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 Misic; Alain Dagher

doi:10.1093/brain/awac187

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

Department of Clinical Medicine - Nuclear Medicine and PET

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

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 language	English
Journal	Brain
Volume	145
Issue	9
Pages (from-to)	3162-3178
Number of pages	17
ISSN	0006-8950
DOIs	https://doi.org/10.1093/brain/awac187
Publication status	Published - Sept 2022

Keywords

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

Access to Document

10.1093/brain/awac187

Cite this

Rahayel, S., Tremblay, C., Vo, A., Zheng, Y-Q., Lehéricy, S., Arnulf, I., Vidailhet, M., Corvol, J-C., ICEBERG Study Group, Gagnon, J-F., Postuma, R. B., Montplaisir, J., Lewis, S., Matar, E., Ehgoetz Martens, K., Borghammer, P., Knudsen, K., Hansen, A., Monchi, O., ... Dagher, A. (2022). Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression. Brain, 145(9), 3162-3178. https://doi.org/10.1093/brain/awac187

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title = "Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression",

abstract = "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.",

keywords = "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",

author = "Shady Rahayel and Christina Tremblay and Andrew Vo and Ying-Qiu Zheng and St{\'e}phane Leh{\'e}ricy and Isabelle Arnulf and Marie Vidailhet and Jean-Christophe Corvol and {ICEBERG Study Group} and Jean-Fran{\c c}ois Gagnon and Postuma, {Ronald B} and Jacques Montplaisir and Simon Lewis and Elie Matar and {Ehgoetz Martens}, Kaylena and Per Borghammer and Karoline Knudsen and Allan Hansen and Oury Monchi and Bratislav Misic and Alain Dagher",

year = "2022",

month = sep,

doi = "10.1093/brain/awac187",

language = "English",

volume = "145",

pages = "3162--3178",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "9",

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Rahayel, S, Tremblay, C, Vo, A, Zheng, Y-Q, Lehéricy, S, Arnulf, I, Vidailhet, M, Corvol, J-C, ICEBERG Study Group, Gagnon, J-F, Postuma, RB, Montplaisir, J, Lewis, S, Matar, E, Ehgoetz Martens, K, Borghammer, P, Knudsen, K, Hansen, A, Monchi, O, Misic, B & Dagher, A 2022, 'Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression', Brain, vol. 145, no. 9, pp. 3162-3178. https://doi.org/10.1093/brain/awac187

TY - JOUR

T1 - Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression

AU - Rahayel, Shady

AU - Tremblay, Christina

AU - Vo, Andrew

AU - Zheng, Ying-Qiu

AU - Lehéricy, Stéphane

AU - Arnulf, Isabelle

AU - Vidailhet, Marie

AU - Corvol, Jean-Christophe

AU - ICEBERG Study Group

AU - Gagnon, Jean-François

AU - Postuma, Ronald B

AU - Montplaisir, Jacques

AU - Lewis, Simon

AU - Matar, Elie

AU - Ehgoetz Martens, Kaylena

AU - Borghammer, Per

AU - Knudsen, Karoline

AU - Hansen, Allan

AU - Monchi, Oury

AU - Misic, Bratislav

AU - Dagher, Alain

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Atrophy/pathology

KW - Brain/pathology

KW - Cerebral Cortical Thinning

KW - Female

KW - Gene Expression

KW - Humans

KW - Male

KW - Neurodegenerative Diseases/pathology

KW - Prions/metabolism

KW - REM Sleep Behavior Disorder/metabolism

KW - Synucleinopathies/diagnostic imaging

KW - alpha-Synuclein/genetics

U2 - 10.1093/brain/awac187

DO - 10.1093/brain/awac187

M3 - Journal article

C2 - 35594873

SN - 0006-8950

VL - 145

SP - 3162

EP - 3178

JO - Brain

JF - Brain

IS - 9

ER -