Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability

Abstract

Atrophy in multiple brain regions has been reported in the early stages of Parkinson's Disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell type distribution and gene expression combine to determine the pattern of disease progression remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here we used MRI data from the Parkinson Progression Markers Initiative to test this model by mapping the progression of brain atrophy over one, two and four years and relating it to brain structural and functional connectivity, cell type expression and gene ontology enrichment analyses. In this longitudinal study, we derived atrophy progression maps for the three time points using deformation-based morphometry applied to T1-weighted MRI from 74 de novo Parkinson's Disease patients (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). After regressing out the expected age and sex effects associated with normal aging, we found that atrophy significantly progressed over two and four years in the caudate, nucleus accumbens, hippocampus, and the temporal, parietal, occipital and posterior cingulate cortex. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's Disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's Disease.

Predicting longitudinal brain atrophy in Parkinson’s disease using a Susceptible-Infected-Removed agent-based model

“…Three main observations were made: first, as demonstrated previously with this dataset (Tremblay et al 2021), atrophy increased significantly over four years, being found in the striatum early on and involving a greater number of cortical regions as disease progresses.…”

“…Two theories currently exist to explain the aSyn-related pathogenesis in the brain: the prion-like protein propagation and the regional vulnerability hypotheses (Brundin & Melki, 2017;Surmeier et al, 2017). According to the prion-like hypothesis, pathologic aSyn imposes its misfolded conformation onto native proteins that can then spread trans-synaptically between neurons, a hypothesis that is supported by several studies in animals (Luk, Kehm, Carroll, et al, 2012;Masuda-Suzukake et al, 2013;Rahayel et al, 2021). More recently, MRI studies performed in humans have shown that the pattern of atrophy observed in de novo patients with PD overlaps with known structural and functional networks (Pandya et al, 2019;Zeighami et al, 2015), suggesting that brain connectivity is a critical determinant of atrophy in synucleinopathies.…”

“…Applied to de novo PD patients, the SIR model has previously demonstrated that SNCA and GBA expression and brain connectivity both significantly influence the distribution of atrophy in the brain of PD patients (Zheng et al, 2019). Furthermore, the same model was recently used to predict the spread of pathologic aSyn injected in different brain regions of wild-type mice (Rahayel et al, 2021). However, no study had yet applied the agent-based model to the analysis of atrophy progression in PD.…”

“…This may be due to the lower number of scans acquired at the four-year time point (85 versus 105 at two years) causing reduced statistical power. Also, attrition bias may be present whereby the group of PD patients still in the study at year 4 had milder disease (Tremblay et al, 2021). Another possibility is that neuron and synapse loss over time modified the patients' connectivity structures, leading to inaccuracies in modeling spread of pathology using a healthy connectome.…”

“…Using this model, we previously recreated the pattern of atrophy observed at baseline in de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI) cohort and demonstrated that both structural connectivity and gene expression were central to shaping the propagation of aSyn in the brain (Zheng et al, 2019). We subsequently used the same model to explain the propagation of pathologic aSyn injected into different brain regions of wild-type mice (Rahayel et al, 2021). Here we apply the model to longitudinal MRI data from PPMI.…”