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Dementia

Aerobic exercise and cognitive function in older adults – new findings

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Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer’s disease (AD).

In older people, aerobic exercise training increases grey and white matter volume, enhances blood flow, and improves memory function.

The ability to measure the effects of exercise on systemic biomarkers associated with risk for AD and relating them to key metabolomic alterations may further prevention, monitoring, and treatment efforts.

However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. 

To address this issue scientists tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health.

They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilised to understand biochemical pathways that may be affected by AD. 

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the “aeRobic Exercise And Cognitive Health (REACH) Pilot Study” (NCT02384993) at the University of Wisconsin.

The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results of the study, published in the journal Frontiers in Endocrinology, showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training in older adults at risk for AD.

Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho.

The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia. 

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis.

Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness. 

The study was conducted by Henriette van Praag, from Florida Atlantic University’s Schmidt College of Medicine and Brain Institute and Ozioma Okonkwo, Wisconsin Alzheimer’s Disease Research Center and Department of Medicine at the University of Wisconsin-Madison.

“Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function,” said van Praag.

“Human studies often utilise expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer’s-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets.” 

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels.

BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning. 

“The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer’s disease,” said van Praag.

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Dementia

50,000 call on government to fix broken dementia research promises

Alzheimer’s Research UK has pleaded with the UK government to invest in dementia studies, as it promised to do back in 2019.

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More than 50,000 people have signed a petition to ask the UK government to double its funding for dementia research and keep the promises it made two years ago.

Boris Johnson initially said there would be £160 million invested into the sector in the 2019 Conservative manifesto, but there has been a lack of movement in this area since.

This has spurred the Alzheimer’s Research UK charity to launch the petition, calling on Number Ten to help fund possible treatments for dementia.

The pandemic has been particularly hard for those with the disease, with a quarter of COVID-related deaths coming from this group.

The charity feels the sector has been neglected in recent years with David Thomas, head of policy at Alzheimer’s Research UK, saying the funding is the best chance of curing the condition.

“Dementia research is an area of huge need,” he said. “There are a huge number of people affected by it and with an aging population that will only increase.

“There are currently no treatments in the UK for the disease so we think research is vitally important to tackling that.

“We’ve seen an historic underfunding for dementia research. When the Conservatives announced their manifesto and made a commitment to double dementia research funding we thought that would be a great step forward.”

An Alzheimer’s Research UK supporter has also made a personal plea with the government to change this.

Olive Munro lives with vascular dementia and this week she submitted a letter to the Prime Minister asking him to make sure future generations do not suffer the same fate as her.

“She supports our campaign,” David said. “Her letter set out the impact that her diagnosis has had on her life and ultimately she wants to ensure that her children and grandchildren don’t have to go through a similar terrible situation.”

“I think it’s a really powerful message Mrs Munro has sent.”

The pandemic has been a big player in regards to this underfunding, but its impact on those with dementia has only heightened these concerns.

As well as this a lack of finances have meant that a number of researchers across all sectors have been lost, only making the situation worse.

This is why the charity has chosen to call on the government now. With the crisis in its latter stages Alzheimer’s Research UK wants to see a similar success that has come about from the vaccination programme.

“We understand that COVID has played its part,” David said. “It has had a significant impact on government priorities and we’re very sensitive to the fact that since the promises were made we have been in this crisis.

“But with the pandemic moving into a different stage and the vaccine programme being such a big success, now feels like the right time to meet that commitment.

“COVID has had a devastating impact on people living with dementia, so we think the pandemic has made this more urgent not less urgent.”

There is support across parliament for this investment, with over 100 MPs across all major parties supporting the move.

The petition has also been signed by some famous names, including Dame Judi Dench, Julie Walters, Stephen Fry and Dame Harriet Walter.

If it were to progress and the government were to double dementia funding then it would have a profound impact on the sector. 

“Ultimately what we hope that funding will lead to is new treatments in this space that will ultimately stop the progression of the disease, which we haven’t got at the moment.

“We also hope it will lead to improvements in detection and diagnosis of the disease as that is really important.

“One particular thing we think the additional funding could do is ensure that we don’t lose a generation of researchers and that we keep and expand that talent, because that’s the people who will be responsible for delivering those life changing treatments.”

Away from the UK there has been some progress in this area.

In America the first dementia treatment in over 20 years was approved recently, which is a landmark move.

David is hoping this can send a clear message to the UK government that progress for this really is possible.

Many in the research industry are hoping this will lead to the approval of further treatments, as well as more investment from big pharmaceutical companies.

There is certainly the appetite for these changes, as Alzheimer’s Research UK has shown, but it is now in the government’s hands to act upon this.

“We have over 50,000 people who have signed the petition and we are well aware that behind each one is a story around the impact dementia has had on them,” he said. 

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Dementia

Novel target shows promise in treating Alzheimer’s and related dementias

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Researchers remain perplexed as to what causes dementia and how to treat and reverse the cognitive decline seen in patients.

In a first-of-its-kind study, however, researchers have discovered that cis P-tau, a toxic, non-degradable version of a healthy brain protein, is an early marker of vascular dementia (VaD) and Alzheimer’s disease (AD).

Their results define the molecular mechanism that causes an accumulation of this toxic protein.

