World Sleep 2022 | Brain atrophy in RBD is shaped by gene expression and structural connectivity

We know that these patients have brain atrophy. So even before having Parkinson’s disease, even before having dementia with Lewy bodies, they already have some brain atrophy appearing. And we know this from previous studies. However, we don’t really know how atrophy appears, what shapes the atrophy that we see in these patients. So what we did is we gathered a lot of RBD patients around the world. So we created a multi-site cohort. So it’s a cohort of 182 RBD patients and 261 healthy control subjects. All of them underwent magnetic resonance imaging. So we had an image of the brain. And what we did is we measured atrophy, brain atrophy in these patients. And then we tried to understand how brain atrophy was shaped in these patients. And the current knowledge is that there are two hypotheses about how these diseases appear in the brain. So there is the prion like hypothesis.

So this says that pathologic alpha-synuclein, which is a protein that is abnormal in the Parkinson’s disease and dementia with Lewy bodies spreads from one cell to the other. So it uses the connectome to spread around the brain. The other hypothesis says that it’s not really that it spreads around the brain, but that some cells show certain morphological, energetic characteristics that make them more vulnerable to accumulating pathological alpha-synuclein. So these are two different hypotheses, and we try to understand how these hypotheses may explain the atrophy that we see in patients and what I’ve used is agent based modeling. So it’s a computational model that simulates spread of pathologic proteins in the brain. So it’s called the Asian based Susceptible-Infected-Removed (SIR) model. It’s derived from epidemiology. So in epidemiology, the SIR model is probably the most well known model to study the spread of a disease in a population.

In epidemiology, every agent is a person. So the pathology is present in the population. One person can be susceptible, infected or removed, but instead of studying how it’s present the population, here, we studied how pathologic alpha-synucleins spreads in the brain. So instead of being agents in the population, it’s proteins in the brain, but it uses the same logic as the epidemiology models. So, we use a model that is based on the constraints of connectome and gene expression of SNCA and GBA. So SNCA and GBA are two genes super important for Parkinson’s disease. SNCA codes for Synthesis of Alpha-synuclein, GBA codes for Glucocerebrosidase, which is a lysosomal enzyme, involved in the degradation of alpha-synuclein. And every brain region is connected between them. So what we do is in silico, in the model, we inject in a brain region, we simulate a spread based on the connectome and gene expression, and it’s going to create automatically in the model, atrophy around the region, around the brain.

And what we do next is we take this atrophy, we compare it to the one that we observed in patients, and if they correlate, then we were able to recreate the atrophy. So the way the model recreated atrophy is probably to a certain extent, the same mechanisms that actually appear in the actual brain. So we took the patients, we measured tissue deformation, cortical thickness, cortical surface area, three different maps. And we parcellated the brain. We used the model, simulated atrophy in the model, we compared them and what we found is that the model was able to recreate tissue deformation in patients and cortical thickness. So the correlation between tissue formation seen in patients and what the model recreated, the correlation value was 0.52, which is high. When it comes to cortical thickness, the correlation was 0.51 which is also very high.

So the model simulates the spread based on the connectome engine expression of SNCA and GBA, and just doing this is able to recreate the atrophy in RB. So this means that the atrophy that we see in patients with isolated RBD before having Parkinson’s disease before having dementia with Lewy bodies is shaped by gene expression and the connectome. Now that we know that the atrophy that we’ve seen in these patients, so these patients do not yet have Parkinson’s disease. They don’t yet have dementia with Lewy bodies. So it’s an amazing moment to give them potential medication. So far we don’t have any medication that may prevent someone developing Parkinson’s disease or dementia with Lewy bodies. However, we need to understand what are the mechanisms that lead to these diseases. And now with such a model, we are able to test hypothesis. So for example, in this study, we show that finally, the atrophy is shaped by connectomics and gene expression.

So basically we know what are the basic mechanisms that create brain atrophy in these patients. So if we want to develop a potential medication that may hinder, that may stop, that may slow down the pathological process, we need to have a model that is able to simulate what’s going on. And this is one such model. Another example of the potential of this model is we used SNCA and GBA, and this was enough to recreate the atrophy in RBD. However, we can test numerous genes. So this is a model to test what are the genes that are actually able to affect atrophy or not. And we can apply this model, not just to atrophy, but also to perfusion, but also to electroencephalography and other imaging modalities to understand what are the basics of these changes too.