The March 22 issue of Neuron reveals that a newly developed mathematical computer program has tracked the manner in which different forms of dementia spread within a human brain, and that it can predict where and approximately when the spread occurs in a patient’s brain neuron to neuron of ‘prion-like’ toxic proteins, which is the same process on which all forms of dementia are based.

Patients and their families could benefit from the findings by being helped to confirm a diagnosis of dementia, which would also enable them to prepare ahead for future cognitive declines that will happen over time. According to lead researcher, Ashish Raj, the program may in the future also assist physicians in identifying suitable brain targets for therapeutic interventions, in a time where targeted drugs against dementia already exist.

Dr. Ashish Raj Ph.D., an assistant professor of computer science in radiology at Weill Cornell Medical College who developed the computer model, explains:

“Think of it as a weather radar system, which shows you a video of weather patterns in your area over the next 48 hours. Our model, when applied to the baseline magnetic resonance imaging scan of an individual brain, can similarly produce a future map of degeneration in that person over the next few years or decades.

This could allow neurologists to predict what the patient’s neuroanatomic and associated cognitive state will be at any given point in the future. They could tell whether and when the patient will develop speech impediments, memory loss, behavioural peculiarities, and so on. Knowledge of what the future holds will allow patients to make informed choices regarding their lifestyle and therapeutic interventions.

At some point we will gain the ability to target and improve the health of specific brain regions and nerve fiber tracts. At that point, a good prediction of a subject’s future anatomic state can help identify promising target regions for this intervention. Early detection will be key to preventing and managing dementia.”

The pioneering computer model is the most recent, as well as the most important evidence to support the idea that dementia is caused by proteins that spread through the brain along networks of neurons.

It extends the results of a widely reported study of Alzheimer’s disease in February in which researchers at the Columbia University Medical Center and the Massachusetts General Hospital discovered in mouse models that Alzheimer’s starts in a particular area of the brain, but then spreads further via misfolded, toxic “tau” proteins.

Dr. Raj describes how he developed his mathematical model of the flow of toxic proteins before demonstrating that the model accurately predicts the patterns of degeneration that occurs in various different forms of dementia.

He explains that his model is based on the recent understanding that all known forms of dementia are accompanied by, and probably caused by abnormal or “misfolded” proteins. All proteins have a specific shape that depends on their particular function. However, misshaped proteins can generate undesired toxic effects, as for instance tau, a misfolded protein that occurs in the brain of Alzheimer’s patients and patients with frontal temporal dementia (FTD).

TDP43 and ubiquitin are other misfolded proteins that are also found in FTD, whilst alpha synuclein is found in Parkinson’s disease.

Misfolded or diseased proteins evoke other proteins to be misfolded, which they touch on a specific neuronal pathway. For this reason these proteins are called ‘prion-like’.

Prion diseases, like mad cow disease, which involve transmission of misfolded proteins, are thought to be infectious from person to person. However, “There is no evidence that Alzheimer’s or other dementias are contagious in that way, which is why their transmission is called prion-like.”

Dr. Raj says that his model of trans-neuronal spread of misfolded proteins is “very simple,” as it models the same process by which any gas diffuses in air, whilst in the case of dementias the diffusion process occurs along connected neural fiber tracts in the brain.

Dr. Raj says:

“This is a common process by which any disease-causing protein can result in a variety of dementias.”

The model identifies the neural sub-networks in the brain in which misfolded proteins will accumulate before they move on to other brain areas that are connected by networks of neurons. The proteins change the function of all brain areas they visit during this process.

Dr. Raj remarks:

“What is new and really quite remarkable is the network diffusion model itself, which acts on the normal brain connectivity network and manages to reproduce many known aspects of whole brain disease patterns in dementias. This provides a very simple explanation for why different dementias appear to target specific areas of the brain.”

Raj managed to match patterns from the diffusion model that traced protein allocation in a healthy brain to the patterns of brain atrophy observed in patients with either Alzheimer’s disease or FTD.

The degeneration of the brain was measured with MRI scans and other tools that were able to quantify the volume of lost brain volume in each region of the patient’s brain. Amy Kuceyeski, Ph.D., co-author and a postdoctoral fellow who works with Dr. Raj, helped to evaluate the brain volume measurements of the patient’s diseased brains.

Dr. Raj concludes:

“Our study demonstrates that such a spreading mechanism leads directly to the observed patterns of atrophy one sees in various dementias. While the classic patterns of dementia are well known, this is the first model to relate brain network properties to the patterns and explain them in a deterministic and predictive manner.”

Written by Petra Rattue