- New model examines how infectious seeds diffuse through the uneven structure of the brain.
- Researchers used MRI scans of an adult brain to create high-resolution simulations in both 2D and 3D.
- These simulations recreate the pattern of damage observed in numerous neurodegenerative disorders.
Neurodegenerative diseases associated with age are multifaceted and complex pathologies. In most cases, their growth is closely related to the progression of certain protein aggregates known as prions.
Prions are infectious seeds that trigger a chain reaction of protein aggregation and misfolding, producing conformational autocatalysis. Gradually, these seeds expand, fragment, and spread to other regions of the brain. This affects the normal functioning of the nervous system and causes cerebral atrophy, necrosis, and ultimately death. This is exactly what happens in Parkinson’s and Alzheimer’s disease and ALS.
Now researchers at Stevens Institute of Technology, Stanford University, and University of Oxford have developed a new model that examines how these infectious seeds diffuse through the uneven structure of the brain. It demonstrates that the distribution of toxic molecules in all diseases depends on the location at which these molecules first appeared.
The simulations indicate that brain damage happens mostly due to the body’s removal of brain cells impaired by the physical impact. Authors believe that their tool will help scientists to block the progression of serious brain disorders.
The Model Ignores Biochemistry
In many neurodegenerative diseases, the initial toxic molecules remain murky but they copy themselves to misfold in a specific way. The disease progresses as the malformed proteins extend through the brain and aggregate in clumps and fibers.
This new model ignores biochemical and cellular mechanisms and simply represents the fundamental processes of propagation and growing numbers of harmful proteins.
Rather than traveling through the fluid outside of cells, toxic molecules in the brain moves through neurons (network of nerve cells). Each nerve cell consists of a nucleus and an axon that transfers electric signals to other nerve cells. Axons account for most of the brain’s white matter, whereas their cell bodies contain the bulk of gray matter.
Reference: APS Physics | doi:10.1103/PhysRevLett.121.158101 | Oxford University
In this model, toxic molecules diffuse along axons at a particular rate and travel through the white matter. They also diffuse into extracellular regions but at a much slower rate. In the gray matter, these molecules diffuse isotropically at a medium rate. Once they diffuse into a new area, they create copies of themselves at a particular rate that depends on the number of toxic proteins present in those areas.
Simulating Toxic Proteins Within The Brain
Clinical data (top) vs. simulation (bottom) | arrows show the propagation of toxic proteins in Alzheimer’s | Credit: A. Goriely / Oxford University
To create high-resolution simulations in both 2D and 3D, authors used MRI scans of an adult brain. The 2D computer simulations were performed in vertical slices (either side-to-side or front-to-back), and 3D simulations covered the complete brain.
Then they mapped the clinical data of Parkinson’s and Alzheimer’s disease progression. According to these data, the toxic proteins start from a particular location and spread in a specific pattern. Author fed these initial conditions to their simulations and they found that simulations accurately recreated the pattern associated with each disorder.
The model can help scientists learn more about the biochemistry by taking its physical aspects into account. The simulations clearly show that diffusion plays a major role in the progression of neurodegenerative disorders. It could give new directions to future interdisciplinary research.