. 2023 Dec;38(12):2269-2281.

doi: 10.1002/mds.29611. Epub 2023 Nov 14.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study

Rebecca Kerestes¹, Max A Laansma^{2

3}, Conor Owens-Walton⁴, Andrew Perry⁵, Eva M van Heese^{2

3}, Sarah Al-Bachari⁶, Tim J Anderson^{7

8}, Francesca Assogna⁹, Ítalo K Aventurato^{10

11}, Tim D van Balkom^{2

3

12}, Henk W Berendse¹³, Kevin R E van den Berg^{14

15}, Rebecca Betts¹⁶, Ricardo Brioschi¹⁰, Jonathan Carr¹⁷, Fernando Cendes^{10

11}, Lyles R Clark¹⁸, John C Dalrymple-Alford^{7

19

20}, Michiel F Dirkx²¹, Jason Druzgal²², Helena Durrant¹⁶, Hedley C A Emsley^{23

24}, Gaëtan Garraux^{25

26}, Hamied A Haroon²⁷, Rick C Helmich^{14

15}, Odile A van den Heuvel^{2

3

12}, Rafael B João^{10

11}, Martin E Johansson²¹, Samson G Khachatryan^{28

29}, Christine Lochner³⁰, Corey T McMillan¹⁸, Tracy R Melzer^{7

19

20}, Philip E Mosley^{31

32}, Benjamin Newman²², Peter Opriessnig³³, Laura M Parkes^{34

35}, Clelia Pellicano⁹, Fabrizio Piras⁹, Toni L Pitcher^{7

19}, Kathleen L Poston³⁶, Mario Rango^{37

38}, Annerine Roos³⁹, Christian Rummel⁴⁰, Reinhold Schmidt⁴¹, Petra Schwingenschuh⁴¹, Lucas S Silva^{10

11}, Viktorija Smith³⁶, Letizia Squarcina⁴², Dan J Stein³⁹, Zaruhi Tavadyan^{28

29}, Chih-Chien Tsai⁴³, Daniela Vecchio⁹, Chris Vriend^{2

12

44}, Jiun-Jie Wang^{43

45

46

47}, Roland Wiest⁴⁰, Clarissa L Yasuda^{10

11}, Christina B Young³⁶, Neda Jahanshad⁴, Paul M Thompson⁴, Ysbrand D van der Werf^{2

3}, Ian H Harding^{1

48}; ENIGMA-Parkinson's Study

Affiliations

¹ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
² Department Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
⁵ Monash Bioinformatics Platform, Monash University, Melbourne, Victoria, Australia.
⁶ Faculty of Health and Medicine, The University of Lancaster, Lancaster, United Kingdom.
⁷ New Zealand Brain Research Institute, Christchurch, New Zealand.
⁸ Neurology Department, Te Whatu Ora - Health New Zealand Waitaha Canterbury, Christchurch, New Zealand.
⁹ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
¹⁰ Department of Neurology, University of Campinas - UNICAMP, Campinas, Brazil.
¹¹ Brazilian Institute of Neuroscience and Neurotechnology, Campinas, Brazil.
¹² Department Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³ Department Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴ Department of Neurology and Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁵ Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
¹⁶ School of Physics and Astronomy, Faculty of Science and Engineering, The University of Manchester, Manchester, United Kingdom.
¹⁷ Division of Neurology, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa.
¹⁸ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁹ Department of Medicine, University of Otago, Christchurch, New Zealand.
²⁰ School of Psychology, Speech and Hearing, University of Canterbury, Christchurch, New Zealand.
²¹ Department of Neurology and Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
²² Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.
²³ Lancaster Medical School, Lancaster University, Lancaster, United Kingdom.
²⁴ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
²⁵ GIGA-CRC in vivo imaging, University of Liège, Liège, Belgium.
²⁶ MoVeRe group, Department of Neurology, CHU de Liège, Belgium.
²⁷ Division of Psychology, Communication and Human Neuroscience, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
²⁸ Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.
²⁹ Centers for Sleep and Movement Disorders, Somnus Neurology Clinic, Yerevan, Armenia.
³⁰ Department of Psychiatry, SA MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Cape Town, South Africa.
³¹ Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³² The Australian eHealth Research Centre, CSIRO Health and Biosecurity, Brisbane, Queensland, Australia.
³³ Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria.
³⁴ Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
³⁵ Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, United Kingdom.
³⁶ Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁷ Excellence Center for Advanced MR Techniques and Parkinson's Disease Center, Neurology unit, Fondazione IRCCS Cà Granda Maggiore Policlinico Hospital, University of Milan, Milan, Italy.
³⁸ Department of Neurosciences, Neurology Unit, Fondazione Ca' Granda, IRCCS, Ospedale Policlinico, University of Milan, Milano, Italy.
³⁹ Department of Psychiatry and Neuroscience Institute, SA MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁴⁰ Support Center for Advanced Neuroimaging, (SCAN) University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁴¹ Department of Neurology, Medical University of Graz, Graz, Austria.
⁴² Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
⁴³ Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan.
⁴⁴ Amsterdam Neuroscience, Brain Imaging, Amsterdam, The Netherlands.
⁴⁵ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City, Taiwan.
⁴⁶ Department of Diagnostic Radiology, Chang Gung Memorial Hospital Keelung Branch, Keelung City, Keelung, Taiwan.
⁴⁷ Department of Chemical Engineering, Ming-Chi University of Technology, New Taipei City, Taiwan.
⁴⁸ Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.

