How Can We Use X-Ray Imaging to Better Understand Neurodegenerative Diseases?

By Rebecca Ingle, Ph.DJan 4 2022

One of the characteristic signs of Alzheimer’s disease is the presence of ‘plaques’ or deposits of proteins in the brain. These deposits consist of beta-amyloid proteins which would normally be cleared by the immune systems. However, Alzheimer’s disease leads to protein malfunctions and issues with the protein folding processes which makes the proteins ‘sticky’ and more prone to clumping that leads to the formation of plaques.¹

Image Credit: Atthapon Raksthaput/Shutterstock.com

Beta-amyloid plaques are not the only signatures of this neurodegenerative disease at the cellular level. Nerve activity in the brain is typically reduced with Alzheimer’s disease due to the formation of neurofibrillary tangles that ‘choke’ nerve activity.² While the exact molecular mechanisms that connect the formation of neurofibrillary tangles to some of the reduced synapse activity associated with Alzheimer’s disease are not fully understood, the formation of such tangles is again related to issues with impaired protein function.

One of the challenges for making a definitive Alzheimer’s diagnosis is that there are few techniques that can fully visualize the cellular changes and plaques in the brain while the patient is alive.³ _­­High resolution magnetic resonance imaging (MRI) can be used but the very long acquisition times are highly undesirable for clinical applications.

There is a need for new imaging methodologies that can be used to diagnose neurodegenerative diseases, including Alzheimer’s disease. A suitable imaging technique needs to have sufficient spatial resolution to be able to resolve the structures in the regions affected by plaques – which have a great deal of nanoscale structure within them of the protein components.⁴

Being able to characterize and identify protein in their live environment, rather than from cellular or animal model studies, would be highly advantageous for the development of new treatments and better identification of the mechanisms behind Alzheimer’s disease.

X-Ray Imaging

One technique that shows promise for the investigation of the human brain tissue and protein deposits is phase-contrast X-ray computed tomography. One of the advantages of this technique is it provides three-dimensional structural information and does not require extensive sample preparation times.⁵

X-ray computed tomography is an X-ray imaged technique that uses a narrow beam of X-ray radiation to image a sample, where the radiation of the source is rotated around the sample in question to create the necessary sections for a fully three-dimensional image. A complete tomography scan generates cross-sectional images of the object that can then be reconstructed using computational approaches.

As it is a non-destructive technique and some materials only weakly absorb the energies of X-ray used, X-ray computed tomography is often used for the investigation of the contents of objects that cannot be opened – such as artifacts of historical importance.

Neurodegenerative Diseases

To study the amyloid plaques present in brain samples from Alzheimer’s patients, the team used X-ray radiation generated using the PETRA III storage ring in Hamburg at the German Electron Synchrotron (DESY). For biological samples, prolonged irradiation with X-rays can lead to tissue damage, so it was important the team could complete its tomography scans before this occurred.

By using phase-contrast information during the tomography scan, unlike typical computed tomography scans that simply rely on absorption/transmission measurements, it was possible to see enhanced contrast of the different structural features in the cellular samples being studied. The use of phase-contrast methodologies is particularly beneficial for soft tissue studies as most non-dense tissues have very little X-ray absorption so it can be difficult to detect the very subtle changes in the direct absorption signals from one region of the sample to another.

Neurodegenerative Diseases

By using machine learning image recognition approaches to reconstruct the full three-dimensional images, the team used this methodology to see neuron cells in the tissue sample. By comparing the images acquired from a range of different patients, the research team found that Alzheimer’s disease has a profound impact on cell nucleation in local sites.

The research showed that cells from patients with neurodegenerative diseases had significantly higher DNA densities in their cells, leading to pronounced differences in the cell nucleus between healthy and affected tissues. By using machine learning approaches, the team compared larger areas of many neuron cells at a time to assess these differences.

Thanks to the relatively fast acquisition and low intensity of the X-ray radiation used, the team imaged samples of a few millimeters very rapidly. The team believes that the method can continue to be scaled to large sample sizes and faster acquisition times with improved refinement of the scanning approaches to minimize the number of experimental data points required without sacrificing the image quality.

As well as being used as a diagnostic technique, phase-contrast X-ray computed tomography may help provide new cellular information on the mechanisms of Alzheimer’s disease and provide important data for the development of new therapies.

References and Further Reading

1. Ashraf, G., Greig, N. H., Khan, T. A., Hassan, I., Shakil, S., Sheikh, I. A., Zaidi, S. K., Wali, M., Jabir, N. R., Firoz, C. K., Naeem, A., Alhazza, I. M., Damanhouri, A., & Kamal, M. A. (2014). Protein misfolding and aggregation in Alzheimer’s disease and Type 2 Diabetes Mellitus. CNS Neurological Disorder Drug Targets, 13(7), 1280–1293. https://doi.org/10.2174/1871527313666140917095514
2. Metaxas, A., & Kempf, S. J. (2016). Neurofibrillary tangles in Alzheimer’s disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics. Neural Regeneration Research, 11(10), 1579–1581. https://doi.org/10.4103/1673-5374.193234
3. Baltes C., Princz-Kranz F., Rudin M., Mueggler T. (2011) Detecting Amyloid-β Plaques in Alzheimer’s Disease. In: Modo M., Bulte J. (eds) Magnetic Resonance Neuroimaging. Methods in Molecular Biology (Methods and Protocols), vol 711. Humana Press. https://doi.org/10.1007/978-1-61737-992-5_26
4. Querol-vilaseca, M., Colom-cadena, M., Pegueroles, J., Nuñez-, R., Luque-cabecerans, J., Muñoz-llahuna, L., Andilla, J., Belbin, O., J, T. L. S.-, Gelpi, E., Clarimon, J., Loza-alvarez, P., Fortea, J., & Lleó, A. (2019). Nanoscale structure of amyloid- β plaques in Alzheimer ’ s disease. Scientific Reports, 9, 5181. https://doi.org/10.1038/s41598-019-41443-3
5. Eckermann, M., Schmitzer, B., Meer, F. Van Der, Franz, J., & Hansen, O. (2021). Three-dimensional virtual histology of the human hippocampus based on phase-contrast computed tomography. Proceedings of the National Academy of Sciences of the United States of America, 118(48), e2113835118. https://www.pnas.org/doi/full/10.1073/pnas.2113835118

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