Regional brain free water and gene expression provide new insights into Parkinson’s disease

137 

Abstract Submission 

Junye Yao^1,2, Dongling Zhang^3,4,5,6, Lingyu Li^1,7, Tao Wu^3,4,5, Hongjian He^1,6,8

¹Center for Brain Imaging Science and Technology, Zhejiang University, Hangzhou, China, ²College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China, ³Center for Movement Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, ⁴China National Clinical Research Center for Neurological Diseases, Beijing, China, ⁵Parkinson’s Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China, ⁶School of Physics, Zhejiang University, Hangzhou, China, ⁷Polytechnic Institute, Zhejiang University, Hangzhou, China, ⁸State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China

Junye Yao  
Center for Brain Imaging Science and Technology, Zhejiang University|College of Biomedical Engineering and Instrument Science, Zhejiang University
Hangzhou, China|Hangzhou, China

Dongling Zhang  
Center for Movement Disorders, Beijing Tiantan Hospital, Capital Medical University|China National Clinical Research Center for Neurological Diseases|Parkinson’s Disease Center, Beijing Institute for Brain Disorders, Capital Medical University|School of Physics, Zhejiang University
Beijing, China|Beijing, China|Beijing, China|Hangzhou, China

Lingyu Li  
Center for Brain Imaging Science and Technology, Zhejiang University|Polytechnic Institute, Zhejiang University
Hangzhou, China|Hangzhou, China

Tao Wu  
Center for Movement Disorders, Beijing Tiantan Hospital, Capital Medical University|China National Clinical Research Center for Neurological Diseases|Parkinson’s Disease Center, Beijing Institute for Brain Disorders, Capital Medical University
Beijing, China|Beijing, China|Beijing, China

Hongjian He  
Center for Brain Imaging Science and Technology, Zhejiang University|School of Physics, Zhejiang University|State Key Laboratory of Brain-Machine Intelligence, Zhejiang University
Hangzhou, China|Hangzhou, China|Hangzhou, China

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra, and the appearance of intraneuronal a-synuclein inclusions (Lewy bodies) (Bloem et al. 2021). Free-water (FW) imaging has emerged as a promising tool for detecting microstructural alterations in brain in vivo. Increased FW values have been suggested as an early diagnostic marker of PD. However, the underlying mechanisms of the increased FW in PD remain unclear despite its association with neuroinflammation, edema, and demyelination (Zhang et al. 2023).
In this study, we used brain FW values and regional gene expression profiles obtained from the Allen Institute for Brain Science (AIBS) to elucidate potential genetic mechanisms for regional microstructural alterations in PD. Characterizing the genetic factors associated with regional FW changes may provide valuable insights into the biological processes driving increased FW in PD. Moreover, identifying promising genetic pathways through this investigation is vital for the development of effective therapeutic interventions.

In this study, we measured FW values in 207 cortical and subcortical regions of 157 PD patients and 56 healthy controls with diffusion-weighted images. Data included in this study were acquired from the Parkinson's Progression Markers Initiative dataset. The protocols are available at www.ppmi-info.org/study-design.
The diffusion weighted images were processed with FSL as detailed in a previous study (Zhang et al. 2023), FW mappings were fitted based on a bi-tensor model (Pasternak et al. 2009). A total of 180 cortical regions from the Glasser atlas, 14 subcortical regions from the CIT168 atlas, 11 thalamic subregions and 2 amygdala subregions from the left hemisphere were selected as regions of interest (ROI). Mean FW values in each ROI were extracted from all participants. PD patients' age- and sex-adjusted regional means were normalized to the control mean for that region by a z-score transformation.
The association between FW z-score and gene expression was investigated using Partial Least Squares (PLS) regression. Gene expression data was obtained from the AIBS using abagen toolbox. Gene ontological (GO) enrichment analysis was performed on the significantly positively weighted genes identified by PLS2 using gProfiler.

In occipital, orbitofrontal and para-hippocampal cortex, amygdala and thalamus, significant increases of FW values in PD patients were detected (Fig. 1a). The FW z-score map had a significant correlation with the regional linearly weighted sum of gene expression scores defined by the PLS2 (Fig. 1b, c, R=0.465, P=4.34×10-13), suggesting that genes positively weighted on PLS2 were also more highly expressed in brain regions with higher FW values.
Using GO analyses, we found genes more highly expressed in regions with higher FW values in PD were enriched for biological processes relating to synaptic and cellular functions (Fig. 2a). There is evidence that Lewy bodies are initially deposit in pre-synaptic terminals (Tagliaferro and Burke 2016), and gradually spread toward neuronal soma, leading to neuronal loss (Uchihara et al. 2016). Then, a-synuclein can be transmitted from cell to cell in a prion-like manner (Luk et al. 2012). Neuroinflammation is associated with synaptic and cellular dysfunction induced by aggregation of Lewy bodies, which in turn may lead to accumulation of free water molecules in the extracellular space.

In this study, regional increases in FW values in PD were explored. Moreover, we found that increased FW values are associated with higher intrinsic levels of gene expression relating to disturbances in synaptic and cellular functions, indicating that these damages might be responsible for the increased free water. These findings provide valuable insights into the underlying neurodegeneration in PD and the specific vulnerabilities of affected brain regions.

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

Genetic Association Studies ²

Transcriptomics

Diffusion MRI

Cortex

Other - Parkinson's Disease; Free-water imaging; Genetics; Transcriptomics