School of Medicine

Damage early in Alzheimer’s disease ID’d via novel MRI approach

An MRI scan of the hippocampus, the brain’s memory center, in an older person with no signs of cognitive decline (left) and a person of similar age with mild Alzheimer’s (right) has been analyzed with a new technique that shows where healthy brain cells have been lost (dark areas). New research from Washington University School of Medicine in St. Louis shows that this novel MRI approach can identify brain cell damage in people at early stages of Alzheimer’s, before tissue shrinkage is visible on traditional MRI scans. (Image: Satya Kothapalli)

Alzheimer’s disease usually is diagnosed based on symptoms, such as when a person shows signs of memory loss and difficulty thinking. Up until now, MRI brain scans haven’t proven useful for early diagnosis in clinical practice. Such scans can reveal signs of brain shrinkage due to Alzheimer’s, but the signs only become unmistakable late in the course of the disease, long after the brain is significantly damaged and most people have been diagnosed via other means.

But new research from Washington University School of Medicine in St. Louis shows that a mathematical analysis of data obtained with a novel MRI approach can identify brain cell damage in people at early stages of Alzheimer’s, before tissue shrinkage is visible on traditional MRI scans and before cognitive symptoms arise.

“This could be a new way to use MRI to diagnose people with Alzheimer’s before they develop symptoms,” said senior author Dmitriy Yablonskiy, PhD, a professor of radiology at the university’s Mallinckrodt Institute of Radiology. “The technique takes only six minutes to acquire data and can be implemented on MRI scanners that are already used worldwide for patient diagnostics and clinical trials.”

Published in the Journal of Alzheimer’s Disease, the study relies on a new quantitative Gradient Echo (qGRE) MRI technique developed in the Yablonskiy lab to show brain areas that are no longer functioning due to a loss of healthy neurons.

“Using this technique in patients with Alzheimer’s disease, we discovered brain areas that look normal on traditional MRI but look dark on qGRE images, which we attribute to significant neurodegeneration,” said Satya V. V. N. Kothapalli, PhD, a staff scientist in radiology and the first author of the study. “We call them ‘dark matter.’”

While traditional MRI is capable of showing where damaged areas of the brain have decreased in volume, the qGRE technique goes a step further, detecting the loss of neurons that precedes brain shrinkage and cognitive decline.

Alzheimer’s disease develops slowly over the course of two decades or more before symptoms arise. First the brain protein amyloid beta accumulates into plaques in the brain, then another brain protein — tau — coalesces into tangles and neurons begin to die. Finally, tissue atrophy becomes visible on MRI brain scans, and cognitive symptoms arise. People at early stages of the disease can be identified via amyloid-PET brain scans or by testing for amyloid in the blood or the cerebrospinal fluid that surrounds the brain and spinal cord, but such tests do not provide information on neuronal damage.

The study involved 70 people ages 60 to 90 who were recruited through the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC). Participants completed extensive clinical and cognitive testing to assess their level of cognitive impairment. The participant group included people with no cognitive impairment as well as those with very mild, mild or moderate impairments.

Each participant underwent either a PET brain scan or a spinal tap to gauge the amount of amyloid plaques in his or her brain. They also underwent MRI brain scans.

Researchers applied the qGRE MRI technique to scan the hippocampus, the brain’s memory center and one of the earliest affected brain regions in Alzheimer’s. Results showed the hippocampus often contained a viable tissue section with relatively preserved neurons and a dark matter dead zone virtually devoid of healthy neurons.

These dark matter areas were present in people who tested positive for amyloid but were not yet experiencing symptoms, and they grew larger as the disease progressed. Compared with traditional MRI measures of brain atrophy, biomarkers for dark matter correlated much better with individual cognitive scores for very mild to moderate dementia.

The study builds on and corroborates findings from Alzheimer’s research that took place at Washington University more than two decades ago when Alzheimer’s was formally diagnosed only through autopsy.

In 2001, John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the Knight ADRC, led a study that examined the brain tissue of deceased Alzheimer’s patients and found that damaged brain regions had begun to lose healthy neurons well before the disease caused a significant loss of brain volume in these areas.

Then, in the early 2000s, Tammie L. S. Benzinger, MD, PhD, a professor of radiology and of neurosurgery, and the Knight ADRC’s director of imaging studies, was among the pioneers at the Mallinckrodt Institute of Radiology to use PET brain scans targeted against amyloid beta as a tool for detecting Alzheimer’s.

In the current study, also co-authored by Morris and Benzinger, researchers documented the same relationship between neuronal loss and Alzheimer’s symptoms using the non-invasive qGRE MRI technique in living patients.

Working with co-author Richard Perrin, MD, PhD, an associate professor of pathology & immunology, the research team also confirmed this relationship under the microscope by examining brain tissues that were donated after the death of a study participant. The postmortem examination showed that the neuronal loss in the hippocampus actually exceeds loss of tissue volume and that these changes are well reflected in MRI measures of dark matter.

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