Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain.
Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses.
To uncover evidence of these disease types, first author Mady Hornig, MD, director of translational research at CII and associate professor of Epidemiology at Mailman, and colleagues used immunoassays to measure levels of 51 immune biomarkers in cerebrospinal fluid samples taken from 32 cases of classical and 27 cases of atypical ME/CFS. All study participants were diagnosed using the same standard criteria, but atypical cases either had prior histories of viral encephalitis, illness after foreign travel or blood transfusion, or later developed a concurrent malady—seizure disorders, multiple sclerosis-like demyelinating disorders, Gulf War Illness, or a range of cancers—at rates much higher than seen in the general population.
Their analysis revealed lower levels of immune molecules in individuals with atypical ME/CFS than those with a classical presentation and course of illness, including dramatically lower levels of interleukin 7 (IL7), a protein linked to viral infections, and interleukin 17A (IL 17A) and chemokine (C-X-C motif) ligand 9 (CXCL9), inflammatory molecules implicated in a variety of neurological disorders.
“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities,” says Hornig. “Importantly, our results suggest that these early biomarker profiles may be detectable soon after diagnosis of ME/CFS, laying a foundation for better understanding of and treatments for this complex and poorly understood illness.”
“Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes,” says co-author Daniel L. Peterson, MD, principal clinician at Sierra Internal Medicine in Incline Village, NV.
The new study builds on earlier research by Hornig and collaborators that found robust evidence of distinct stages in ME/CFS. A pair of 2015 publications based on analyses of blood and cerebrospinal fluid showed differences in the immune signatures of ME/CFS patients who had the disease for three years or less as compared with those who had been ill for more than three years. The researchers reported that patients were flush with cytokines and chemokines until around the three-year mark—suggesting an over-activated immune response in that phase of the illness; thereafter the immune system showed evidence of “exhaustion,” and levels of immune molecules dropped.
In the new study, both subsets of ME/CFS patients showed signs of an unbalanced or dysregulated immune system within the central nervous system, with immune markers different than those seen in healthy individuals. However, the dampened immune profiles previously observed after the three-year mark were only observed in individuals with the classical form of the disease, not in those with atypical ME/CFS. Among subjects in the atypical group, levels of cytokines and chemokines were more likely to remain steady or increase.
According to Hornig, instead of the immune exhaustion seen in later phases of classical ME/CFS, atypical patients may be experiencing a “smouldering inflammatory process” in which the immune system is still working to recover, although she acknowledges that much work remains to be done to confirm this hypothesis. Alternatively, these findings could suggest a pathway to disease in atypical individuals that involves biomarkers not captured in the 51-molecule assay, potentially even involving non-immune-related processes. Atypical individuals may also have genetic susceptibilities that lead their immune systems to respond differently than in classical cases.

Columbia University Mailman School of Public Health]
www.mailman.columbia.edu/public-health-now/news/scientists-discover-biological-evidence-atypical-chronic-fatigue-syndrome

A multi-institutional group of researchers, led by investigators at Children’s Hospital Los Angeles and the University of Michigan, have identified a simple and inexpensive tool for assessing the prognosis of paediatric brain tumours called ependymomas. Their study, which demonstrates the epigenetic mechanism behind these tumours, may offer future opportunities for novel therapeutic options.

Childhood posterior fossa ependymomas (PF) are tumours found largely in the hind brain (consisting of the cerebellum, pons and the brainstem) of children. Routine assessment of tumour grade and other markers in PF ependymomas do not correlate well with outcomes in these tumours, highlighting the need for new prognostic markers. Genomic sequencing efforts have not identified mutations in these tumours, and the origin of PF ependymomas remains obscure.

While lacking recurrent genetic mutations, a subset of these tumours exhibit alterations in DNA methylation. In this study, the researchers looked at modification of histones – protein components of the chromatin around which DNA winds, and which play a role in gene regulation – in particular, histone H3.

Co-lead investigator, Sriram Venneti, MD, PhD, of the Department of Pathology at the University of Michigan, observed that histone H3 is modified differently in paediatric posterior fossa ependymoma. Specifically, 80 percent of these tumours exhibited loss of the H3K27me3 a repressive mark, while 20 percent of tumours retained H3K27me3.  Researchers went back and looked at MRIs and outcomes of children treated for these tumours and identified that tumours with loss of H3K27me3 tumours behaved more aggressively and showed poor overall survival.  This suggests that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.

