Biomarker test can detect Alzheimer's pathology earlier

 

Years before tau tangles show up in brain scans of patients with Alzheimer's disease, a biomarker test developed at the University of Pittsburgh School of Medicine can detect small amounts of the clumping-prone tau protein and its misfolded pathological forms that litter the brain, cerebrospinal fluid and potentially blood, new research published today in Nature Medicine suggests.

The cerebrospinal fluid biomarker test correlates with the severity of cognitive decline, independent of other factors, including brain amyloid deposition, thereby opening doors for early-stage disease diagnosis and intervention.

Since amyloid-beta pathology often precedes tau abnormalities in Alzheimer's disease, most biomarker efforts have focused on early detection of amyloid-beta changes. However, the clumping of tau protein into well-ordered structures referred to by pathologists as "neurofibrillary tangles" is a more defining event for Alzheimer's disease as it is more strongly associated with the cognitive changes seen in affected people.

"Our test identifies very early stages of tau tangle formation -- up to a decade before any tau clumps can show up on a brain scan," said senior author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. "Early detection is key to more successful therapies for Alzheimer's disease since trials show that patients with little-to-no quantifiable insoluble tau tangles are more likely to benefit from new treatments than those with a significant degree of tau brain deposits."

Since many elderly people who have amyloid-beta plaques in their brains will never go on to develop cognitive symptoms of Alzheimer's disease during their lifetime, the widely adopted diagnostics framework developed by the Alzheimer's Association specifies the three neuropathological pillars necessary to diagnose the disease -- combined presence of tau and amyloid-beta pathology and neurodegeneration. In a quest for early and accessible biomarkers for Alzheimer's disease, Karikari's earlier work showed that a brain-specific form of tau, called BD-tau, can be measured in blood and reliably indicate the presence of Alzheimer's disease-specific neurodegeneration. Several years prior, Karikari showed that specific forms of phosphorylated tau, p-tau181, p-tau217 and p-tau212, in the blood can predict the presence of brain amyloid-beta without the need for costly and time-consuming brain imaging.

But these tools largely detect amyloid pathology, so the issue of early detection of tau still looms large. While tau-PET remains a reliable and accurate predictor of tau burden in the brain, the test's utility is limited by availability, low resolution, high cost, labor and sensitivity. At present, tau-PET scans can pick up the signal from neurofibrillary tangles only when a large number are present in the brain, at which point the degree of brain pathology has become pronounced and is not easily reversible.

In this latest research, using the tools of biochemistry and molecular biology, Karikari and team identified a core region of the tau protein that is necessary for neurofibrillary tangle formation. Detecting sites within that core region of 111 amino acids, a sequence they call tau_258-368,can identify clumping-prone tau proteins and help initiate further diagnostics and early treatment. In particular, the two new phosphorylation sites, p-tau-262 and p-tau-356, can accurately inform the status of early-stage tau aggregation that, with an appropriate intervention, could potentially be reversed.

"Amyloid-beta is a kindling, and tau is a matchstick. A large percentage of people who have brain amyloid-beta deposits will never develop dementia. But once the tau tangles light up on a brain scan, it may be too late to put out the fire and their cognitive health can quickly deteriorate," said Karikari. "Early detection of tangle-prone tau could identify the individuals who are likely to develop Alzheimer's-associated cognitive decline and could be helped with new generation therapies."

Other authors of this research are Eric Abrahamson, Ph.D., Xuemei Zeng, Ph.D., Anuradha Sehrawat, Ph.D., Yijun Chen, M.S., Tharick Pascoal, M.D., Ph.D., and Milos Ikonomovic, M.D., all of Pitt; Tohidul Islam, Ph.D., Przemys?aw Kac, M.S., Hlin Kvartsberg, Ph.D., Maria Olsson, B.S., Emma Sjons, B.S., Fernando Gonzalez-Ortiz, M.D., M.S., Henrik Zetterberg, M.D., Ph.D., and Kaj Blennow, M.D., Ph.D., all of University of Gothenburg, Sweden; Emily Hill, Ph.D., Ivana Del Popolo, M.S., Abbie Richardson, M.S., Victoria Mitchell, M.S., and Mark Wall, Ph.D., all of the University of Warwick, UK; Stijn Servaes, Ph.D., Joseph Therriault, Ph.D., Cécile Tissot, Ph.D., Nesrine Rahmouni, M.S., and Pedro Rosa-Neto, M.D., Ph.D., all of McGill University, Canada; Denis Smirnov, Ph.D., and Douglas Galasko, M.D., both of University of California, San Diego; Tammaryn Lashley, Ph.D., of University College London, UK.

This study was supported by, among others, the National Institute on Aging (grants R01AG083874, U24AG082930, P30AG066468, RF1AG052525-01A1, R01AG053952, R37AG023651, RF1AG025516, R01AG073267, R01AG075336, R01AG072641, P01AG14449, and P01AG025204, among others), the Swedish Research Council (grant 2021-03244), the Alzheimer's Association (grant AARF-21-850325), the Swedish Alzheimer Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Emil and Wera Cornells Foundation and a professorial endowment fund from the Department of Psychiatry, University of Pittsburgh.

Journal Reference:

1. Tohidul Islam, Emily Hill, Eric E. Abrahamson, Stijn Servaes, Denis S. Smirnov, Xuemei Zeng, Anuradha Sehrawat, Yijun Chen, Przemysław R. Kac, Hlin Kvartsberg, Maria Olsson, Emma Sjons, Fernando Gonzalez-Ortiz, Joseph Therriault, Cécile Tissot, Ivana Del Popolo, Nesrine Rahmouni, Abbie Richardson, Victoria Mitchell, Henrik Zetterberg, Tharick A. Pascoal, Tammaryn Lashley, Mark J. Wall, Douglas Galasko, Pedro Rosa-Neto, Milos D. Ikonomovic, Kaj Blennow, Thomas K. Karikari. Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease. Nature Medicine, 2025; DOI: 10.1038/s41591-024-03400-0 

Courtesy:

University of Pittsburgh. "Biomarker test can detect Alzheimer's pathology earlier." ScienceDaily. ScienceDaily, 10 February 2025. <www.sciencedaily.com/releases/2025/02/250210132601.htm>.

 

 

 

New treatment may offer quick cure for common cause of high blood pressure

 

Doctors at Queen Mary University of London, Barts Health NHS Trust, and University College London have led the development of a simple, minimally invasive Targeted Thermal Therapy (Triple T) that has the potential to transform medical management of a common, but commonly overlooked, cause of high blood pressure.

This breakthrough, published today in The Lancet, could, after further testing, help millions of people worldwide who currently go undiagnosed and untreated.

In the UK, Triple T, known scientifically as endoscopic ultrasound-guided radiofrequency ablation, was rigorously tested, in collaboration with researchers from University College London, University College Hospital NHS Trust, Cambridge University NHS Trust, and the University of Cambridge.

A hidden cause of high blood pressure

High blood pressure affects one in three adults, of whom a hormonal condition called primary aldosteronism accounts for one in twenty cases. However, fewer than one percent of those affected are ever diagnosed.

The condition occurs when tiny benign nodules in one or both adrenal glands produce excess aldosterone, a hormone that raises blood pressure by increasing salt levels in the body. Patients with primary aldosteronism often do not respond well to standard blood pressure medications and face higher risks of heart attacks, strokes, and kidney failure.

A game-changing alternative to surgery

Until now, the only effective cure for primary aldosteronism has been surgical removal of the entire adrenal gland, requiring general anaesthesia, a two-to three-day hospital stay, and weeks of recovery. As a result, many patients go untreated.

Triple T offers a faster, safer alternative to surgery, by selectively destroying the small adrenal nodule without removing the gland. This is made possible by recent advances in diagnostic scans, using molecular dyes that accurately identify and locate even the smallest adrenal nodules. Those in the left adrenal gland are seen to be immediately adjacent to the stomach, from where they can be directly targeted.

The new treatment harnesses the energy of waves, adapting two well-established medical techniques: radiofrequency or microwaves generate heat in a small needle placed into the malfunctioning tissue, causing a controlled burn; ultrasound uses reflected sound waves to create a real-time video of the procedure.

In Triple T, as in routine endoscopy, a tiny internal camera -- in this case using ultrasound as well as light -- is passed by mouth into the stomach. The endoscopist visualises the

adrenal gland and guides a fine needle from the stomach precisely into the nodule. Short bursts of heat destroy the nodule but leave the surrounding healthy tissues unharmed. This minimally invasive approach takes only 20 minutes and eliminates the need for internal or external incisions.

Successful trial shows promise

The study is called FABULAS, the name being an acronym for Feasibility study of radiofrequency endoscopic ABlation, with ULtrasound guidance, as a non-surgical, Adrenal Sparing treatment for aldosterone-producing adenomas.

FABULAS tested Triple T in 28 patients with primary aldosteronism, whose molecular scan had pinpointed a hormone-producing nodule in the left adrenal gland. The new procedure was found to be safe and effective, with most patients having normal hormone levels six months later. Many participants were able to stop all blood pressure medications, with no recurrence of the condition.

Professor Morris Brown, co-senior author of the FABULAS study and Professor of Endocrine Hypertension at Queen Mary University of London, said: "It is 70 years since the discovery in London of the hormone aldosterone, and, a year later, of the first patient in USA with severe hypertension due to an aldosterone-producing tumour. This patient's doctor, Jerome Conn, predicted, with perhaps only minor exaggeration, that 10-20% of all hypertensions might one day be traced to curable nodules in one or both glands. We are now able to realise this prospect, offering 21st-century breakthroughs in diagnosis and treatment."

One of the trial participants, Michelina Alfieri, shared her experience:

"Before the study, I suffered from debilitating headaches for years despite multiple GP visits. As a full-time worker and single parent, my daily life was severely affected. This non-invasive treatment provided an immediate recovery -- I was back to my normal routine straight away. I'm incredibly grateful to the team for giving me this choice."

What's next?

The success of FABULAS has led to a larger randomised trial called 'WAVE', which is comparing Triple T with traditional adrenal surgery. The results are expected in 2027.

Professor Stephen Pereira, Chief Investigator of FABULAS and Professor of Hepatology & Gastroenterology at UCL Institute for Liver and Digestive Health, added: "With appropriate training, this less invasive technique could be widely offered in endoscopy units across the UK and internationally."

Clinical Endocrinology Lead at Addenbrooke's Hospital and Professor of Clinical Endocrinology at the University of Cambridge, Professor Mark Gurnell, said: "This breakthrough was made possible thanks to the collaborative development of novel PET tracer molecules, which enable non-invasive diagnosis by allowing us to precisely locate and treat adrenal nodules for the first time.

"Thanks to this work, we may finally be able to diagnose and treat more people with primary aldosteronism, lowering their risk of developing cardiovascular diseases and other complications, and reducing the number of people dependent on long-term blood pressure medication," he added.

A major step forward for hypertension treatment

For the millions of people suffering from undiagnosed primary aldosteronism, this research offers new hope. Safely targeted thermal therapy, delivered by mouth, could replace major surgery, allowing faster recovery and better outcomes.

With further studies underway, this breakthrough treatment could soon become a standard procedure worldwide, transforming care for patients with this curable form of hypertension.

The research was primarily supported by Barts Charity, National Institute for Health and Care Research (NIHR) through the Barts and Cambridge Biomedical Research Centres (BRCs), and the British Heart Foundation.

It is being followed by a larger randomised trial, called 'WAVE', which will compare TTT to traditional surgery in 120 patients. The results are expected in 2027.

Journal Reference:

1. Giulia Argentesi, Xilin Wu, Alexander Ney, Emily Goodchild, Kate Laycock, Yun-Ni Lee, Russell Senanayake, James MacFarlane, Elisabeth Ng, Jessica Kearney, Sam O'Toole, Jackie Salsbury, Nick Carroll, Daniel Gillett, John A Tadross, Alison Marker, Edmund M Godfrey, George Goodchild, Jonathan P Bestwick, Mark Gurnell, Heok Cheow, Stephen P Pereira, William M Drake, Morris J Brown, Jose Bastos, Elena D Benu, Elizabeth Cervi, Patrizia Ebano, Razeen Mahroof, Iulia Munteanu, August Palma, Patrick Wilson. Endoscopic, ultrasound-guided, radiofrequency ablation of aldosterone-producing adenomas (FABULAS): a UK, multicentre, prospective, proof-of-concept trial. The Lancet, 2025; DOI: 10.1016/S0140-6736(24)02755-7 

Courtesy:

Queen Mary University of London. "New treatment may offer quick cure for common cause of high blood pressure." ScienceDaily. ScienceDaily, 10 February 2025. <www.sciencedaily.com/releases/2025/02/250210132401.htm>.