Imagine that you're walking past a building. From the outside, it appears to be in perfect shape. The windows, doors, roof, and framing all look sound. But then a structural engineer comes out the front door wearing a hard hat and tells you to step away—the building could fall down at any time. From the moment he went inside, the engineer could see visible signs of damage—large cracks in the load-bearing walls, columns buckling—that indicate a deteriorating and decaying structure.
It's too late now for the building: There's too much damage to its internal structure. Any attempt to shore it up would just be delaying the inevitable. But what if that structural engineer could see inside the load-bearing walls and columns? Then he might be able to detect the earliest signs of deterioration before it was too late to fix them.
That's exactly what some of the world's leading physicists and radiologists are trying to do with the human brain and nervous system, using an advanced form of magnetic resonance imaging (MRI) called diffusion kurtosis imaging. It's still fairly new and experimental, but standard MRI systems can be retrofitted to use the technology without adding more than a few minutes to a traditional MRI scan.
Radiologists use standard MRI to measure the volume of structures in the brain. When a person has Alzheimer's disease, standard MRI may show a decline in the overall volume of the hippocampus, an area of the brain that plays a critical role in memory. But standard MRI cannot show the changes in the brain that develop before the hippocampus starts to shrink—a time when drug therapies on the horizon might be able to change the course of the disease. That's where diffusion imaging—and beyond that, diffusion kurtosis imaging—comes in.
“MRI looks at water,” explains Joseph Helpern, Ph.D., professor of radiology, psychiatry and physiology & neuroscience at New York University's Langone Medical Center. Dr. Helpern is one of the original developers of diffusion kurtosis imaging. “The beautiful clinical images provided by MRI tell us a lot about the gross anatomy of the human brain; they can even give us some information about the biophysics [such as volume and speed of movement] of the water in the tissue.”
But to really understand what's going on in the brain, it may not be enough to look only at how much water there is or how fast it's moving. Another key parameter is called diffusion. “If I had special goggles to let me watch water molecules ‘walk around’ in a swimming pool, I'd see that the water moves randomly, not in any one direction,” Dr. Helpern explains. “But eventually, I'd see that random motion develop into a spherical pattern where the water has been. That's diffusion.”
If your pool has structures in it—like your brain does—the water will move in more defined patterns. A wall might cause the water molecules to diffuse on one side but not the other. If the pool has long plastic tubes in it, the water inside the tubes can move along the length of the tubes, but not between the tubes.
The microstructures of the brain, such as the neurons and axons, are like those walls and tubes—they keep the water moving in a certain direction and prevent it from moving in other directions. Using diffusion imaging, scientists can see these very fine microstructures—not visible on standard MRI—and learn if they're working properly. For example, water moving along an axon in the brain should not move very far in a perpendicular direction because it's constrained by the boundaries of the axon. But if diffusion imaging shows that water is starting to flow not just along the axon but more upward and downward, this may indicate that the axon is losing its protective myelin—a marker of multiple sclerosis (MS). And, a number of studies have shown that diffusion imaging is more sensitive than standard MRI to the early changes in the brain that predict future memory decline in dementias such as Alzheimer's.
But even regular diffusion imaging has its limitations. To map some of the more unusual movements of water molecules in the brain, Dr. Helpern and a colleague, NYU Associate Professor of Radiology and Physiology & Neuroscience Jens Jensen, Ph.D., devised diffusional kurtosis imaging. Think of going from ordinary diffusion imaging to diffusion kurtosis imaging as going to see the movie Avatar in a regular theater—and then seeing it again in 3-D.
Diffusion kurtosis imaging may be particularly important for understanding injuries to the gray matter of the brain, which has become a key part of MS research in recent years. Most MS therapies only treat the inflammation caused by the disease. But in the pipeline are several treatments that could be neuroprotective—that is, keep the neurons and axons in the brain's gray matter from breaking down.
“We need a valid, sensitive marker to monitor a patient's response to these neuroprotective treatments, and I believe kurtosis has the potential to be this marker,” says Mathilde Inglese, M.D., Ph.D., associate professor of radiology and neurology at NYU. “Kurtosis may also help us diagnose MS as early as possible, and studies have shown that early diagnosis leads to a better clinical outcome.”
Diffusion kurtosis imaging is also likely to advance the understanding and early diagnosis of dementias like Alzheimer's disease, something Dr. Helpern and Dr. Jensen are now investigating in an NIH-funded study involving 80 patients with mild cognitive impairment—a precursor to dementia—and 80 age-matched controls. “We're getting better information with diffusion kurtosis imaging, which is likely to give us a better way of characterizing the changes associated with Alzheimer's disease at the earliest possible stage,” says Dr. Jensen. “At some point, we hope to have therapies that can stop or slow down the progression of the disease. And if we catch it early, we can hopefully prevent most of the worst damage done by Alzheimer's disease.”