PMID: 37964373
PMCID: PMC10754393
DOI: 10.1002/mds.29611

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study

Rebecca Kerestes et al. Mov Disord. 2023 Dec.

. 2023 Dec;38(12):2269-2281.

doi: 10.1002/mds.29611. Epub 2023 Nov 14.

Authors

Affiliations

¹ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
² Department Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
⁵ Monash Bioinformatics Platform, Monash University, Melbourne, Victoria, Australia.
⁶ Faculty of Health and Medicine, The University of Lancaster, Lancaster, United Kingdom.
⁷ New Zealand Brain Research Institute, Christchurch, New Zealand.
⁸ Neurology Department, Te Whatu Ora - Health New Zealand Waitaha Canterbury, Christchurch, New Zealand.
⁹ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
¹⁰ Department of Neurology, University of Campinas - UNICAMP, Campinas, Brazil.
¹¹ Brazilian Institute of Neuroscience and Neurotechnology, Campinas, Brazil.
¹² Department Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³ Department Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴ Department of Neurology and Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁵ Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
¹⁶ School of Physics and Astronomy, Faculty of Science and Engineering, The University of Manchester, Manchester, United Kingdom.
¹⁷ Division of Neurology, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa.
¹⁸ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁹ Department of Medicine, University of Otago, Christchurch, New Zealand.
²⁰ School of Psychology, Speech and Hearing, University of Canterbury, Christchurch, New Zealand.
²¹ Department of Neurology and Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
²² Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.
²³ Lancaster Medical School, Lancaster University, Lancaster, United Kingdom.
²⁴ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
²⁵ GIGA-CRC in vivo imaging, University of Liège, Liège, Belgium.
²⁶ MoVeRe group, Department of Neurology, CHU de Liège, Belgium.
²⁷ Division of Psychology, Communication and Human Neuroscience, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
²⁸ Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.
²⁹ Centers for Sleep and Movement Disorders, Somnus Neurology Clinic, Yerevan, Armenia.
³⁰ Department of Psychiatry, SA MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Cape Town, South Africa.
³¹ Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³² The Australian eHealth Research Centre, CSIRO Health and Biosecurity, Brisbane, Queensland, Australia.
³³ Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria.
³⁴ Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
³⁵ Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, United Kingdom.
³⁶ Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁷ Excellence Center for Advanced MR Techniques and Parkinson's Disease Center, Neurology unit, Fondazione IRCCS Cà Granda Maggiore Policlinico Hospital, University of Milan, Milan, Italy.
³⁸ Department of Neurosciences, Neurology Unit, Fondazione Ca' Granda, IRCCS, Ospedale Policlinico, University of Milan, Milano, Italy.
³⁹ Department of Psychiatry and Neuroscience Institute, SA MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁴⁰ Support Center for Advanced Neuroimaging, (SCAN) University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁴¹ Department of Neurology, Medical University of Graz, Graz, Austria.
⁴² Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
⁴³ Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan.
⁴⁴ Amsterdam Neuroscience, Brain Imaging, Amsterdam, The Netherlands.
⁴⁵ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City, Taiwan.
⁴⁶ Department of Diagnostic Radiology, Chang Gung Memorial Hospital Keelung Branch, Keelung City, Keelung, Taiwan.
⁴⁷ Department of Chemical Engineering, Ming-Chi University of Technology, New Taipei City, Taiwan.
⁴⁸ Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.

