New brain scanning method safely tracks how Alzheimer’s drugs work in living patients

A recent study published in the journal Molecular Psychiatry provides evidence that a combination of non-invasive brain scanning and computer modeling can successfully measure how a dementia drug interacts with specific brain receptors in living patients. The research suggests that this approach could replace invasive procedures to confirm how well new treatments work in the brain. These findings offer a practical way to speed up the testing and development of novel therapies for Alzheimer’s disease.

“To make progress in new treatments for Alzheimer’s disease, we need tests (tools, assays) that can ‘see’ the changes in the living human brain with the same level of detail and insight that is taken for granted in animal models,” explained study author James Rowe, a professor of cognitive neurology at the University of Cambridge.

Traditionally, medical researchers have relied on animal models or post-mortem tissue to understand how drugs affect brain cells. Direct tests on living human brains are often unrealistic because of the protective blood-brain barrier and the solid enclosure of the skull.

This anatomical reality creates a significant hurdle when trying to prove that a new experimental drug actually reaches its intended target. The scientists conducted this study to test if they could measure a drug’s exact mechanism of action from the outside of the body without needing blood tests, biopsies, or injections. They focused on a well-known Alzheimer’s medication called memantine to see if their non-invasive methods could accurately detect how the drug operates.

Memantine is typically prescribed to treat moderate to severe Alzheimer’s disease. The scientists focused their attention on N-methyl-D-aspartate receptors, which are specific docking stations on brain cells that help manage memory and learning. In a healthy brain, these receptors are tightly regulated by magnesium, which acts like a biological blocker to prevent excess calcium from flooding and damaging the cells.

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In Alzheimer’s disease, this natural blocking mechanism tends to fail. This failure leads to an overload of calcium that disrupts brain function and contributes to progressive cognitive decline. The drug memantine helps by restoring this block and protecting the cells from becoming overloaded with calcium.

To observe these microscopic actions, the scientists used a technique called magnetoencephalography. This is a highly sensitive neuroimaging method that maps brain activity by recording the small magnetic fields produced by natural electrical currents in the brain. The scientists combined this non-invasive scanning method with advanced computer models that mathematically simulate the complex electrical behavior of brain cell networks.

“We proposed that the combination of magnetoencephalography with detailed computational models of an individual patient’s brain can achieve this. Since a lot is known about the drug memantine and its clinical benefit in Alzheimer’s, we used it as the test case for our method to study people with dementia,” Rowe said.

The scientists conducted two separate experiments to test their approach. In the first experiment, they recruited 19 neurologically healthy adults. The participants completed two brain scanning sessions spaced two weeks apart, receiving a 10-milligram dose of memantine in one session and a placebo pill in the other.

During the scans, the participants passively listened to a series of repeating audio tones that occasionally changed in pitch. The tones were played at half-second intervals over multiple five-minute blocks to establish a predictable rhythm. This repetitive auditory procedure triggers a specific brain reaction known as mismatch negativity.

Mismatch negativity is an automatic neurological response to an unexpected sound that disrupts an established pattern. It relies heavily on healthy N-methyl-D-aspartate receptors to function properly and process the new auditory information. The scientists found that memantine successfully increased the blockage of the N-methyl-D-aspartate receptors, exactly as the drug is designed to do.

The advanced computer models accurately detected this microscopic change simply by analyzing the magnetic fields generated during the audio task. This provided strong evidence that the mathematical models could accurately track drug effects inside a living human brain. The combination of safe brain scanning and customized computer modeling allowed the researchers to confirm the drug’s mechanism without invasive procedures.

In the second experiment, the scientists tracked 42 patients diagnosed with mild cognitive impairment or Alzheimer’s disease. All of these patients had tested positive for amyloid proteins, which are a hallmark biological sign of the disease. The researchers measured the patients’ brain activity using the same audio task at the beginning of the study.

The researchers then conducted a follow-up scan for 30 of these individuals about 16 months later to see how their brains had changed. The scientists observed that the brain’s automatic response to unexpected sounds was significantly weaker in the patients with Alzheimer’s disease compared to the healthy adults. This electrical response became even weaker as the disease naturally progressed over the 16-month period.

The neurological response was also weaker in patients who scored lower on the Mini-Mental State Examination, which is a standard questionnaire used to measure cognitive impairment. Lower scores on this standard test indicate more severe symptoms of dementia. Using their computer models, the scientists found that the natural blockage of the N-methyl-D-aspartate receptors was noticeably reduced in the patients with Alzheimer’s disease.

This reduction in receptor blocking worsened as the patients’ cognitive scores declined. It also worsened over time between the first and second scanning sessions. These findings confirm that Alzheimer’s disease and the drug memantine have opposite effects on the brain.

“The combination of safe, non-invasive MEG scanning with biophysical models of each patient’s brain, was able to show the correct mechanism of action of the drug,” Rowe told PsyPost. “This clears the way to explore the potential of new drugs. The importance of our study was to be able to detect how it works just from scanning the brain from the ‘outside,’ in living people non-invasively, with no bloods, no biopsy, no injections.”

The scientists emphasize that dementia is an illness that can be treated, much like cancer or diabetes. Ongoing research will eventually yield new and better therapies, and tools like these brain scans will help identify those therapies faster.

BuT the study does have a few limitations that should be noted. The computer models only focused on two specific brain regions to keep the mathematics manageable, even though the brain’s response to sound involves a much larger network. Including the entire network would have made the computer simulations too complex to run efficiently.

For future research, the scientists plan to test the effects of newer experimental drug treatments using this same method. They hope their scanning technique can quickly show whether a new drug is successfully interacting with its intended target in the brain.

“Our method can be used to tell if a new drug is worth investing more time and resources on, or whether it can be put aside and let researchers focus on other options,” Rowe said. “This means we could reduce the time, risk and cost of testing new drugs. It’s a team effort – with patients, doctors and researchers all working together.”

The study, “Alzheimer’s disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography,” was authored by Juliette H. Lanskey, Amirhossein Jafarian, Laura E. Hughes, Melek Karadag, Ece Kocagoncu, Matthew A. Rouse, Natalie E. Adams, Michelle Naessens, Vanessa Raymont, Mark Woolrich, Krish D. Singh, Richard N. Henson, and James B. Rowe.