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Model may explain how deep brain stimulation treats Parkinson’s

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Parkinson's
Deep brain stimulation relieves some of the motor symptoms that Parkinson's patients experience

People with Parkinson’s disease and their doctors confront many unknowns, including the answer to exactly how deep brain stimulation (DBS) relieves some of the motor symptoms patients experience.

In a new study, scientists at Boston University and The Picower Institute for Learning and Memory at MIT present a detailed model explaining the underlying circuit dynamics, providing an explanation that, if experimentally confirmed, could improve the therapy further.

Among the things that are known about Parkinson’s disease is that a deficit of the neuromodulator dopamine is associated with abnormally high beta-frequency rhythms (brain waves at a frequency of about 20 Hz).

DBS, involving the delivery of high-frequency electrical stimulation to a brain region called the subthalamic nucleus (STN), apparently suppresses these elevated beta rhythms, restoring a healthier balance with other rhythm frequencies and better movement control.

The new biophysically-based computational model described in the Proceedings of the National Academy of Sciences posits that the beneficial effect of DBS arises from how it interrupts a vicious cycle promoting runaway beta in a circuit loop between the STN and a region called the striatum.

In 2011, study co-author Michelle McCarthy, research assistant professor of mathematics and statistics at BU, used mathematical models to show how, in the absence of dopamine, runaway beta might arise in the striatum from excessive excitement among striatum-dwelling cells called medium spiny neurons (MSNs).

The model, led by Picower Institute postdoc Elie Adam, builds on McCarthy’s finding.

Joining Adam and McCarthy are co-authors Emery N Brown, Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy Kopell, William Fairfield Warren Distinguished Professor of Mathematics and Statistics at BU.

The quartet’s work suggests that under healthy conditions, with adequate dopamine, cells in the striatum called fast-spiking interneurons (FSIs) can produce gamma-frequency rhythms (30-100 Hz) that regulate the beta activity of the MSNs.

But without dopamine, the FSIs are unable to limit the MSN activity and beta comes to dominate a whole circuit loop connecting the STN to the FSIs, to the MSNs, to other regions and then back to the STN.

“The FSI gamma is important to keep the MSN beta in check,” Adam said. “When dopamine levels go down, the MSNs can produce more beta and the FSIs lose their ability to produce gamma to quench that beta, so the beta goes wild.

“The FSIs are then bombarded with beta activity and become conduits for beta themselves, leading to its amplification.”

When DBS high-frequency stimulation is applied to the STN, the model shows, that replaces the overwhelming beta input received by the FSIs and restores their excitability.

Reinvigorated and freed from those beta shackles, the interneurons resume producing gamma oscillations (at about half the DBS stimulation frequency, typically at 135 Hz) that then suppress the beta activity of the MSNs.

With the MSNs no longer producing too much beta, the loop leading back to the STN and then to the FSIs is no longer dominated by that frequency.

“DBS stops the beta from propagating towards FSIs so that it is no longer amplified, and then, by additionally exciting FSIs, restores the ability of FSIs to produce strong gamma oscillations, that will in turn inhibit beta at its source,” Adam said.

The model reveals another important wrinkle. Under normal circumstances, different levels of dopamine help shape the gamma produced by the FSIs. But the FSIs also receive input from the brain’s cortex.

In Parkinson’s disease, where dopamine is absent and beta becomes dominant, the FSI’s lose their regulatory flexibility, but amid DBS, with beta dominance disrupted, the FSIs can instead become modulated by input from the cortex even with dopamine still absent.

That allows them a way to throttle the gamma they provide to the MSNs, and enable a harmonious expression of beta, gamma and theta rhythms.

By providing a deep physiology-based explanation of how DBS works, the study may also offer clinicians clues to how to make it work best for patients, the authors said.

The key is finding the optimal gamma rhythms of the FSIs, which may vary a bit from patient to patient.

