Deciphering the signals from the ageing brain | MEDICUS 2024 Issue 1

Deciphering the signals from the ageing brain
By Dr Chua Li Min, Science writer

Credit: iStock.com / wildpixel

The occasional forgotten errand, misplaced keys or spectacles: we’ve all been there. These harmless blips in our memory tend to become more frequent with age, a gentle drift some dismiss simply as a natural part of ageing. But for 55 million people worldwide, such seemingly trivial memory lapses mark the beginning of a distressing and irreversible decline that spirals away from the path of normal ageing.

In Singapore, 44,000 people were living with dementia in 2015, a number that on the current population ageing trajectory is estimated to double by 2030.

“Ageing is the strongest risk factor for dementia,” said Dr Ng Kok Pin, a senior consultant from the Department of Neurology at the National Neuroscience Institute who runs the Memory Clinic, where he sees patients as young as in their 50s who have experienced bouts of forgetfulness.

And one of the first things he assesses is the extent of their cognitive impairment because unlike ageing, dementia is defined by a gradual loss of nerve cells that leads to widespread damage of the brain. “If the patient presents to the clinic at a fairly late stage when there are established cognitive and functional impairment, then there will be less of a diagnostic dilemma,” added Ng, who is also a clinical associate professor with the SingHealth Duke-NUS Neuroscience Academic Clinical Programme.

But more often than not, his patients fall into a grey area—displaying only a mild degree of cognitive impairment or even achieving normal scores on cognitive screening tests.

“So the onus is on us, as clinicians then to decide who is likely to be in a very early stage of neurodegeneration and at-risk of cognitive decline and dementia. For this group of patients, it is crucial that we monitor them closely and regularly and provide timely intervention to delay the progression of their condition.”

But what about the patients who don’t make it to the clinic?

“As of now, you can’t turn back the clock with cognitive impairment, but you can slow the decline over time. So really changing people’s mindsets about what it means, and destigmatisation is really important.”
Assoc Prof Angelique Chan

Admitting it’s more than just forgetfulness

More than one in ten people over the age of 60 live with some form of undiagnosed cognitive impairment, said Associate Professor Angelique Chan, director of the Duke-NUS Centre for Ageing Research and Education (CARE).

This figure emerged from a survey by Chan and her team at CARE of more than 3,000 elderly residents above the age of 60 staying in Singapore’s Whampoa district.

“I think there’s a lot of stigma still around getting treatment for cognitive impairment. Patients are probably less likely to go for treatments, particularly if they’re not well educated. Sometimes it requires family members to notice, and then to suggest that the older person gets looked at in the clinic,” she said.

Associate Professor Angelique Chan feels that more long-term studies are needed to evaluate the effectiveness of interventions in care // Credit: Duke-NUS

Increasing public awareness about the condition would help to prevent people from slipping through the cracks, suggests Chan. It would also enable patients to understand that the symptoms which they are experiencing are medical issues, and not because of personal weakness.

“As of now, you can’t turn back the clock with cognitive impairment, but you can slow the decline over time. So really changing people’s mindsets about what it means, and destigmatisation is really important,” added Chan.

This information would also help prepare caregivers for what to expect, and ease some of the burden associated with caring for someone with dementia.

Is it ageing or degeneration?

Back at the memory clinic, tools such as brain imaging allow clinicians like Ng to assess the brain health of an individual. He uses them to look for signs of shrinkage in specific regions of the brain, particularly areas that are involved in learning and memory.

At the clinic, magnetic resonance imaging scans offer clinicians like Ng the opportunity to examine changes in a patient’s brain // Credit: iStock.com / haydenbird

This is done using visual-rating scales, which help provide a general sense of the level of brain shrinkage in specific areas, such as the hippocampus, a region involved in memory, learning and emotion within the brain.

While this provides some clues, it is sometimes complicated by changes that are a natural consequence of ageing.

“As we age, our brain volume will gradually decrease globally. However, in neurocognitive disorders, certain brain areas tend to shrink first during the early stages of the disease,” explained Ng.

These shrinkages are caused by a flurry of events taking place at the cellular level, added Professor Zhang Suchun, director of Duke-NUS’ Neuroscience & Behavioural Disorders Programme: “We actually see a loss of nerve cells due to cell death, whereas some cells appear to have shrunk, or undergone degeneration.”

An illustration showcasing the extent of shrinkage in a diseased brain // Credit: iStock.com / Shivendu Jauhari

An illustration showcasing the extent of shrinkage in a diseased brain // Credit: iStock.com / Shivendu Jauhari

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While the changes taking place at the molecular level may be obvious, spotting the difference between ageing and degeneration in brain scans, particularly in the early stages of a disease, can be difficult.

