Worldwide analysis of brain microstructure across Parkinson’s disease stages

190 

Abstract Submission 

Conor Owens-Walton¹, Sarah Al-Bachari², Tim Anderson^3,4,5, Fernando Cendes^6,7, John Dalrymple-Alford^4,8, Michiel Dirkx⁹, Jason Druzgal¹⁰, Hedley Emsley^11,12, Rick Helmich^9,13, Michele Hu¹⁴, Johannes Klein¹⁴, Christine Lochner¹⁵, Corey McMillan¹⁶, Tracy Melzer¹⁷, Fabrizio Piras¹⁸, Kathleen Poston¹⁹, Reinhold Schmidt²⁰, Petra Schwingenschuh²⁰, Gianfranco Spalletta¹⁸, Dan Stein²¹, Duygu Tosun²², Odile van den Heuvel^23,24, Chris Vriend^24,23, Jiun-Jie Wang^25,26,27, Paul Thompson¹, Neda Jahanshad¹, Ysbrand van der Werf^24,28

¹Imaging Genetics Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA, ²Lancaster Medical School, Lancaster University, Lancaster, UK, ³Department of Medicine, University of Otago, Christchurch, New Zealand, ⁴New Zealand Brain Research Institute, Christchurch, New Zealand, ⁵Neurology Department, Te Wahtu Ora - Health New Zealand Waitaha, Christchurch, New Zealand, ⁶Department of Neurology, University of Campinas, Campinas, São Paulo, Brazil, ⁷Brazilian Institute of Neuroscience and Neurotechnology, Campinas, São Paulo, Brazil, ⁸Te Kura Mahi ā- Hirikapo, School of Psychology, Speech and Hearing, University of Canterbury, Christchurch, New Zealand, ⁹Department of Neurology and Center of Expertise for Parkinson & Movement Disorders, Nijmegen, Netherlands, ¹⁰Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA, ¹¹Lancaster Medical School, Lancaster University, Lancaster, United Kingdom, ¹²Department of Neurology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom, ¹³Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands, ¹⁴Oxford Parkinson’s Disease Centre, Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom, ¹⁵SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch Universi, Stellenbosch, South Africa, ¹⁶University of Pennsylvania, Philadelphia, Pennsylvania, USA, ¹⁷New Zealand Brain Research Institute, Christchurch, Christchurch, ¹⁸Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy, ¹⁹Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA, ²⁰Department of Neurology, Medical University of Graz, Graz, Austria, ²¹SA MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Cape Town, South Africa, ²²Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA, ²³Amsterdam UMC, Deptartment of Psychiatry, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, ²⁴Amsterdam UMC, Department of Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, ²⁵Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung, Taiwan, ²⁶Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan, ²⁷Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City, Taiwan, ²⁸Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

Conor Owens-Walton, PhD  
Imaging Genetics Center, Keck School of Medicine, University of Southern California
Los Angeles, California, USA

Sarah Al-Bachari  
Lancaster Medical School, Lancaster University
Lancaster, UK

Tim Anderson, MD, PhD  
Department of Medicine, University of Otago|New Zealand Brain Research Institute|Neurology Department, Te Wahtu Ora - Health New Zealand Waitaha
Christchurch, New Zealand|Christchurch, New Zealand|Christchurch, New Zealand

Fernando Cendes  
Department of Neurology, University of Campinas|Brazilian Institute of Neuroscience and Neurotechnology
Campinas, São Paulo, Brazil|Campinas, São Paulo, Brazil

John Dalrymple-Alford, PhD  
New Zealand Brain Research Institute|Te Kura Mahi ā- Hirikapo, School of Psychology, Speech and Hearing, University of Canterbury
Christchurch, New Zealand|Christchurch, New Zealand

Michiel Dirkx, MD, PhD  
Department of Neurology and Center of Expertise for Parkinson & Movement Disorders
Nijmegen, Netherlands

Jason Druzgal  
Department of Radiology and Medical Imaging, University of Virginia
Charlottesville, Virginia, USA

Hedley Emsley  
Lancaster Medical School, Lancaster University|Department of Neurology, Lancashire Teaching Hospitals NHS Foundation Trust
Lancaster, United Kingdom|Preston, United Kingdom

Rick Helmich  
Department of Neurology and Center of Expertise for Parkinson & Movement Disorders|Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University
Nijmegen, Netherlands|Nijmegen, Netherlands

Michele Hu, MD, PhD  
Oxford Parkinson’s Disease Centre, Department of Clinical Neurosciences, Oxford University
Oxford, United Kingdom

Johannes Klein  
Oxford Parkinson’s Disease Centre, Department of Clinical Neurosciences, Oxford University
Oxford, United Kingdom

Christine Lochner, PhD  
SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch Universi
Stellenbosch, South Africa

Corey McMillan, PhD  
University of Pennsylvania
Philadelphia, Pennsylvania, USA

Tracy Melzer, TRM  
New Zealand Brain Research Institute
Christchurch, Christchurch

Fabrizio Piras  
Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation
Rome, Italy

Kathleen Poston  
Department of Neurology & Neurological Sciences, Stanford University
Palo Alto, California, USA

Reinhold Schmidt  
Department of Neurology, Medical University of Graz
Graz, Austria

Petra Schwingenschuh  
Department of Neurology, Medical University of Graz
Graz, Austria

Gianfranco Spalletta, MD, PhD  
Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation
Rome, Italy

