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

Abstract

Brain atrophy 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 also 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 map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson’s disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. 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 inversely 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. All brain maps generated here are available on request.

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

“…This tissue expansion may represent an increase in CSF volume in the perisylvian area. These results confirm previous analyses of this dataset using slightly different methodology (Tremblay et al, 2021).…”

“…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.…”

“…A W-score approach was then used to account for the normal effects of age and sex on brain morphometry (La Joie et al, 2012; Tremblay et al, 2021). The regional deformation values from each PD patient’s image were converted into age- and sex-corrected W-scores based on the values observed in the 157 controls available at baseline.…”

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression

“…The influence of connectivity is in line with several studies showing that cerebral connectivity forecasts the atrophy seen in neurodegenerative diseases, 66–68 including Parkinson’s disease. 20, 21 The influence of SNCA and GBA gene expression also agrees with mutations in these genes being significant risk factors for Parkinson’s disease and dementia with Lewy bodies. 69–71 We observed that, whereas randomizing GBA expression always interfered with the model’s ability to recreate atrophy, the randomization of SNCA expression only led to a disruption at the 40% connection density, suggesting that GBA expression exerts an effect on the spread (and hence atrophy) that is more consistent than SNCA .…”

“…4, 12–17 In line with this, MRI studies performed in patients with Parkinson’s disease also show that atrophy patterns are shaped by connectivity. 18–20…”