AsianScientist (Aug. 15, 2018) – Cocooned in protective sheaths of sturdy bone, tightly woven membranes and cushioning fluids, the brain is the body’s equivalent of Fort Knox—a site heavily barricaded and armed against the outside world.

But while the blood-brain barrier and other cranial defenses keep dangers out, they also seal medically important information in, making neurological diseases notoriously difficult to detect in their early stages.

Take the buildup of amyloid-β protein plaques in the brains of patients with Alzheimer’s disease, for example. Short of an autopsy, this stealthy accumulation can only be detected with expensive positron-emission tomography (PET) scans, or by measuring amyloid-β levels in cerebrospinal fluid—a procedure which requires an uncomfortable lumbar puncture.

Imagine, however, if you could detect Alzheimer’s disease the same way diabetics monitor their blood glucose levels: with a simple blood test. To develop such a test, researchers must find and measure molecules in the blood (called biomarkers) that are reliably associated with Alzheimer’s disease progression in the brain—a long-sought-after goal that has until recently eluded the field.

From the brain to the blood

“One of the main difficulties in developing blood biomarkerbased tests for any neurological disease, including Alzheimer’s disease, is the existence of the blood-brain barrier, which blocks information flow from the brain into the blood,” explained Dr. Katsuhiko Yanagisawa of the National Center for Geriatrics and Gerontology (NCGG) in Obu, Japan.

An exception is amyloid-β, which is transported across the blood-brain barrier into the blood. In January 2018, Yanagisawa’s laboratory detailed a prototype blood test in the journal Nature, using levels of amyloid-β fragments in plasma to distinguish Alzheimer’s patients from healthy individuals.

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The team used antibodies to ensnare the fragments in question, and then mass spectrometry to measure their levels—a hybrid technique known as immunoprecipitation-mass spectrometry. Yanagisawa said that his team’s use of ratios of amyloid-β fragments of different sizes, rather than the absolute levels of any one single fragment, was key to the success of the test, which held up against PET scan data and measurements of cerebrospinal fluid amyloid-β in cohorts in Japan and Australia.

More validation in different settings and over longer periods of time is needed before the test can make it into the clinic, emphasized Yanagisawa, who directs the NCGG’s Center for Development of Advanced Medicine for Dementia. When it does, he thinks the test will improve the design of clinical trials by allowing researchers to recruit patients in earlier stages of dementia. To date, all trials of potential Alzheimer’s therapies have failed; one theory is that without a good method for early detection, patients are being recruited too late for drug candidates to be effective.

Trials and tribulations

But missed treatment windows probably aren’t the only reasons behind the persistent failure of Alzheimer’s clinical trials. Recent work suggests that in the case of γ-secretase inhibitors—a class of drug meant to prevent the formation of amyloid-β plaques in the brain—the drug candidates themselves may not have behaved as expected.

In laboratory experiments, Dr. Masayasu Okochi and Dr. Shinji Tagami of Osaka University, Japan, were surprised to find that the γ-secretase inhibitor semagacestat in fact increased the accumulation of amyloid-β fragments in neurons, rather than suppressing it as expected. Taking a closer look, they realized that the drug was actually blocking the release of amyloid-β from cells, resulting in a toxic buildup of the protein inside them.

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Their results have two important implications. First, they could explain why γ-secretase inhibitors, despite their promise in the laboratory, have seen abysmal results in large clinical trials; in some cases, the compounds even worsened the cognitive decline of trial subjects, said Okochi.

Second, while the ratio of amyloid-β fragments in the blood could be useful for diagnosing patients early and recruiting them into clinical trials, it may be a less than-ideal biomarker for judging the effectiveness of drug candidates in these trials. Reduced levels of amyloid-β in the blood don’t necessarily mean that a drug is doing a good job of targeting the protein; rather—as in the case of semagacestat—the drug might be holding the protein captive inside the brain, where it can do the most damage.

In light of this evidence, Okochi and Tagami recommend that drug candidates be more thoroughly investigated before they are moved into clinical studies.

“There are still many ongoing clinical trials of compounds targeting amyloid-β; we think it is better to check whether the drugs have unexpected functions like what we found,” said Tagami.

Despite these complexities, our knowledge of Alzheimer’s biomarkers has advanced far enough that some are calling for a new way of looking at the disease. In April 2018, a coalition of experts writing in The Journal of the Alzheimer’s Association proposed that—at least for research purposes—diagnostic criteria for Alzheimer’s should be based on established biomarkers such as amyloid-β, rather than on patient symptoms. In the future, this “biological definition” of the disease—perhaps encapsulated in a drop of blood—may well become the norm.

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This article was first published in the July 2018 print version of Asian Scientist Magazine.
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Copyright: Asian Scientist Magazine; Photo: Lam Oi Keat/Asian Scientist Magazine.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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