PMID: 37964373
PMCID: PMC10754393
DOI: 10.1002/mds.29611

Abstract

Background: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated.

Objective: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group.

Methods: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated.

Results: Overall, people with PD had a regionally smaller posterior lobe (d_max = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (d_max = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (d_max = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17).

Conclusions: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: MRI; Parkinson's disease; cerebellum; disease staging.

PubMed Disclaimer

Conflict of interest statement

Relevant conflicts of interest/financial disclosures

P.S. reports personal fees from Bial, AbbVie and Boston Scientific.

G.G. owns stocks in Koios Care (https://www.koios.care/) and has received consultancy fees from Abbvie Belgium, Zambon Belgium and EG Belgium (Stada group). He also received an Honorarium from Abbvie Belgium, Zambon Belgium and EG Belgium.

M.D. has received Honoraria from Movement Disorders Society, Quebec.

I.H.H. has provided consulting services to PTC Therapeutics, Steminent Biotherapeutics, BioAge Labs, Exicure Inc, unrelated to this work.

K.P. owns stocks in Amprion and Curasen. She has also received honoraria from invited scientific presentations to universities and professional societies not exceeding $5000/yr and provides consulting services to Curasen.

D.J.S. has received consultancy fees from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. He has also received royalties from American Psychiatric Publishing, Cambridge University Press, Elsevier Press, and Oxford University Press

Figures

**Figure 1.**
Atlas-based effect size (Cohen’s d) map, MNI-based coronal slices (top: y= −72; bottom: y= −54) and forest plots (Cohen’s d +/− 95% confidence interval) of the significant between-group differences for all people with PD vs. controls. Note: negative effect sizes reflect people with PD < controls. Regions significant at P_{FDR corrected} < 0.05 are depicted in red.

**Figure 2.**
**Left panel:** Atlas-based effect size (Cohen’s d) map and MNI-based coronal slices (top: y= −62; bottom: y= −48) of the significant between-group differences for HY1 participants vs. controls. Regions significant at P_{FDR corrected} < 0.05 are depicted in blue. **Right panel:** Effect sizes for left (top) and right (bottom) lobule V cerebellar volume associated with each disease stage. Negative values reflect lower volume in the PD group compared to controls. Bars represent 95% confidence intervals.

**Figure 3.**
**Left panel:** Atlas-based effect size (Cohen’s d) map and MNI-based coronal slices (top: y= −72; bottom: y= −54) of the significant between-group differences for HY4–5 participants vs. controls. **Right panel**: Effect sizes for left (top) and right (bottom) lobule VIIB cerebellar volume associated with each disease stage. Negative values reflect lower volume in participants compared to controls. Bars represent 95% confidence intervals.

See this image and copyright information in PMC

References

1. Laansma MA, Bright JK, Al-Bachari S, et al. International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson’s Disease. Mov Disord. 2021;36(11):2583–2594. - PMC - PubMed
1. Balsters JH, Ramnani N. Cerebellar plasticity and the automation of first-order rules. J Neurosci. 2011;31(6):2305–2312. - PMC - PubMed
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Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study

Affiliations

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous