Promising Discovery: Skin Test Identifies Rare Brain Disease With 90% Accuracy

This breakthrough could revolutionize the diagnosis of progressive supranuclear palsy (PSP), a rare neurodegenerative disease with a dismal course. With a simple skin biopsy, doctors will be able to confirm the disease in a less invasive and faster way, helping patients receive appropriate treatment and follow-up sooner. In addition, the high accuracy of the test could improve the selection of participants for clinical trials, which is essential for the development of more effective therapies in the future.

Progressive supranuclear palsy (PSP), or Steele Richardson Olszewski Syndrome, is a rare neurodegenerative disease that severely affects motor coordination, balance and the ability to swallow. It belongs to a group of brain diseases caused by the gradual death of nerve cells, and shares similarities with other well-known diseases, such as Parkinson's.

However, progressive supranuclear palsy has its own characteristics and challenges, especially in diagnosis, which is often difficult and often confused with other conditions. This is partly due to the lack of specific and accessible tests that can identify the disease early and accurately.

In neurodegenerative diseases, such as progressive supranuclear palsy, one of the key processes is the accumulation of misfolded proteins inside nerve cells.

These proteins, such as tau or alpha-synuclein, lose their normal shape and begin to group together abnormally, which interferes with the functioning of the cells and contributes to their death.

This buildup damages different regions of the brain and nervous system, resulting in progressive symptoms such as muscle stiffness, frequent falls, and difficulty speaking and swallowing.

These misfolded proteins can now be detected in the fluid that circulates in the brain and spinal cord (cerebrospinal fluid), obtained through a lumbar puncture. However, this procedure is invasive, not always available, and cannot be performed on all patients.

As a result, many cases are diagnosed based solely on symptoms observed by doctors, which can lead to errors, especially in less common diseases such as progressive supranuclear palsy. It also hinders research, as patients with incorrect diagnoses may end up participating in studies focused on other diseases, such as Parkinson's, compromising the results.

MRI and DaTscan (a nuclear imaging test that allows doctors to see dopamine levels in the brain) are characteristic of progressive supranuclear palsy (PSP). Image: “‘Round-the-houses’ sign” by James B. Rowe, University of Cambridge Department of Clinical Neurosciences, Cambridge, Cambridgeshire, UK. License: CC BY 4.0

With this in mind, researchers have developed an innovative skin biopsy-based test to directly detect the presence of misfolded tau proteins specific to progressive supranuclear palsy.

The idea came from previous studies in which scientists had developed a test to identify the misfolded alpha-synuclein protein (a hallmark of Parkinson’s) in the skin. This test had already shown good results and was being validated for use in research and, eventually, in clinical settings.

Neuron-oligodendrocyte interaction mechanisms potentially involved in α-syn accumulation: oligodendroglial uptake of α-syn from surrounding neurons and the extracellular environment, via endocytosis and passive transmembrane diffusion. Image by Lecturio.

Using the same technology, the researchers adapted the test to recognize a specific form of the tau protein that accumulates in people with progressive supranuclear palsy. This technique, called the seeding amplification assay (SAA), acts as a kind of “misfolded protein detector”: if the misfolded protein is present, the test can amplify it and make its presence visible.

The seeding amplification assay (SAA) is a laboratory technique that works like a “multiplication test” to detect small amounts of misfolded proteins that are associated with neurodegenerative diseases such as Parkinson’s or progressive supranuclear palsy (PSP).

If there is a tiny “seed” of faulty protein in the sample (such as from skin or brain fluid), the test creates a controlled environment that allows that protein to multiply rapidly, much like yeast making bread rise.

At the end of the process, scientists can identify whether that abnormal protein is present, even in very small amounts, helping to diagnose the disease with high accuracy. It’s like turning up the volume of something barely audible until it becomes clear and unmistakable.

The seeding amplification assay (SAA). Image Lou et al. ACS Chemical Neuroscience Vol 15/Issue 18

The results were promising. In skin samples from PSP patients, the test detected misfolded tau in 90% of cases. In contrast, the protein was barely found in people with other similar diseases, such as Parkinson's, multiple system atrophy, and corticobasal degeneration, and was never detected in healthy people.

This shows that the test has both high sensitivity (detecting the disease when it is present) and high specificity (not giving false positives in people who do not have the disease).

This breakthrough could revolutionize the diagnosis of PSP. With a simple skin biopsy, doctors will be able to confirm the disease in a less invasive and faster way, helping patients receive appropriate treatment and follow-up sooner.

In addition, the accuracy of the test could improve the selection of participants for clinical trials, which is essential for the development of more effective therapies in the future. Researchers are now conducting multicenter trials, that is, in different hospitals and research centers, to validate the clinical use of this new test.

READ MORE:

Four-Repeat Tau Seeding in the Skin of Patients With Progressive Supranuclear Palsy

Ivan Martinez-Valbuena, M. Carmela Tartaglia, Susan H. Fox, Anthony E. Lang, Gabor G. Kovacs 

JAMA Neurol. 2024;81(11):1228-1230. 

doi:10.1001/jamaneurol.2024.3162

Abstract:

The emergence of α-synuclein seeding amplification assays (SAA) has provided a new tool to support a clinical diagnosis of Parkinson disease (PD)1 and multiple system atrophy (MSA). This technology enables the detection of aggregated forms of α-synuclein (the neuropathologic hallmark of these diseases) in brain, cerebrospinal fluid, and in peripheral tissues, such as skin.