Developing blood tests for neuropsychiatric disorders

Many neuropsychiatric conditions — including Alzheimer’s disease, chronic depression and severe social withdrawal (or ‘hikikomori’) — are notoriously difficult to diagnose. But the ability to detect trace amounts of certain compounds in the blood could make it much easier to screen for such conditions.

Now, by drawing on their expertise in mass spectrometry, researchers at Shimadzu Corporation in Kyoto, Japan, and their collaborators are seeking to identify and measure novel blood plasma biomarkers for various neurological conditions.

“Finding effective blood biomarkers could greatly improve diagnostics and treatments, providing reassurance and enhancing patients’ quality of life,” notes Koichi Tanaka. He leads the Koichi Tanaka Mass Spectrometry Research Laboratory at Shimadzu and was awarded the Nobel Prize in Chemistry in 2002 for his pioneering research into soft laser desorption for identifying proteins.

A member of Tanaka’s team, Shimadzu researcher Naoki Kaneko is helping to develop blood biomarkers for dementia. He believes that mass spectrometry — a technology first developed more than 100 years ago — has reached a point where it can aid in the diagnosis of neurological conditions.

“Mass spectrometers are now sophisticated enough to measure many kinds of molecules, from proteins and sugars to DNA and metabolites,” Kaneko says. “As mass-spectrometry systems become smaller, cheaper and easier to use, widespread clinical use of this technology could enable accurate screening for multiple disorders from a single blood test.”

Amyloid in the blood

A key characteristic of the development of Alzheimer’s disease is the formation of plaques of the protein amyloid-beta in the brain. These plaques build up around neurons, and they are thought to disrupt brain function, leading to cognitive degeneration.

Since amyloid-beta begins to accumulate between neurons years before any other symptoms become apparent, detecting plaques could provide any early warning system. “Accurate measurement of amyloid-beta in the blood could even determine a person’s likelihood of developing Alzheimer’s disease 20 years later,” says Kaneko.

Amyloid-beta accumulation is currently determined by positron emission tomography (PET) scans of a patient’s brain or by using an immunoassay to search for amyloid-beta in cerebrospinal fluid. But PET scans are expensive, while obtaining cerebrospinal fluid is invasive.

“Testing amyloid-beta in the blood would be much simpler and less invasive for both patients and medics,” says Tanaka.

A major challenge to realizing such blood tests are the minuscule levels of amyloid-beta in the blood. “Amyloid-beta seeps from the brain into the bloodstream in trace amounts,” says Tanaka. “We need to screen out the common components of blood to detect these elusive molecules.”

Tanaka and co-workers have overcome this problem by using antibody-coated beads to isolate proteins of interest from a blood sample and then employing a sophisticated mass spectrometry technique known as matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry¹.

Proof of the pudding

To test their technique, the team collaborated with the National Center for Geriatrics and Gerontology, in Japan, and the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL). Using cohorts with and without Alzheimer’s symptoms, they conducted blind analysis of blood samples and compared the results with PET scans. Their biomarker blood test reliably identified individual levels of amyloid-beta in the brain².

Shimadzu’s team worked with a Japanese initiative that is recruiting 20,000 healthy volunteers to look for preclinical signs of dementia. The trials further tested the blood biomarker for Alzheimer’s disease.

Tanaka doesn’t envisage blood tests replacing PET scans when diagnosing Alzheimer’s; rather they will be useful for initial screening of patients.

“There have been suggestions that if progression of Alzheimer’s can be determined from blood samples, then PET scans won’t be needed,” says Tanaka. “However, peripheral blood cannot determine the condition of specific brain regions. Combining the two methods will provide the most accurate diagnosis.”

The team is now looking for biomarkers for other forms of dementia, including dementia with Lewy bodies, as well as exploring biomarkers for healthy ageing and longevity.

Depression biomarkers

While physical diseases can regularly be diagnosed and acknowledged, people with other kinds of brain-related disorders such as depression are often stigmatized because their condition cannot be easily verified.

“The mind and body are inextricably linked,” says Takahiro Kato, a psychiatrist at Kyushu University in Fukuoka, Japan. “At its heart, my search for mental-health-related blood biomarkers is an anti-stigma campaign.”

Shimadzu’s liquid chromatography–mass spectrometry technologies are essential for Kato’s research. Kyushu University and Shimadzu entered into a joint research agreement in 2022.

In a 2016 study, Kato’s team revealed that 3-hydroxybutyrate is a potential metabolic biomarker for predicting the severity of depression³. They highlighted several other biomarkers specific to individual symptoms of major depressive disorder.

“We were surprised to find the same biomarkers across three independent cohorts,” says Kato. “Depression has a myriad of symptoms including fatigue and suicidal ideation. Our network analysis revealed that each symptom has a possible independent biological biomarker.”

For example, their data hints that levels of both tryptophan and kynurenine-related metabolites could be linked to suicide ideation3. If such biomarkers can be measured using a simple blood test, it could encourage people to seek help quicker, notes Kato.

The team is now gathering data from larger cohorts to validate these biomarkers for depression. 

Testing for hikikomori

Hikikomori is a major social problem in Japan, with a 2023 government survey estimating that nearly 1.5 million people have withdrawn from society, rarely leaving their homes or communicating with others for six months or more.

This debilitating psychological state is now becoming increasingly common across the world, particularly following the COVID-19 pandemic.

“Hikikomori is a significant cultural mental-health disorder for our time,” says Kato, who has set up the world’s first outpatient clinic specializing in hikikomori within a university hospital.

In addition to conducting psychological tests on patients, Kato’s team, in collaboration with Shimadzu, is collecting blood plasma for liquid chromatography–mass spectrometry analysis⁴. They are collating longitudinal data, examining metabolites in people with varying severity of hikikomori over time.

The team has recently published preliminary results⁴. “We’ve found several metabolite biomarkers that potentially differ in individuals with hikikomori and in healthy controls,” says Kato. “These findings may hint at ways of extending therapeutic approaches, such as dietary interventions.”

Kato recently published a set of diagnostic criteria for hikikomori⁵. His team is also developing a stress-screening model, which combines stress-susceptibility classifications with blood biomarkers to monitor stress in the workplace. In collaboration with Shimadzu, Kato hopes to establish a comprehensive blood-testing service for use in national mental-health care and annual health checks.

Tanaka sees biomarker detection as playing a vital role in promoting health, both mental and physical. “Multiple strands of research are needed to prevent or cure diseases, making innovation through collaboration between different disciplines and stakeholders essential,” concludes Tanaka. “Every biomarker discovery helps us refine and optimize our hardware.”

References

1. Kaneko, N. et al. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 90, 104–117 (2014).
2. Nakamura, A. et al. Nature 554, 249–254 (2018).
3. Setoyama, D. et al. PLOS One 11, e0165267 (2016).
4. Setoyama, D. et al. Dialog. Clin. Neurosci. 23, 14–28 (2021).
5. Kato, T. A. et al. World Psychi. 19, 116–117 (2020).

The text of this article was originally produced in partnership with Nature Portfolio as an advertisement feature. It was published on 27 February 2025 in the online version of Nature (nature.com), a weekly international journal, publishing the finest peer-reviewed research in science and technology. ( https://www.nature.com/articles/d42473-024-00345-3 )