagnosis is associated with significantly lower plasma BDNF, although BDNF may be elevated early in the course of illness, decreasing with time.

The authors conclude in the context of the biological characteristics of PTSD, it is challenging to extract relevant findings for practical application. The identification of reliable and accurate PTSD biomarkers will be a substantial breakthrough for improving clinical care.