Another Piece of the Puzzle: An Expanded Role for MRI in Diagnosing Alzheimer’s and Guiding Treatment
By Beth W. Orenstein
Radiology Today
Vol. 22 No. 1 P. 14

More than 5 million Americans are living with Alzheimer’s disease, according to the Alzheimer’s Association. By 2050, that number is expected to nearly triple to 14 million. One of the biggest challenges with Alzheimer’s is that it’s difficult to diagnose, especially when it’s in its early stages and potentially more treatable. A lot of current research focuses on the use of PET for brain imaging because the main hallmark of Alzheimer’s is the size and number of beta-amyloid plaques seen on PET images. Research, including a study in the Journal of the American Medical Association, published in April 2019, has shown that PET can detect these Alzheimer's-related “plaques” in the brains of patients with mild cognitive impairment and dementia.

Now, new research is showing that MRI may also be used to help detect early signs of Alzheimer’s, direct treatment of the disease, and provide valuable insights into brain pathologies. It may prove to be an even better imaging modality. When it comes to Alzheimer’s, Ricky Man-Shing Wong, PhD, a professor at Hong Kong Baptist University (HKBU), believes MRI has several advantages, including that it is widely available in clinical settings and, unlike PET, requires no radioactive tracer. Wong notes that PET is expensive, invasive, and affords low spatial resolution, while MRI does not have these limitations.

Interesting Contrast
However, no MRI contrast agent has been clinically approved for real-time imaging of beta-amyloid in the brain. The lack of contrast agents inspired the team at HKBU to see what they could do, Wong says. “We were inspired by what we learned from publications and conferences we attended.” 

What the team developed is a novel nanomaterial with a silica layer for imaging beta-amyloid in the brain. It loads and coats gadolinium-based nanoparticles, a chemical substance commonly used as an MRI contrast agent, with a specially designed silica layer that can accommodate a proprietary, noncytotoxic fluorescent cyanine dye. Cyanine dye is an organic compound used to visualize and quantify beta-amyloid proteins. The dye-absorbed silica coating layer turns the gadolinium-based nanoparticles into a biocompatible, biostable, and nontoxic agent.

“This agent is permeable to cell membranes, able to penetrate blood-brain barriers, and neuroprotective for biomedical applications,” Wong says. The researchers experimented with it in mice and were able to show that the modified nanoparticles can bind with beta-amyloid contents and enhance MR signals to differentiate beta-amyloid contents in the brain, in terms of size and number, when MRI is applied, Wong says.

“By modifying the surface-functionalized layer of the gadolinium-based nanoparticles, we have developed a versatile and sensitive MRI contrast agent for the diagnosis of Alzheimer’s disease,” Wong says. “It proved effective in our mouse model.”

In a study published in Advanced Functional Materials in February 2020, the researchers injected their modified nanoparticles into transgenic mice with overexpressed beta-amyloid peptides and a control group of mice. When they performed MRIs on the brains of these mice, they saw that the magnetic signals were stronger and longer in the transgenic mice than the control mice.

“This proved that the modified nanoparticles had passed through the blood-brain barriers to bind with the beta-amyloid contents in the brain,” Wong says.

Previous research has shown that the size and number of beta-amyloid spots in human brains increases with the age of the Alzheimer’s patients. The HKBU research team also observed that the brightness of the brain sections of the transgenic mice increased with age. They saw more bright spots in the older transgenic mice and almost no bright spots in the control mice.

“The results demonstrate the sensitivity and effectiveness of the modified nanoparticles in beta-amyloid targeting and imaging,” Wong says.

Potential Therapeutic Role
The team has not been able to test their contrast agent in humans. “We are required to go through clinical trials before receiving FDA approval for it to be used clinically,” Wong says. “And it may take three to five years for such studies and approval.”

Meanwhile, the team plans to continue to optimize the properties of the nanoparticle-based MRI contrast agent, such as the enhancement of its sensitivity, specificity, and clearance duration, to facilitate its practical uses. “We are also exploring a molecular-based MRI contrast agent as an alternative option for beta-amyloid imaging,” Wong says. Wong knows of no other MRI contrast agents in development for Alzheimer’s but notes that HKBU also reported the first superparamagnetic, iron oxide, nanoparticle-based MRI contrast agent for beta-amyloid plaque imaging in 2018.

If the HKBU team is able to confirm that their novel agent has clinical application in humans, Wong says it could not only help with early detection of Alzheimer’s but also routine screening and monitoring of disease progression. It could possibly play an important role in the efficacy of potential drugs for the treatment of Alzheimer’s as well, he says.

In addition, Wong says, the team found that its modified nanoparticles may have inhibited beta-amyloid from clustering. This finding could mean that the nanoparticles have the potential to be therapeutic. “This is another direction of investigation for our research team in the future,” Wong says. 

