10 Mar 2020

Study highlights gap in ageing brain research

L-R: Dr Mujun Sun (first author) and A/Prof
Sandy Shultz (last author)
by Anne Crawford

Neurological conditions such as traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis and Alzheimer's disease are leading causes of morbidity and mortality affecting millions of people worldwide. Yet the majority of clinical trials testing drugs for these common conditions have failed.

The Department of Neuroscience’s Associate Professor Sandy Shultz is among a growing number of scientists asking whether the failure to translate findings of preclinical studies to the clinic is because many patients with these conditions are middle-aged or older, yet most preclinical studies test only young adult animals.

Indeed, Associate Professor Shultz found in a recent review paper looking at the issue that even in the age-related Alzheimer’s disease, only 10% of preclinical studies incorporated aged animals. In stroke, where age is also a risk factor, the proportion was only 3-4%.

“We have an ageing world population that’s being affected by conditions we don’t have treatments for,” Associate Professor Shultz said.

The paper, published in Neuroscience and Biobehavioral Reviews, was triggered by research conducted recently in the department looking into different age responses in traumatic brain injury (TBI).

“We were seeing really interesting findings in terms of how the brain responds to insult depending on age,” Associate Professor Shultz said. “This prompted us to look at other areas of neurological disease as well to see whether or not similar issues were being reported in that literature.

“What became quite striking was there was a real gap in the literature out there about how age altered the course of neurological disease,” he said. “The little research that has been done in the young brain versus old brain shows that they respond to injury and disease differently. These studies certainly suggested that age was an important factor to consider.”

Traditionally male animals have been used because they are easier to study as scientists don’t have to take into account effects of the female reproductive cycle, another “disconnect” between preclinical and clinical studies, Associate Professor Shultz said.

He said scientists used younger animals because experiments could be done less expensively and faster, meaning studies could be turned over faster.

“Ageing broadly affects biological processes involved in a range of neurological conditions and if we want to develop drugs that are appropriate for these conditions that are primarily affecting older people we need to research them in older animals.”

A natural biological process, ageing involves a range of biological changes in the body including: changes in immune responses, called immunosenescence; protein dysregulation (including for tau and amyloid beta, proteins involved in Alzheimer’s disease); increased low-grade inflammation; increased oxidative stress; accumulated DNA damage; mitochondrial dysfunction and cerebrovascular abnormalities.

While other factors were involved in whether or not a neurological condition occurs, such as genetics, seven of the top 10 neurological conditions had age as a risk factor, Associate Professor Shultz said. The review focused on studies that had been conducted in TBI, stroke, Parkinson’s disease, Alzheimer’s disease and other dementias and multiple sclerosis.

He said the paper, written by experts in each of the conditions examined, was well-received and that the push by scientists towards using ageing animals was gaining momentum.

The paper concludes that much research is needed to better characterise how ageing modulates the pathobiology and outcomes in many of the diseases highlighted in the paper.

It was critical that scientists conduct preclinical work in older animals to increase the likelihood of developing effective treatments to treat debilitating neurological conditions in patients across the lifespan, it said.

Practitioners needed to acknowledge the importance of considering age in deciding on appropriate treatment strategies.

First author on the paper was Dr Mujun Sun, Research Fellow in the Department of Neuroscience Trauma Group.

Sun M, McDonald SJ, Brady RD, Collins-Praino L, Yamakawa GR, Monif M, O'Brien TJ, Cloud GC, Sobey CG, Mychasiuk R, Loane DJ, Shultz SR. The need to incorporate aged animals into the preclinical modeling of neurological conditions. Neurosci Biobehav Rev. 2020 Feb;109:114-128. doi: 10.1016/j.neubiorev.2019.12.027.

To read about similar Department of Neuroscience studies:

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