Researchers at the University of Texas’ Center for BrainHealth® at Dallas are investigating a possible new early indicator of Alzheimer’s disease decline: the measurement of the energy metabolism of the living human brain using cutting-edge imaging techniques.
Scientists developed a unique method to visualize energy consumption and reserves in the brain using phosphorus magnetic resonance spectroscopy using a 7 Tesla ultra-high field MRI scanner. Their results suggest that neurological energy metabolism may be impaired in mild cognitive impairment (MCI), the stage of decline between healthy aging and more severe disease states such as dementia and Alzheimer’s disease.
Dr. Namrata Das, PhD’20, program specialist and research neuroscientist at the School of Behavioral and Brain Sciences, is the lead author of the study, which was published online April 6 in Frontiers in Neuroscience.
“Much of what we know about cognitive decline at the molecular level comes from post-mortem brain exams or animal models,” said Das, who also has a doctorate and a master’s in public health. “We wanted to monitor in real time the biological mechanisms that are causing this decline in humans in order to better understand the various factors.”
Senior writer Sandra Bond Chapman, PhD, chief director of the Center for BrainHealth at UT Dallas, said the results showed “new ways to advance discovery.”
This research offers a promising new way to uncover brain health – or an early disruption to its health – from changes in metabolism. The new approach is to use 7 Tesla magnetic resonance imaging, a non-invasive, safe technology. It has exciting implications for early detection of Alzheimer’s disease and the potential to measure the disease’s response to treatments. “
Sandra Bond Chapman, the Dee Wyly Distinguished University Chair in BrainHealth
Although Alzheimer’s disease was first defined more than a century ago, treatment is still difficult to achieve. According to Das, this is because “several mechanisms become abnormal, causing a cascade of events, and we don’t know which comes first.
“Most of the current research is focused on the accumulation of beta-amyloid and tau protein in the brain. Here we are trying to see if there are other early markers that can be followed live via imaging. We hope our results will translate into these Integrated measurements of tau and beta-amyloid provide more in-depth information. “
The researchers theorize that the energy level disruption occurs early in Alzheimer’s disease, based on previous post-mortem work which indicated that metabolic deficit is less in earlier stages of Alzheimer’s disease than in severe cases.
“This research has paved the way for us to use imaging technology to answer those questions,” said Das.
The current study was conducted at the Advanced Imaging Research Center (AIRC), a collaborative facility shared by UT Dallas and other North Texas facilities and located on the UT Southwestern Medical Center campus. The facility houses several MRI scanners that work with magnetic fields up to 7 Tesla (7T) for human studies. MRIs with such strong magnets – the magnet in a 7T machine is more than twice as strong as clinical 3T MRIs – can illuminate metabolic processes and provide unprecedented detail in the resulting images.
In the study, 41 participants – 15 cognitively normal, 15 with MCI, and 11 with early Alzheimer’s disease – received assessments of executive function, memory, attention, visual skills, and language. The 7T MRI scans focused on measuring the ratios between the energy molecules adenosine triphosphate (ATP) and phosphocreatine (PCr), as well as inorganic intracellular phosphate.
“Most of the energy in a cell comes from the mitochondria,” said Das. “It is believed that mitochondrial dysfunction occurs early in Alzheimer’s disease and that ATP and PCr are not properly synthesized. With 3T MRI, we couldn’t see these molecular levels accurately. 7T gets us there.”
The researchers’ scans of the participants’ temporal lobes showed that the ratio of PCr to ATP – which Das calls the energy reserve index – correlated with the participants’ detection levels.
“The energy reserve was lower in patients with mild cognitive impairment and even lower in patients with Alzheimer’s,” she said. “We believe this is the first paper to confirm that MCI’s energy reserves are in many cases dwindling years before Alzheimer’s disease onset.”
While 7T MRI machines are not yet widely used for routine clinical evaluation of patients, Das said the techniques used in the research study could be adapted to commonly available 3T machines.
“Technology is advancing in such a way that we may soon be able to change what we see on 7T scans to detect them on 3T, and 3T is available everywhere,” she said. “We can optimize some of the MRI parameters we use to acquire these images with 3T, as we did with proton spectroscopy. We hope this can be achieved in the next few years.”
In the future, the research team intends to combine this energy-level biomarker with positron emission tomography scans that measure beta-amyloid and tau protein, the most well-known markers for Alzheimer’s disease. In the meantime, Das will continue her research on the use of MRI to find novel neuroimaging markers at Harvard Medical School’s McLean Imaging Center starting July 1.
“We hope to see if the brain’s abnormal energy metabolism is related to the accumulation of beta-amyloid and tau,” said Das. “Researchers have believed for years that such metabolic deficiencies could precede such accumulations, but only now, with 7T, do we have the modality to find out.”
Das, N. et al. (2021) Phosphate Brain Energy Metabolism and Cognition in Alzheimer’s Disease: A Spectroscopic Study Using 31 Phosphorus Magnetic Resonance Spectroscopy with Whole Brain Volume Coil at 7 Tesla. Limits in Neuroscience. doi.org/10.3389/fnins.2021.641739.