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

Shady Rahayel, Christina Tremblay, Andrew Vo, Ying-Qiu Zheng, Stéphane Lehéricy, Isabelle Arnulf, Marie Vidailhet, Jean-Christophe Corvol, ICEBERG Study Group, Jean-François Gagnon, Ronald B Postuma, Jacques Montplaisir, Simon Lewis, Elie Matar, Kaylena Ehgoetz Martens, Per Borghammer, Karoline Knudsen, Allan Hansen, Oury Monchi, Bratislav MisicAlain Dagher

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review


Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, p = 0.0007) and tissue deformation (r = 0.52, p = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

Original languageEnglish
Pages (from-to)3162-3178
Number of pages17
Publication statusPublished - Sept 2022


  • Atrophy/pathology
  • Brain/pathology
  • Cerebral Cortical Thinning
  • Female
  • Gene Expression
  • Humans
  • Male
  • Neurodegenerative Diseases/pathology
  • Prions/metabolism
  • REM Sleep Behavior Disorder/metabolism
  • Synucleinopathies/diagnostic imaging
  • alpha-Synuclein/genetics

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