International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease

Laansma, Max A.; Bright, Joanna K.; Al–Bachari, Sarah; Anderson, Tim; Ard, Tyler; Assogna, Francesca; Baquero, Katherine; Berendse, Henk W.; Blair, Jamie C.; Cendes, Fernando; Dalrymple‐Alford, John C.; Bie, Rob M.A. de; Debove, Ines; Dirkx, Michiel F.; Druzgal, Jason; Emsley, Hedley; Garraux, Gaëtan; Guimarães, Rachel; Gutman, Boris A.; Helmich, Rick C.; Klein, Johannes; Mackay, Clare E.; McMillan, Corey T.; Melzer, Tracy R.; Parkes, Laura M.; Piras, Fabrizio; Pitcher, Toni L.; Poston, Kathleen L.; Rango, Mario; Ribeiro, Letícia F.; Rocha, Cristiane S.; Rummel, Christian; Santos, Lucas S.R.; Schmidt, Reinhold; Schwingenschuh, Petra; Spalletta, Gianfranco; Squarcina, Letizia; Heuvel, Odile A. van den; Vriend, Chris; Wang, Jiun‐Jie; Weintraub, Daniel; Wiest, Roland; Yasuda, Clarissa; Jahanshad, Neda; Thompson, Paul M.; Werf, Ysbrand D. van der

doi:10.1002/mds.28706

Cited by 64 publications

(72 citation statements)

References 42 publications

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“…This mostly posterior cortical pattern of atrophy progression is similar to the atrophy distribution observed in the ENIGMA-Parkinson’s Study including 2367 patients with Parkinson’s disease and 1183 HC. 78 Our findings showed alterations in the default mode, limbic, dorsal attention, frontoparietal and visual networks over this time. No relationship was found between the atrophy progression in any of the resting-state networks and the change in clinical symptoms.…”

Section: Discussionsupporting

confidence: 53%

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

Tremblay

Rahayel

et al. 2021

Brain Communications

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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.

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Section: Discussionsupporting

confidence: 53%

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

Tremblay

Rahayel

et al. 2021

Brain Communications

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“…We also compared the PRS effect maps to those of the ENIGMA consortium, who measured cortical thickness and surface area from T1 MRI scans of 2,367 PD patients and 1,183 healthy controls (Laansma et al, 2021). We observed a positive correlation between the two cortical thickness maps (r = 0.37, pspin <0.005, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Most cases of PD are thought to be due to misfolded pathogenic alpha-synuclein, whose accumulations are visible at post-mortem as Lewy bodies and neurites (Brundin and Melki, 2017; Burré et al, 2018; Henderson et al, 2019b). Misfolded alpha-synuclein propagates through the brain via neuronal connections; its accumulation is associated with loss of certain neuronal populations (notably dopamine neurons), but also widespread loss of synapses with an associated diffuse pattern of brain atrophy on MRI (Bellucci et al, 2016; Gcwensa et al, 2021; Laansma et al, 2021; Schulz-Schaeffer, 2010; Zeighami et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Neuroanatomical correlates of polygenic risk for Parkinson’s Disease

Abbasi

Tremblay

Rajimehr

et al. 2022

Preprint

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Parkinson's Disease (PD) is a progressive neurodegenerative disorder with a long prodromal course. Most cases are sporadic but a polygenic risk score (PRS) recently constructed from genome-wide association studies (GWAS) has identified 90 variants that contribute to disease vulnerability. While some of the genes identified affect known disease pathways, the mechanisms by which genetic risk renders individuals vulnerable remain mostly unknown. Understanding how PD PRS manifests in the brain could inform disease modeling and prevention. Here we use genetic and neuroimaging measures from over 30,000 healthy adults from the UK Biobank to show that PD PRS is associated with cortical thinning in a posterior pattern that significantly overlaps with cortical atrophy seen in PD. We also show that this PD PRS cortical profile overlaps with the distribution of genes associated with excitatory neurons and synaptic signaling, is dependent on anatomical connectivity and on regional expression of the most significant genes from the GWAS, most of which impact the autophagy-lysosomal pathway. Conversely, PD PRS is associated with a global increase in cortical surface area. We discuss potential mechanisms for the effects of genetic risk on cortical thickness and surface area, and suggest that the divergent effects may reflect separate routes of genetic vulnerability.

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“…Cortical thickness changes in PD were not the primary focus of this study and have been documented extensively both cross‐sectionally (Laansma et al, 2021; Mak et al, 2015; Melzer et al, 2012; Pereira et al, 2014; Segura et al, 2014; Wilson et al, 2019; Zarei et al, 2013) and longitudinally (Ibarretxe‐Bilbao et al, 2012; Mak et al, 2015); however, they are worth mentioning at this stage as they can shed light on other results in this study. The present work found no significant differences in cortical thickness between PD‐CU and Controls groups, which is consistent with several previous studies (Ibarretxe‐Bilbao et al, 2012; Melzer et al, 2012; Zarei et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease

Owens‐Walton

Adamson

Walterfang

et al. 2022

Eur J of Neuroscience

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People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD‐related dementia compared with PD‐related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD‐related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD‐related dementia, which occur in line with changes to the cortex in this advanced disease stage.

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International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 64 publications

References 42 publications

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

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

Neuroanatomical correlates of polygenic risk for Parkinson’s Disease

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease

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