Research news and online first at the MJA

New leads on dementia and Alzheimer’s

Researchers from the University of Adelaide and the National Human Genome Research Institute in the US claim to have found an explanation for the failure of clinical trials of drugs targeting proteins in the brain that were thought to cause dementia and Alzheimer’s. Published in Human Molecular Genetics, the authors assembled evidence from a wide range of human studies and animal models of dementia-related diseases to show that inflammation is a major cause, not just a consequence. They show that many genes linked with dementia regulate our susceptibility and response to inflammatory damage. Inflammation has long been known to increase as dementia-related diseases progress, but only now is it identified as the cause. Previously, it was thought to act simply to clean up tissue damage caused by the protein aggregates. The new work turns previous thinking around. The genetic linkages imply that the inflammation comes first, and the tissue damage second. “We know that inflammation has different phases – early on, it can be protective against a threat by actively degrading it, but if the threat is not removed, then persistent inflammation actually causes cell death,” said project leader Professor Robert Richards from the University of Adelaide’s School of Biological Sciences. “Many genes linked with dementia operate at the level of controlling cellular inflammation. Both internal and external triggers interact with these genes to play a part. Inflammation is the point through which many triggers converge. Inflammation is a very effective defence against foreign agents such as viruses. But as we get older and accumulate mutations, our cells can make proteins and DNA products that mimic viruses, and these build up in the system. Normally, our cells barcode their own products to tell them apart from foreign agents. When these barcodes aren’t in place, our cells can’t properly distinguish ‘self’ and ‘non-self’ trigger molecules. The result is inflammation that escalates and spreads.” Certain types of gene mutation cause these systems to fail earlier or more often and can increase as we age – possibly accounting for age-related increased risk of developing dementia. By reducing some elements of inflammation, it may be possible to reduce dementia symptoms.

Patients with blood type O may be at greater risk of death from severe trauma

Japanese researchers have found that blood type O is associated with high death rates in severe trauma patients. Published in Critical Care, the study found that patients with severe trauma (those with an injury that has the potential to cause long term disability or death) who have blood type O had a death rate of 28%, compared with a rate of 11% in patients with non-O blood types. Patients with blood type O have been shown to have lower levels of von Willebrand factor – a blood clotting agent – than those with other blood types. Lower levels of von Willebrand factor may be linked to higher levels of haemorrhage. The authors suggested that a lower level of the factor is a possible explanation for the higher death rate in trauma patients with blood type O. The authors used data from medical records of 901 patients with severe trauma who had been transported to either of two tertiary emergency critical care medical centres in Japan during 2013–2016. They cautioned that all the patients whose data were analysed in this study were Japanese and, therefore, there was a need for further research to understand if the findings apply to other ethnic groups. Additionally, there was no evaluation of the impact of the individual blood types A, AB or B on severe trauma death rates. Instead, the authors compared type O to non-O blood type which may have diluted the effect of individual blood types on patient survival.

Cell nutrition links to cancer growth

Flinders University researchers have systematically mapped the core genes and biological processes associated with the ability of tumour cells to survive nutrient stress. Adaptation to limited nutrient environments is a key feature of cancer cells within solid tumours. Published in Open Biology, the study used high throughput screening technology to identify genes that regulate fitness when cells are grown in a rich nutrient environment compared with minimal environment. Analysis of these genes identified a large number of biological processes, including chromatin and transcriptional regulation, nutritional uptake and transport pathways. Of these processes, the researchers found that chromatin organisation–regulation, transmembrane and vesicle-mediated transport play key roles in supporting fitness. “This now paves the way to a molecular understanding of cell adaptation to the chronic and acute fluctuations in nutrient supply that all cells experience at some stage, and which is a key feature of cancer cells within solid tumours,” said lead researcher, Associate Professor Janni Petersen, from the Flinders Centre for Innovation in Cancer.

Small study finds MDMA could ease PTSD in veterans and first responders

A small experimental study has tested the safety and effectiveness of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in 26 service personnel with post-traumatic stress disorder (PTSD). The US study, published in The Lancet Psychiatry, suggested that carefully supervised administration of MDMA (the main active drug compound found in ecstasy), delivered in a clinical setting alongside intensive psychotherapy, was safe and might enhance the benefits of psychotherapy in the treatment of PTSD. However, the outcomes of a phase 3 trial will be needed before the potential for the therapy to influence available treatments can be fully assessed. The study did not include an inactive placebo control group, nor did it compare the intervention to current treatments. All 26 service personnel (22 veterans, three firefighters and one police officer) who took part in the study had PTSD for at least 6 months resulting from a traumatic experience during their service. Participants were randomly assigned to receive 30 mg (seven participants), 75 mg (seven) or 125 mg (12) doses of MDMA plus psychotherapy. Neither the participants nor their clinicians were informed of the doses they received. Six (23%) of the participants had previously taken ecstasy two to five times before the study. Before the first dose of MDMA, participants took part in three 90-minute psychotherapy sessions to establish a therapeutic alliance with the therapist and prepare for the MDMA experience. MDMA was then administered during 8-hour experimental sessions of specially adapted psychotherapy. These were followed by an overnight stay, 7 days of telephone contact, and three 90-minute psychotherapy sessions aimed at integrating the experience. Overall, each course of treatment included 18 hours of non-drug psychotherapy and 16–24 hours (two to three sessions) of MDMA-assisted psychotherapy. One month after the second session took place, more participants in high dose groups no longer met diagnostic criteria for PTSD compared with the low dose group. On average, the 75 mg and 125 mg groups experienced greater decreases in PTSD symptom severity compared with the 30 mg group. While the authors found statistically significant differences even though the study was not powered for this, further research from large multisite phase 3 studies is required to obtain definitive results regarding safety and efficacy. All groups reported adverse events that emerged after the treatment, including anxiety, headache, fatigue, muscle tension and insomnia. During the treatment, transient increases in suicide ideation were observed, including one participant with a history of suicide attempts who was admitted to hospital by their psychiatrist after the session, but who later completed the study.

Online first at the MJA

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