“Detection of H3K27me3 by immunohistochemical staining is a widely available and cost effective surrogate molecular marker.  This test can be readily implemented in most departments of pathology and provides a much-needed tool to risk stratify and identify ependymoma patients who would potentially benefit from epigenetic therapies,” said co-lead investigator Alexander R. Judkins, MD, of the Department of Pathology and Laboratory Medicine at CHLA and Keck School of Medicine of the University of Southern California.

This loss in H3K27me3, along with other epigenetic changes, was similar to that observed in another type of paediatric brain tumour of the hind brain region termed diffuse intrinsic pontine gliomas (DIPGs).  This suggests that both of these tumours arise from similar epigenetic states. Intriguingly, researchers found that certain progenitor cells in this part of the brain also showed low H3K27me3, suggesting – as both tumours share epigenetic similarities – that low methylation of H3K27me3 is important to the development of tumours in this region of the brain.

Children’s Hospital of Los Angeles www.chla.org/press-release/biomarker-identified-aid-prognosis-pediatric-ependymomas

Researchers from Trinity College Dublin have shown for the first time that Motor Neurone Disease (MND) — also known as Amyotrophic Lateral Sclerosis (ALS) — and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked.
By analysing the genetic profiles of almost 13,000 MND cases and over 30,000 schizophrenia cases, the researchers have confirmed that many of the genes that are associated with these two very different conditions are the same.
In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between MND and psychiatric conditions has been shown.
Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said: “This study demonstrates the power of genetics in understanding the causes of diseases."
"While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.”
Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre at Beaumont Hospital Dublin, Orla Hardiman, is the senior author and lead investigator on the project.
Professor Hardiman said: “Our work over the years has shown us that MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.”
She continued: “So instead of thinking of MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilise the failing brain networks." 
“The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one. We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock-on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions."
The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman. These studies showed that people with MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide.
This was first noted as family histories were ascertained from people with MND in the National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013.
This led the Trinity group to team up with European collaborators in MND including the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia to see if these epidemiological observations could be due to a genetic overlap between MND and schizophrenia.
The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.

Trinity College Dublin
www.tcd.ie/news_events/articles/scientists-discover-shared-genetic-origin-for-mnd-and-schizophrenia/7681

The Wellcome-funded diagnostic – developed by researchers at University College London (UCL) and the Western Eye Hospital – allows doctors to see individual nerve cell death in the back of the eye.
Early detection means doctors can start treatment before sight loss begins. The test also has potential for early diagnosis of other degenerative neurological conditions, including Parkinson’s, Alzheimer’s and multiple sclerosis.
Professor Francesca Cordeiro, at UCL Institute of Opthamology, who led the research, said: "Although detection has been improving, most patients have lost a third of vision by the time they are diagnosed.
"Now, for the first time, we have been able to show individual cell death and detect the earliest signs of glaucoma. While we cannot cure the disease, our test means treatment can start before symptoms begin."
Glaucoma affects 60 million people worldwide and one in ten go blind.
The new technique means patients could be diagnosed up to ten years earlier than is currently possible.
Bethan Hughes, Wellcome’s Strategic Development Lead for Innovation, said: "This innovation has the potential to transform lives for those who suffer loss of sight through glaucoma, and offers hope of a breakthrough in early diagnosis of other neurodegenerative diseases."
Loss of sight in patients with glaucoma is caused by the death of cells in the retina at the back of the eye – apoptosis.
The new technique is called DARC, which stands for detection of apoptosing retinal cells.
It uses a specially developed fluorescent marker which attaches to cell proteins when it’s injected into patients. Damaged retinal cells appear as white fluorescent spots during eye examination.
Initial clinical trials were carried out on a small number of glaucoma patients and compared with tests on healthy people to establish the test’s safety.
DARC uses equipment that is already part of routine hospital eye examinations.
The researchers hope that eventually it may be possible for opticians to do the tests. This would mean even earlier detection of the disease.
Treatment for glaucoma is much more successful when it is begun in the early stages of the disease.
Further studies will now be carried out into DARC and how it could be used to detect other neurodegenerative conditions where increasing numbers of nerve cells are lost as the disease progresses.

Wellcome Trust
wellcome.ac.uk/news/new-eye-test-detects-earliest-signs-glaucoma