“It’s very challenging to say that this is due to degeneration and not due to ageing,” added Ng, who is looking into other ways of enhancing the diagnosis of brain diseases.

Clinical Associate Professor Ng Kok Pin

Clinical Associate Professor Ng Kok Pin is exploring ways to enhance the diagnosis of brain diseases with biomarkers // Credit: National Neuroscience Institute

“When you are more definitive (about the diagnosis), it enables clinicians to make more definitive treatment plans, and enables patients to plan ahead for their lives and their families,” he explained.

What else can we do

Besides getting patients to receive treatment in the clinic, there are other ways to help them cope at home.

“Getting the older person outside for an hour a day, just to walk around helps,” said Chan, who noticed how this activity led to a reduction in the memory and behavioural problems for patients in her survey.

It also includes letting patients stay in environments where they are most familiar with: “Having older people age in place when they have cognitive impairment is most ideal,” said Chan. Conversely, moving them “will create even more trouble for them as they try to process new navigation routes in a new environment”.

But as many people remain undiagnosed, more needs to be done to ensure they can benefit from these interventions.

“These interventions have to be scaled at the community-level,” stressed Chan.

At the GK Goh Centre for Neuroscience, where Professor Zhang Suchun (right) is dissecting the mechanisms underlying ageing in the brain // Credit: Norfaezah Abdullah, Duke-NUS

Getting to the root of the problem

Beyond ensuring people get the care and support they need to alleviate the symptoms of dementia, scientists are digging deeper to try to understand what happens in the brain leading to dementia.

What is the first domino to fall and can that be prevented?

“If we identify something that signifies brain ageing, we can potentially do something to slow the ageing process.”
Prof Zhang Suchun

These questions are foremost in Zhang’s mind. So together with his team at the GK Goh Centre for Neuroscience, where he is centre director, Zhang aims to tease apart natural ageing from neurodegeneration.

“Understanding this process is fundamental to know why we have these diseases when we age. So I propose going the other way around. If we identify something that signifies brain ageing, we can potentially do something to slow the ageing process,” said Zhang.

What is so “worrisome” about brain diseases that happen during old age, added Assistant Professor Alfred Sun, who is also with the Neuroscience and Behavioural Disorders Programme, is the way in which they manifest: “The fact that your loved ones can no longer recognise you. That’s just too much to bear.”

It is also what keeps Zhang and the team going in their pursuit to unlock the mysteries of the ageing brain.

Leveraging a technique that he had pioneered to create induced pluripotent stem cells from blood, Zhang has come up with model systems that enable him to simulate how the brain deteriorates.

By getting the stem cells to grow into nerve cells, he plans to scrutinise the changes taking place, comparing the cells grown from a healthy individual and those derived from individuals where ageing is either accelerated or premature.

Compared with preclinical models, this approach is faster and more closely mirrors what is happening in the body, explained Zhang, who is hopeful that this approach will help to finally reveal the brain’s well-hidden mysteries.

Assistant Professor Alfred Sun

Assistant Professor Alfred Sun is researching into the mechanisms leading to neurodegeneration in Parkinson’s disease // Credit: Duke-NUS

The process of producing induced pluripotent stem cells from blood, which Zhang’s team then uses to grow them into nerve cells // Credit: Zhang Suchun, Duke-NUS

“So far, we don’t know what causes the problem. But we want to try to figure out the common biochemical or molecular processes underlying the ageing process,” he said.

“This, of course, is a huge but difficult undertaking,” admitted the veteran neuroscientist of more than 20 years, but one that he is prepared to take on. “If we can reach that goal, that would be a huge achievement, because not only will we be able to tease out the process, but also potentially identify some targets for intervention.”

Adding lab-grown brain power to their quest

To cover all the bases, Zhang is branching into the three-dimensional realm by printing cells in the culture dish using a mini printer. “The cells connect with each other, and it looks like what we see in the brain. We can also analyse the cells layer by layer,” he explained.

An image of the printed cells // Credit: Zhang Suchun, Duke-NUS

An image of the printed cells // Credit: Zhang Suchun, Duke-NUS

With this technique, Zhang hopes to identify if and how human neural networks go astray during the ageing process.

Sun, on the other hand is turning to mini-brains to solve the mystery behind Parkinson’s disease, another neurodegenerative disease that can also lead to dementia. “We were able to shortcut the disease progression significantly,” said Sun, who noticed the classic hallmarks of the disease in the organoids within half a year. He plans to follow this lead to dissect the mechanisms underlying the disease.

Mini brains grown on a culture plate // Credit: Alfred Sun, Duke-NUS

Mini brains grown on a culture plate // Credit: Alfred Sun, Duke-NUS