Alzheimer’s stealthy modus operandi coming into clearer focus

RSNA, CHICAGO—Alzheimer’s disease has long been thought to wreak its havoc on once-clear minds by stashing amyloid plaque on the brain’s gray matter, the part most densely populated by nerve cells. New research using a specialized MRI method shows that the brain’s white matter—which conducts messages across brain regions—may play a larger role than previously thought.

The study was presented during a press conference at RSNA’s annual meeting by co-author Jeffrey Prescott, MD, PhD, a radiology resident at Duke University Medical Center in Durham, N.C. He described how he and colleagues used diffusion tensor imaging (DTI), an MRI method that assesses the integrity of white matter tracts in the brain by measuring how easy it is for water to move along them. The study analyzed results from 102 patients enrolled in a national study called the Alzheimer's Disease Neuroimaging Initiative (ADNI) 2.

“Amyloid is known to really increase significantly pre-symptomatically, so the patient has the most burden increase in amyloid before they even present symptoms, before anyone even notices that something is wrong,” said Prescott. “Once they start to develop symptoms they really don’t gain much more amyloid in the brain, but their cognitive decline is pretty precipitous.”

Current trials for treatment primarily focus on the dementia phase, said Prescott, stating that a primary goal of his research is to find the pre-symptomatic patients, identify them and treat them before they start to develop symptoms. “The question is, who are these pre-symptomatic patients?” he said. “How much time until they develop symptoms? When do we start treating? These questions are pretty far from being answered, but they are the focus of a lot of work right now.”

Prescott said his team used connectomics, the imaging technique that defines how highly complex connections in the brain, functional as well as structural, change over time when aging normally or affected by Alzheimer’s.

“We want to find a way to actually characterize the brain, and the way we do that is to simplify everything,” said Prescott, who then briefly described how the researchers set each of the various regions as a node and the connections between those regions as edges. Graphs created by the connections between regions and edges allowed the study team to come up with reproducible metrics calculations.

For example, they developed one measurement to see how many connections go to a specific region of the brain—a test of the connections’ strength—while another quantifies efficiency, or how easy it is for a signal to travel from one node to another.

“Our findings were in patients in an early stage of Alzheimer’s, with mild cognitive impairment, which is kind of where we want to get to assess whether treatment can be started at that time,” sad Prescott, adding that the new study is an extension of previous work that focused on a single point in time at which pre-symptomatic patients showed decreased brain structural connections due to amyloid buildup.

“So we have findings to suggest that there are early changes in the brain that we can detect with neuroimaging,” said Prescott, “which can help identify patients who are developing early Alzheimer’s”—all with an eye on developing early treatments. asked Prescott how Alzheimer’s looks different from, and similar to, imaging of other forms of brain deterioration.

“There have been many applications of the connectomics methodology to schizophrenia, other psychiatric diseases and other forms of neurodegenerative disease such as frontotemporal dementia,” he said, adding that his work has so far focused exclusively on Alzheimer’s. “Any disease that is thought to be based in the brain, there’s probably been an application of connectomics to it or developing application of connectomics to it.”

Whether or not connectomics pans out and leads to prevention or treatment remains to be seen. Still, understanding what Alzheimer’s does to the brain by witnessing its slow-motion destruction in action can only move things forward.

“The one thing about Alzheimer’s disease that is different is that we can actually see the core pathologies in vivo, with PET imaging,” Prescott continued. “We have amyloid imaging tracers that are known to be associated with Alzheimer’s, and there also new tracers of tau, which is another type of protein that is actually more specific for Alzheimer’s disease. That is still in clinical trials, not yet ready for clinical use, but it’s actually a pretty exciting area, because we think Alzheimer’s now will become a disease where a pathology that has been known for 100 years we can finally see in patients who we are worried about—and then see how that changes the brain in ways that may be associated with actual cognitive symptoms.”

According to the CDC, around 5 million Americans have Alzheimer’s disease now, and the count may climb to 15 million by 2050.