If that can be determined, then tuning the DBS stimulation frequency to promote that gamma output should ensure the best results.

Before that can be tested, however, the model’s fundamental findings need to be validated experimentally. The model makes predictions necessary for such testing to proceed, the authors said.

The National Institutes of Health provided funding for the research.

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Medtronic targets US$784m MiniMed IPO

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Less than a year after unveiling plans to spin off its diabetes division, Medtronic has confirmed it is seeking to raise US$784 million through an initial public offering of its MiniMed business.

The company intends to offer 28 million ordinary shares at an expected price range of US$25 to US$28 per share.

Underwriters will be granted a 30-day option to purchase up to a further 4.2 million shares at the IPO price.

Once listed, the newly independent company will trade on the Nasdaq under the ticker symbol “MMED”, implying a potential valuation of as much as US$7.86 billion.

Medtronic announced last year that it would separate its US$2.8 billion diabetes unit to create what it described as the only company in the sector to offer a fully integrated insulin management ecosystem.

The business centres on the MiniMed 780G insulin pump, alongside its continuous glucose monitoring systems and smart insulin pen technology.

The diabetes division employs more than 8,000 people and is headquartered in Northridge, California, near Los Angeles.

As the group’s smallest segment by revenue, the spin-off forms part of a wider strategy to streamline Medtronic’s portfolio.

That restructuring has included the formation of kidney care-focused joint venture Mozarc Medical with DaVita in 2023, as well as the company’s exit from the ventilator market the following year.

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Stem cell therapy improves frailty mobility

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A stem cell therapy improved mobility in older adults with age-related frailty after nine months in a phase 2b trial, compared with placebo.

Frailty is a condition in which older people become less able to cope with everyday or sudden stress, leaving them more vulnerable to illness, injury and poor outcomes after surgery.

The study tested laromestrocel, an intravenous therapy derived from donor bone-marrow mesenchymal stem cells.

A total of 148 ambulatory adults with frailty took part, with researchers assessing physical performance and patient-reported outcomes.

Participants receiving the therapy walked further in the six-minute walk test, a standard measure of physical capacity.

After nine months, the treatment group walked an average of 63.4 metres more than those given placebo, a result described as clinically meaningful. At six months, the improvement was 41.3 metres but did not reach statistical significance.

The trial was conducted by Longeveron, a Miami-based clinical stage biotechnology company developing regenerative cell therapies for rare paediatric and chronic age-related conditions.

Joshua M. Hare, chief science officer at Longeveron, said: “We are highly encouraged by these Phase 2b results that demonstrate the potential of stem cell therapy to improve the condition of patients with ageing-related frailty.

“Those with Ageing Frailty are disproportionately compromised in their ability to cope with every day and acute stressors, are at high vulnerability to disease and injury, and are at increased risk for poor outcomes and death after surgery.

“This development area is at the core of Longeveron’s mission advancing stem cell therapies addressing life threatening conditions in the most vulnerable populations children and the elderly.”

Researchers also identified a potential biomarker, meaning a measurable biological indicator, linked to treatment response.

Higher doses of laromestrocel were associated with reductions in soluble TIE-2, a protein involved in blood vessel signalling.

Laromestrocel is being evaluated across several conditions.

The company said the findings point to a possible stem cell therapy approach for managing reduced mobility and other features of age-related frailty.

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Agetech investment and innovation round-up

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Global market to hit US$740bn in 2026, longevity needs lifts? ‘little brain’s’ big role, ageing ethics questioned…and more

IRISH insight and analysis company Research and Markets estimates the global ageing economy will surpass US$740bn this year.

These projections by the company, which is based next to the Guinness Brewery in Dublin, come in its latest paper, entitled: Longevity Market Report 2026-2036.

It takes a holistic view of the ageing economy encompassing consumer wellness, institutional healthcare, technology and regenerative medicine.

