Post by Anastasia Sares
What's the science?
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by a loss of memory and the abnormal aggregation of proteins in the brain. A diagnosis of Alzheimer’s disease can only be confirmed after an individual’s death, by an autopsy revealing plaques and neurofibrillary tangles in the brain. What if we could visualize these plaques in the living brain through MRI? This would allow us to detect the disease earlier and monitor different therapies to see how they are working. This week in NeuroImage, Chen and colleagues outlined and tested a protocol to better measure these protein plaques using a specific type of MRI sequence called chemical exchange saturation transfer (CEST).
How did they do it?
MRI uses a strong magnetic field and radiofrequency (RF) pulses to excite or change the magnetic states of atoms (such as hydrogen) and then detect the signals these atoms give off using RF coils. Tissues can be differentiated because the magnetic states of hydrogen atoms are influenced by their microenvironment; for example, hydrogen atoms in water molecules versus those attached directly to proteins give off signals at slightly different frequencies (expressed in “ppm” from water frequency).
CEST is a special MRI technique that 1) excites hydrogen atoms attached to proteins, 2) waits for the excited hydrogen atoms to exchange places with hydrogen atoms in the surrounding water molecules, thereby indirectly saturating water (giving us the “saturation transfer” based on “chemical exchange”) and then 3) excites water hydrogen atoms to obtain their signals. Because exciting the now saturated hydrogen atoms in water leads to their suppression, these water hydrogen atoms would give off less signal than those that were not indirectly saturated. By comparing water signals obtained with and without indirect saturation, CEST can detect and quantify the proteins (for a short explanation of CEST, click here, for more detail click here).
CEST is currently most useful for identifying strokes and tumors. The authors made some adjustments to the CEST protocol to make it more effective for detecting plaques in AD (employing shorter RF pulses to limit direct saturation, fast signal acquisition to reduce motion artifacts, and adding extra baseline/control scans at 8ppm to improve data analysis). They then tested their MRI sequence in a number of ways. First, they used it on phantoms, or test tubes with different solutions of varying protein aggregation. These included egg whites, hair conditioner, a glutamate solution, and a protein called BSA (bovine serum albumin) that can link up to make larger or smaller molecules depending on the temperature it is exposed to. After measuring the signal from the phantoms, the authors moved to in vivo testing with mice, with one group of mice being genetically modified to consistently develop neural plaques as they age. They expected to find a difference between the MRI scans of the control mice versus AD mice.
What did they find?
The phantom tests showed that the new CEST sequence was effective in differentiating protein signals from other signals. When BSA phantoms were tested, there was greater signal loss after more protein aggregation had occurred, suggesting the sequence was sensitive to signal changes due to protein aggregation. The results from the mouse MRI showed a significantly reduced signal (at -3.6ppm) for the AD mice compared to the wild type mice. This suggested that there were more aggregated proteins in the brains of AD mice. The authors concluded that their sequence could be used successfully to detect plaques in the brain
What's the impact?
This study demonstrated the viability of a new MRI protocol for detecting aggregated proteins, like Alzheimer’s plaques, in brain tissue. Though this new protocol will require further exploration to confirm its usefulness, it could eventually allow us to detect plaque formation in humans before the cognitive symptoms of Alzheimer’s appear, to start combating it early.
Chen et al. Protein aggregation linked to Alzheimer's disease revealed by saturation transfer MRI. NeuroImage (2018).Access the original scientific publication here.