Furthermore, they showed that a monoclonal antibody (mAb) that targets this toxic protein was able to prevent disease pathology and memory loss in AD- and VaD-like preclinical models.

Additionally, this treatment was even capable of reversing cognitive impairment in an AD-like preclinical model.

The study was conducted by researchers at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center (BIDMC) at Harvard Medical School.

Onder Albayram, co-lead author and assistant professor in the Division of Cardiology in the Department of Medicine at MUSC, said: “We believe our findings have not only discovered cis P-tau as a previously unrecognized major early driver of VaD and AD but also identified a highly effective and specific immunotherapy to target this common disease driver for treating and preventing AD and VaD at early stages.”

Aging is a normal part of life – we experience weakening of our bones and muscles, stiffening of our blood vessels and some memory lapses.

But for around 50 million people worldwide, these memory lapses become progressively more severe, ultimately leading to a diagnosis of dementia.

Dementia is an umbrella term that covers AD, which accounts for 60 to 80 per cent of cases; VaD, the second most common cause; and other less common pathologies.

Currently, there are no effective treatments for AD. Interestingly, most AD cases have a vascular component, suggesting a broader relationship between cognitive function and healthy brain vasculature.

A better understanding of that relationship could provide a platform to discover novel therapeutic targets.

“Our work provides evidence that cis P-tau may be a pathogenic factor that explains VaD, which is not generally linked to other dementias,” added Chenxi Qiu, co-lead author and a postdoctoral research fellow at BIDMC, Harvard Medical School. 

In a preclinical model of VaD, young mice showed signs of brain inflammation and memory loss within one month.

However, treating these mice with the cis P-tau mAb prevented neural degradation and cognitive decline out to six months. In a separate preclinical model of AD, old mice showed severe cognitive impairment.

This severe impairment was significantly reversed when mice were given the cis P-tau mAb. 

“These data show that cis P-tau could be an early upstream pathogenic factor common to both diseases,” said Albayram.

Translating information gained from preclinical models to humans is often difficult, but this study offers reasons to be optimistic.

Accumulation of cis P-tau caused dramatic changes in the genetic architecture of affected cells in a VaD model; these changes were consistent with those seen in human AD patients.

The researchers went on to show that treatment with the cis P-tau mAb reversed 85 to 90 per cent of those changes suggesting the power of this potential therapy.

“The genomic landscape really adapts after the silencing of this toxic protein,” said Albayram. “That was a big discovery.” 

Not only are Albayram and Qiu excited about these findings, but colleagues at MUSC are already quite enthusiastic about this work.

The research opens the door for new potential immunotherapies and highlighted several new areas of research that need to be explored.

While the researchers delineated a pathway that leads to the accumulation of cis P-tau, the underlying linkage between vascular abnormalities and activation of the pathway needs to be identified.

A better understanding of how toxic cis P-tau interacts with the healthy trans P-tau could provide further insights into the progression of AD disease.

AD and VaD might not be the only diseases affected by high levels of cis P-tau. Other brain disorders with a vascular component might also arise from this toxic protein, but further study will be required to establish such a link.

“Cis P-tau may be a common, early and pathogenic factor underlying traumatic brain injury, VaD and AD,” said Qiu.

As we get older and our memory begins to lapse – misplacing our car keys or forgetting the name of a new acquaintance – we fear the possibility that these are the first signs of dementia.

And while there is currently no approved treatment to reverse the physiological effects of dementia, this new research may provide hope that new therapies are around the corner.

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Dementia

Alzheimer’s drug given US approval

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The first new treatment for Alzheimer’s disease for nearly 20 years has been approved by regulators in the United States.

Aducanumab targets the underlying cause of Alzheimer’s, the most common form of dementia, rather than its symptoms.

An estimated 850,000 people live with dementia in the UK – around 100,000 of whom with early stage dementia could benefit from the drug – with the US approval of aducanumab giving hope that it could next be approved here. 

Aducanumab – which has had a controversial trial period to date – targets amyloid, a protein that forms abnormal clumps in the brains of people with Alzheimer’s that can damage cells and trigger dementia, including memory and thinking problems and communication issues.

In March 2019, late-stage international trials of aducanumab, involving about 3,000 patients, were halted when analysis showed it was no better, given as a monthly infusion, at slowing the deterioration of memory and thinking problems than a dummy drug.

But later that year, the US manufacturer Biogen analysed more data and concluded higher doses of aducanumab significantly slowed cognitive decline.

Charities have hailed the development as “promising” but stressed that it is the “beginning of the road”. 

“It’s promising to see that aducanumab has been approved for use in people with early stage Alzheimer’s disease—the first drug to be approved in nearly 20 years by the US regulatory authorities,” says Dr Richard Oakley, head of research at Alzheimer’s Society. 

“We await the opinion of the European Medicines Agency and the outcome of any application made to the UK regulatory authorities, to give clarity to people with early Alzheimer’s disease in the UK. 

“Whatever the outcome of their decision, this is just the beginning of the road to new treatments for Alzheimer’s disease. As this drug will only benefit a proportion of people in the early stages of Alzheimer’s disease, there are hundreds of thousands more who may not be eligible, so we must keep searching for drugs for all stages of Alzheimer’s disease and for other types of dementia.”

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