In a press release, accompanying the launch Research And Markets, say: “The longevity market is undergoing a structural shift, moving beyond predominantly consumer-driven wellness offerings toward institutionally funded healthcare solutions.

“Insurers, employers, health systems and pharmaceutical companies are increasingly integrating longevity-focused strategies to address the challenges of ageing populations, rising chronic disease burden and long-term cost sustainability.

“This evolution is accelerating demand for integrated platforms that enable early risk identification, targeted prevention and ongoing clinical engagement across the life course.”

Canadian researchers at McGill University say they have found a direct link between age‑related declines in the ‘little brain’ and worsening motor skills.

‘Little brain’ levers

Lead research author Eviatar Fields, a McGill doctoral student in the Integrated Program in Neuroscience, highlights how diminishing neuron activity in the cerebellum – at the base of the skull and known as the little brain – can impact gait, balance and agility.

The research pinpointed how changes in Purkinje cells – a key type of cerebellar neuron – drive this decline and translate into measurable changes in behaviour and physical function.

“By demonstrating how the changes that happen to Purkinje cells in age are causally linked to changes in gait, motor co-ordination and balance, our work provides new avenues for therapies that may prevent or delay motor aging.”

“This provides new hope for extending health span and ultimately improving quality of life and independence in elderly people,” said Mr Fields.

German lift company TK Elevator, is projecting a surge in demand as the global population ages and people find it increasingly difficult to use the stairs.

“As populations age – and that’s happening in Europe, it’s going to happen in China, everywhere else – there’s a need to put in elevators,” said Uday Yadav, its chief executive, speaking to the FT.

Longevity lifts

There are 22 million lifts worldwide, of which 30 per cent are more than 20 years old and potentially ripe to be refitted, he added.

TK Elevator, which was sold by German industrial conglomerate Thyssenkrupp to private equity firms Advent and Cinven for €17.2bn in 2020, is said to be looking at a potential €25bn market listing. Its revenues topped €9bn last year.

Researchers funded by the American Heart Association say the amino acid Taurine increased the life expectancy of mice, and monkeys by up to 25%.

Taurine is one of the most abundant amino acids within our bodies. It is secreted naturally and can be found in foods such as turkey, chicken, shellfish, and dairy.

It has the ability to lower blood pressure, act as an anti-inflammatory agent, and support cardiovascular health, but the concentration within human blood decreases as we age.

As well as longevity, the mice that were fed taurine exhibited improved bone density, muscle mass, pancreas function, and gut health.

Ethical questions

British GP and Medical Director Rammya Mathew has questioned the ethics of longevity highlighting how patients are being charged hefty sums of money ‘for investigations that are often unnecessary, of uncertain benefit, or unsupported by robust evidence’.

She added: “This is framed as empowering patients with knowledge, but it risks crossing the line into over-medicalisation of healthy people.”

The article published in the British Medical Journal continues: “I have watched this field with growing interest, particularly as an increasing number of high profile clinicians, some of whom have held senior roles in the NHS, move into private longevity medicine.

“Practising privately is not unethical in itself. But it does place doctors in an environment where the evidence base is often less clear, commercial pressures are more explicit, and the temptation to conflate innovation with benefit is real.”

Levels of the Nicotinamide Adenine Dinucleotide (NAD+) – a vital coenzyme found in every human cell – are the target of new research by the Nestlé Institute of Health Sciences.

The research published in the Nature Metabolism Journal indicates that certain NAD+ precursors can boost cellular energy levels and influence gut microbiome activity.

The study discovered that NAD+ precursors – nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) increased circulating NAD+ concentrations.

NAD+ levels decline with age in multiple tissues – muscle, liver, brain and skin – by as much 65% from young adulthood to old age.

This contributes to hallmarks of aging like mitochondrial dysfunction, reduced energy production, impaired DNA repair, increased inflammation, and cellular senescence.

Ongoing research has shown that restoring NAD+ (via precursors) improves mitochondrial function, metabolic health, and resilience.

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