Dan Stein  
SA MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University
Cape Town, South Africa

Duygu Tosun  
Department of Radiology and Biomedical Imaging, University of California San Francisco
San Francisco, California, USA

Odile van den Heuvel  
Amsterdam UMC, Deptartment of Psychiatry, Vrije Universiteit Amsterdam|Amsterdam UMC, Department of Anatomy and Neurosciences, Vrije Universiteit Amsterdam
Amsterdam, Netherlands|Amsterdam, Netherlands

Chris Vriend, PhD  
Amsterdam UMC, Department of Anatomy and Neurosciences, Vrije Universiteit Amsterdam|Amsterdam UMC, Deptartment of Psychiatry, Vrije Universiteit Amsterdam
Amsterdam, Netherlands|Amsterdam, Netherlands

Jiun-Jie Wang  
Department of Diagnostic Radiology, Chang Gung Memorial Hospital|Healthy Aging Research Center, Chang Gung University|Department of Medical Imaging and Radiological Sciences, Chang Gung University
Keelung, Taiwan|Taoyuan City, Taiwan|Taoyuan City, Taiwan

Paul Thompson, PhD  
Imaging Genetics Center, Keck School of Medicine, University of Southern California
Los Angeles, California, USA

Neda Jahanshad, PhD  
Imaging Genetics Center, Keck School of Medicine, University of Southern California
Los Angeles, California, USA

Ysbrand van der Werf  
Amsterdam UMC, Department of Anatomy and Neurosciences, Vrije Universiteit Amsterdam|Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam
Amsterdam, Netherlands|Amsterdam, Netherlands

Diffusion tensor imaging (DTI) can reveal the profile and progression of white matter (WM) microstructural features in Parkinson's disease (PD). Even so, single-site studies and reviews show conflicting changes associated with the disorder [1,2], potentially due to small sample sizes, cohort heterogeneity, and varying analysis methods. To address these issues, we performed a coordinated multisite analysis of data from 17 international cohorts from Africa, Asia, Europe, Oceania, North and South America, providing a large sample sized to detect WM abnormalities across Hoehn and Yahr (HY) stages of PD.

We analyzed whole brain diffusion MRI data (17 sites; 3T, single b-value shell, 1000 s/mm^2; diffusion encoding gradients: 7-80) from 1,312 participants with PD and 885 controls (age: 20-89 years; 39% female). PD participants were categorized into HY disease progression stages: 1 (n=275), 2 (n=742), 3 (n=220) and 4/5 (n=75). Image processing pipelines followed ENIGMA-DTI protocols [3]. Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated and then skeletonized using tract-based spatial-statistics [4]; mean DTI metrics were extracted for 21 WM regions of interest (ROI) [5]. A mega-analytic approach, modeling site as a random effect, and adjusting for age and sex, was used to evaluate group differences between PD-HY subgroups and controls. We tested for associations between DTI measures and time since diagnosis, Montreal Cognitive Assessment (MoCA) scores, and MDS-UPDRS-III scores across the entire PD cohort.

Relative to controls, HY1 participants showed higher FA across the entire WM skeleton (d=0.30) and in 4 ROIs. HY2 PD participants had lower FA in the fornix (d=-0.26), while HY3 PD participants showed lower FA across the entire WM skeleton (d=-0.24) and 9 ROIs. HY4/5 PD participants had much greater FA decreases across the entire WM skeleton (d=-0.74), and in 20 out of 21 ROIs (Fig. 1). Relative to controls, HY1 PD participants displayed lower MD across the entire WM skeleton (d=-0.19) and in 5 ROIs. HY2 PD participants displayed lower MD at the fornix/stria terminalis (d=-0.22), retrolenticular limb of the internal capsule, fornix and the hippocampal cingulum. No significant MD differences were detected in HY3 PD participants. HY4/5 PD participants displayed higher MD in the fornix (d=0.69), and in 7 ROIs. HY4/5 PD participants also displayed lower MD in the hippocampal cingulum (d=-0.32) (Fig. 2). Time since diagnosis (PD n=1,441) was negatively correlated with FA across the entire WM skeleton (d=-0.09). We also found positive correlations between time since diagnosis and MD in the genu of the corpus callosum (d=0.08), the anterior corona radiata and external capsule. MoCA scores (PD n=953), were positively correlated with FA across the entire WM skeleton (d=0.12) and negatively correlated with MD across the entire WM skeleton (d=-0.13). MDS-UPDRS-III scores (n=597) were inversely associated with FA across the entire WM skeleton (d=-0.17). MD in the fornix was positively correlated with MDS-UPDRS-III scores (d=0.13).

Pronounced patterns of FA differences emerged when stratifying PD participants according to HY stage. Widespread WM microstructural alterations in people with PD appeared as higher FA and lower MD in the initial HY stage. This pattern was reversed at advanced HY stages. Poorer clinical function associated with lower FA and higher MD. Higher FA, early in the disorder, may relate to compensatory reorganization of neural circuits indicative of adaptive neuroplasticity [6], while lower FA and higher MD may reflect neurodegeneration [7]. Prior work on brain morphometry by ENIGMA-PD has also shown greater subcortical volumes at HY stage 1, before shifting to thinner cortical GM and lower subcortical volumes at advanced disease stages [8].

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Diffusion MRI ²

Movement Disorder

MRI

White Matter

WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC