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Powerful imaging technology unveils biomarkers of the future

Dawn Brazell | MUSC News Center | June 10, 2013

Joseph A. Helpern, Ph.D., uses diffusional kurtosis imaging to find insights into such conditions as Alzheimer's disease, stroke, epilepsy and ADHD.

As a physicist, knowing the language that water speaks offers benefits, particularly if you’re gifted in translating that language in a way that potentially uncovers a method for the early detection for Alzheimer’s disease.

Establishing neuroimaging biomarkers for the early detection of this disease is crucial for the development of earlier interventions when treatments could be more effective and at least delay the disease’s progress, preserving the quality of life, said Joseph A. Helpern, Ph.D., a SmartState Endowed Chair in Brain Imaging.

A recent article from his research group, “Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease,” appeared in the American Journal of Neuroradiology.

Helpern is no newcomer to imaging. The director of MUSC’s Center for Biomedical Imaging is credited with building the first 3-Tesla MRI almost 23 years ago and now considered the clinical state-of-the-art. He and long-time collaborator Dr. Jens H. Jensen also developed diffusional kurtosis imaging (DKI), the MRI method that was highlighted in this latest study and being used to study a wide range of diseases.

Magnetic resonance imaging of the brain of a healthy person is shown in top row, a patient with mild cognitive impairment (middle), and a patient with Alzheimer's (bottom) using diffusional kurtosis imaging. 

This is the beauty of being a researcher in the field of imaging, which cuts across all fields of medicine, he said.

“The research we’ve been doing and the development of technology that we’re translating into the clinic is really exciting because it’s showing that we have exquisite sensitivity into imaging biomarkers early on into diseases such as Alzheimer’s disease, epilepsy, attention deficit hyperactivity disorder (ADHD), stroke and many others.”

Researchers applied DKI-based tissue modeling of the white matter in the brain to investigate the sensitivity, diagnostic accuracy and associations of specific microstructural changes that happen through the course of Alzheimer’s disease. Findings suggest that there is widespread breakdown in myelin integrity in the transition from normal aging to a stage of amnestic mild cognitive impairment, with a loss in axonal density occurring later in the disease.

The bottom line is that the imaging works to depict those changes. “Perhaps someday quantitative neuroimaging will be included with annual medical checkups in order to detect the earliest signs of AD before clinical symptoms arise,” Helpern said in the conclusion of the paper. “Then we will intervene with a future therapy that prevents the progression of this devastating disease.”

Developing potential neuroimaging biomarkers is one of the key strategies included in the 2012 National Alzheimer’s Project Act, as well as for President Obama’s BRAIN initiative. “A biomarker tries to detect something that changes early on in the disease that sends up a red flag and notifies us that things are going bad,” he said.

MRI is based on the ability to get signals from water molecules in the body and turn them into images for clinicians. It can be done non-invasively and without the radiation concerns of other types of scans. For DKI, Helpern said it all involves studying the random walk of a water molecule, which is called diffusion.

“Water communicates in a language that allows us to ask certain things about its environment. I can ask the water molecule, for example, how far can you travel before you bump into something? The water molecule, through all the technology of computers and big magnets says, ‘I can travel about 10 microns before I bump into something.’”

He then can ask if it can travel in all distances equally or if there is one hallway that’s easier to travel. In scientific terms, that’s called anisotropy, and it turns out that axons or the wiring in the brain are like tubes that water can travel down easily. Interestingly, the water molecules behave differently in various sections of the brain, such as traveling through white and gray matter, for example, and researchers can use this information to assign different color scales in DKI.

Imaging scientists then can use DKI to see the microarchitecture of neural tissue and identify early changes that could be predictive of Alzheimer’s much as a structural engineer could note cracks and structural changes in a building’s walls and avert danger. “This paper shows that our diffusional kurtosis imaging is sensitive enough to be able to separate people with normal aging from people with mild cognitive impairment. That’s actually pretty big because we’re already pretty good at diagnosing Alzheimer’s disease. We need to be better at diagnosing them earlier in the disease.”

Researchers assign color scales in DKI to identify the microarchitecture of neural tissue. 

DKI, which has been licensed to Siemens Medical, is currently implemented in scanners at over 150 sites worldwide. The goal is to develop the tool’s power. 

“It’s a language we’re developing, but we haven’t developed it enough so that we can ask all the right questions.”

Yet, that is.

The pieces are coming together to radically shape imaging diagnosis in a variety of medical areas. Helpern and colleagues have another paper coming out in the journal Human Brain Mapping highlighting work being done in ADHD, which affects so many children now.

“This paper shows that the developmental trajectory – how the brain forms, its wiring and how it builds itself in the early stages between 8 and 18 in normal children is different than in ADHD children. This is hard physical, imaging evidence that these children are different. There are real microstructural differences. That’s really significant because we need better quantitative and objective tools for diagnosis.”

It’s also significant because it provides an objective tool to see the effectiveness of medications, an area of interest for upcoming studies.

Helpern said two other areas of excitement for DKI are in the areas of stroke and epilepsy.

“The hot area in stroke right now is in rehabilitation. If someone has a stroke the question is whether or not there are enough other areas in the brain that can help regain the loss of function, such as motion and talking.”

Helpern said researchers are measuring the functional activity of stroke patients along the cortical spinal track, an area related to the ability to move their legs properly. The images are taken pre-and-post physical therapy to see which patients will respond to this kind of therapy. It could potentially be a very helpful prognostic tool for therapists, he said.

With epilepsy, it can be very difficult to locate exactly where in the brain the problem of seizures originates. Some patients don’t respond to drugs and have to have surgery, where a part of their brain causing the seizures is removed. “I think everyone can understand why it’s so important to get that right.”

It’s a very costly process to get the matrix right using a variety of medical techniques to make this determination, he said.  “The initial results that we’ve gotten from DKI are really are quite spectacular. We’ve stumbled onto a new imaging modality that is exquisitely sensitive to brain changes in epilepsy.”

It can radically affect research into treatment options. For example, conventional imaging used for temporal lobe epilepsy shows primarily one area of the brain lighting up. Using DKI, larger areas of the brain light up as well, giving researchers new clues into the disease. “Now we can start to formulate hypotheses about what is going on and what we can do for treatment, as well.”




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