Focus on White Matter
Researchers from New York University’s (NYU) Grossman School of Medicine published a study in Academic Radiology online in October in which they used MRIs of the brain to detect tissue damage, showing early signs of cognitive decline with more than 70% accuracy. The study was funded by grants from the National Institutes of Health and from the Alzheimer’s Disease Association. It took about a year to complete the research, according to Jingyuan “Josh” Chen, PhD, lead author and a research assistant professor in the Alzheimer’s Disease Research Center at NYU.

The study did not involve the use of contrast agents, and Chen does not believe that a contrast agent is necessary; he says they may even be dangerous for older patients, who are more likely to have Alzheimer’s. Also, he notes, “you can’t use contrast on patients with renal disease.”

The NYU team’s research focuses on small bright spots on MR images called white matter hyperintensities, also known as leukoaraiosis. An increased number and size of intense white spots seen on the mostly gray brain images have long been linked to memory loss and emotional problems, especially as people age. The researchers found that more spots on MRI and their occurrence in the center of the brain also correlate with the worsening of dementia and other brain-damaging conditions, such as stroke and depression. The spots represent fluid-filled holes in the brain, lesions that are believed to develop from the breakdown of blood vessels that nourish nerve cells.

“The current methods for grading white matter lesions rely on little more than the ‘trained eye,’” Chen says. Readers use a three-point scale, with a score of 0 meaning minimal white spots and a score of 2 or 3 meaning more significant disease. Chen and his colleagues developed a new tool that can provide a uniform, objective method for calculating the volume and location of these spots in the brain.

Mapping Lesions
To complete the study, the NYU team selected 72 MRI scans at random from the Alzheimer’s Disease Neuroimaging Initiative, a national database of older adults that has been running since 2004. The scans were from an equal number of elderly men and women, mostly white and older than 70. Some in the group had normal brain function, some showed mild cognitive decline, and some suffered from severe dementia.

The team used the latest MRI techniques to accurately map the brain’s surface. Computer software enabled them to calculate the precise position and volume measurements for all of the white matter lesions that could be observed. They tabulated lesion volumes—3D measurements in liters. The tabulated volumes were based on each lesion’s distance from the side surfaces of the brain.

Normal volumes ranged between 0 mL (no lesions) and 60 mL (some lesions.) Those with severe disease had volumes greater than 100 mL. Then the researchers cross-matched their measurements with what was known about the patients. They found that, in seven out of 10 cases, their volume calculations correctly correlated with the patient’s actual diagnosis.

Chen says volumes of white matter lesions above the normal range should be taken as an early warning, although white matter alone is not sufficient to certify a finding of early dementia. “It should be considered along with other factors,” he says. These factors include a history of brain injury, memory loss, and hypertension, all of which could be related to cognitive decline and other brain and blood vessel diseases.

The professors call their calculator for properly sizing white matter hypersensitivities bilateral distancing. Senior study investigator Yulin Ge, MD, a professor in the department of radiology at NYU Langone, agrees: “Our bilateral distancing calculator offers radiologists and other clinicians an additional standardized test for assessing these lesions in the brain, well before severe dementia or stroke damage occurs.”

Available Online for Free
The researchers are providing the tool online to physicians at no cost. “Mental disease is often called an ‘invisible wound,’ as people often don't know or refuse to believe they have it,” Chen says. “By publishing our quantitative method and making it available for free, we hope to help more people better see the invisible wound of Alzheimer's.”

Chen hopes the standardized tracking and measuring tool can also play a role in monitoring the growth of white matter lesions relative to that of other tau and beta-amyloid proteins, which, as other researchers have shown, are believed to be a cause of dementia and Alzheimer’s disease. “The buildup of either substance also could prove or disprove one or more of the theories about what biological processes actually lead to various forms of dementia,” Chen says. Alzheimer’s is the most common cause of dementia. About 70% of people with dementia have Alzheimer’s; dementia is not a specific disease.

More studies are needed to confirm their findings, Ge says. The researchers plan to broaden and test their measuring tool on another set of nearly 1,500 brain scans to include a more diverse group from the same database. They also are looking at using other advanced MRI techniques, such as diffusion imaging. Diffusion imaging may be helpful in showing whether lesions have more water movement than others in brain tissues, “and could confirm our hypothesis,” Ge says.

“We don’t fully understand Alzheimer’s yet,” Chen says. Studies such as NYU’s can hopefully “improve our understanding about what the role of these lesions is and, once we have a better idea of that, perhaps we can develop treatments that can be modified and more targeted.”

— Beth W. Orenstein of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to Radiology Today.