Researchers Developing Cognitive Stress Test For Alzheimer’s Disease

Peter Snyder Ph.D.
Peter Snyder Ph.D.

One of the main challenges to detecting the early onset of Alzheimer’s disease in older adults is distinguishing between normal memory loss that comes with a healthy but aging brain and actual neuron cell loss caused by the disease. Being able to make this distinction as early as possible would help physicians and researchers make earlier diagnoses and identify possible volunteers for clinical trials of new medicines. 

Just as cardiologists use treadmills and EKG exams for stress tests of the heart, neurologists need a “cognitive stress test” to exercise the brain, looking for weaknesses that may indicate a problem.  Results of a new study have found that combining a well-known and inexpensive drug with a highly sensitive cognitive test can give clinicians the early warning system they need to diagnose Alzheimer’s in their patients.

The presence of beta amyloid plaques in the brain is a telltale sign for Alzheimer’s disease, but to see and measure them requires an expensive positron emission tomography (PET) scan.  This may not be affordable for an individual patient in a clinical setting and is not economical for a research study that requires hundreds of volunteers in multiple countries. In many parts of the world, PET imaging is not even an available option. A low-cost, intermediate test is required to provide an early assessment and justify advancing to the next diagnostic step. 

Putting any kind of system under stress, whether it is a bridge, a heart or even a brain, can reveal hidden vulnerabilities that aren’t apparent in normal conditions.  In a cardiac stress test, walking (or running) on a treadmill pushes the heart to work harder than normal.  A cardiologist monitors and evaluates the heart’s performance by watching the live EKG results.

Researchers from Brown University, Pfizer and Cogstate are developing a similar stress test for the brain.  From previous studies, they knew that a specific class of neurotransmitter, the cholinergic system, has a direct effect on spatial working memory and problem solving in the brain, often referred to as our executive function. 

“These are cognitive functions that rely on the cholinergic system in the brain, and this is the same system that is affected very early in Alzheimer’s disease,” said Peter Snyder Ph.D., lead author of the study and professor of neurology at Brown University’s Alpert Medical School. “We believe that the cholinergic system is damaged in the very earliest stages of the disease – along with the early beginnings of build-up of amyloid plaques in the brain.” 

Scopolamine, a cheap, well-understood drug often used to counter motion sickness, is also known to affect the cholinergic system, impairing it for a period of time.  Just as walking on a treadmill stresses the heart, scopolamine is used to stress the brain looking for early signs of hidden amyloid plaque.

However, the limitation to using the drug during research is that the usual, large dose of 0.3 to 0.6 mg subcutaneous injection can take 9 to 11 hours of recovery time before its effect on the patient wears off.  However, there was not a cognitive assessment tool sensitive enough to detect changes at lower doses. 

As a solution, Snyder and Paul Maruff Ph.D., Chief Science Officer at Cogstate, developed the computerized Groton Maze Learning Test (GMLT) to measure very slight and subtle changes to executive function in patients. They designed the tool to allow testing at much lower dosing burden to the patient.  In this computer-based test, users are asked to find a path through a maze of hidden boxes by clicking on adjacent squares until they get to the final box. 

In a recent experiment, Snyder, Maruff and their colleagues tested 26 healthy adults, aged 55-75 years, with at least two risk factors of Alzheimer’s disease.  However, it was confirmed through PET scans that these volunteers had low cortical beta amyloid at the time of testing and had not been diagnosed with the disease. They were tested at baseline with the GMLT, then given a micro-dose of scopolamine, 0.2 mg. After testing again at 1, 3, 5, 7 and 8 hours after dosing, the participants showed significant changes in executive function after just 3 hours.

Besides showing that the GMLT could detect a cognitive change from a very low dose of scopolamine, the test subjects were able to recover fully after just five hours, instead of 9-11 hours at higher doses.

“The lynch-pin to using such a low dose is to pair it with a test that provides a reliable and sensitive signal,” said Snyder. “Our paper shows that the GMLT – a computer-based hidden maze learning test – is so sensitive to small perturbations of the cholinergic system, that we can use the “micro-dosing” of scopolamine and get nice, reliable cognitive effects that resolve within 5 hours.”

The research has been published in the March issue of the journal “Alzheimer’s and Dementia”.

As part of a larger study, this initial finding is an encouraging first step to being able to use the cognitive stress test to accurately predict the presence of amyloid plaque in the brain without the expense of a PET scan.

“Our goal is to create a cognitive stress test that predicts risk of disease, in older adults in the preclinical stage, in many parts of the world where PET imaging is either too expensive or simply not available,” said Snyder. “We hope that this new test will have both a public health purpose, as well as to be useful for screening subjects for clinical trials.”

Questions or comments? Please contact Dan Peterson