FMRI exposes visual deficits in a progressive stage of a Parkinson’s Disease mouse model
Poster No:
170
Submission Type:
Abstract Submission
Authors:
Ruxanda Baiao1, Francisca Fernandes1, Sara Monteiro1,2, Patricia Figueiredo2, Tiago Outeiro3, Noam Shemesh1
Institutions:
1Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal, 2Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal, 3Department of Experimental Neurodegeneration, University of Göttingen, Göttingen, Göttingen
First Author:
Co-Author(s):
Sara Monteiro
Champalimaud Research, Champalimaud Foundation|Instituto Superior Técnico, Universidade de Lisboa
Lisbon, Portugal|Lisboa, Portugal
Champalimaud Research, Champalimaud Foundation|Instituto Superior Técnico, Universidade de Lisboa
Lisbon, Portugal|Lisboa, Portugal
Tiago Outeiro
Department of Experimental Neurodegeneration, University of Göttingen
Göttingen, Göttingen
Department of Experimental Neurodegeneration, University of Göttingen
Göttingen, Göttingen
Introduction:
Parkinson's disease (PD) is marked by α-synuclein aggregates, brain volume reduction, and declines in motor and cognitive functions1. With 70% of PD patients exhibiting diminished visual acuity2,3, there's evidence of involvement in sensory systems. While the αSYN mouse model has been extensively studied at molecular5,6,7 and behavioral8 levels, its functional deficits remain ambiguous. Our investigation utilizes fMRI to delve into potential impairments in the visual pathway. Through validation via C-FOS expression9 and pCASL mapping10, our study aims to deepen our understanding of the functional implications within PD pathology.
Methods:
All animal experimentation procedures received prior approval from both institutional and national authorities in adherence to European Directive 2010/63.
Animal subjects included the transgenic αSYN mouse model11 (C57BL/6-DBA/2Thy1-αSYN) and their corresponding wildtype littermates, aged 39±3 weeks and weighing approximately 42g±15g.
Visual fMRI experiments were performed under medetomidine sedation on a 9.4T Bruker BioSpec scanner; Binocular stimulation was executed12 in mice (N=12/13 PD/WT) using two blue LEDs (λ=470nm) placed above the eyes, alternating between rest (40 seconds) and stimulation (20 seconds) at a frequency of 1Hz during the fMRI design.
fMRI acquisitions used GE-EPI with TR/TE=1250/12ms, FOV=15x12mm^2, resolution=150×150μm^2, slice thickness=0.45mm (10slices). Data preprocessing, GLM activation mapping, and ROI analysis13 were performed using SPM12.
C-FOS expression was quantified through immunohistochemistry9 from other N=6/6 PD/WT animals.
In a separate cohort (N=3/3 PD/WT) a pCASL sequence10 was used for high-resolution (100x100μm^2) CBF mapping under isoflurane sedation.
Animal subjects included the transgenic αSYN mouse model11 (C57BL/6-DBA/2Thy1-αSYN) and their corresponding wildtype littermates, aged 39±3 weeks and weighing approximately 42g±15g.
Visual fMRI experiments were performed under medetomidine sedation on a 9.4T Bruker BioSpec scanner; Binocular stimulation was executed12 in mice (N=12/13 PD/WT) using two blue LEDs (λ=470nm) placed above the eyes, alternating between rest (40 seconds) and stimulation (20 seconds) at a frequency of 1Hz during the fMRI design.
fMRI acquisitions used GE-EPI with TR/TE=1250/12ms, FOV=15x12mm^2, resolution=150×150μm^2, slice thickness=0.45mm (10slices). Data preprocessing, GLM activation mapping, and ROI analysis13 were performed using SPM12.
C-FOS expression was quantified through immunohistochemistry9 from other N=6/6 PD/WT animals.
In a separate cohort (N=3/3 PD/WT) a pCASL sequence10 was used for high-resolution (100x100μm^2) CBF mapping under isoflurane sedation.
Results:
Following visual stimulation, healthy controls exhibited strong activation in the visual pathway (Fig.1A). In contrast, PD mice showed lower t-statistics and reduced activation compared to controls. Anatomically placed ROIs in key visual pathway structures (Fig.1B) supported these findings, displaying significant reductions in fMRI signals across most areas in PD mice, with a control area showing no notable differences.
C-FOS protein expression analysis revealed marked reductions in protein expression across all visual areas compared to WT controls (Fig.2A). However, in a control ROI (entorhinal cortex), no significant differences were observed between groups (Fig.2A-iv). Preliminary CBF measurements aimed at detecting vascular differences showed no significant distinctions (Fig.2B). It's important to note that our scanning protocol involved only 3 animals per group, potentially limiting the detection of small effect sizes.
C-FOS protein expression analysis revealed marked reductions in protein expression across all visual areas compared to WT controls (Fig.2A). However, in a control ROI (entorhinal cortex), no significant differences were observed between groups (Fig.2A-iv). Preliminary CBF measurements aimed at detecting vascular differences showed no significant distinctions (Fig.2B). It's important to note that our scanning protocol involved only 3 animals per group, potentially limiting the detection of small effect sizes.
Conclusions:
This extensive study unveiled deficiencies in fMRI signals across the entire visual pathway, validated by neuronal origins through C-FOS experiments and pCASL. Initial CBF measurements eliminated potential vascular differences14, indicating that observed functional map variances predominantly arise from other factors. This suggests reduced neuronal activity within the visual regions in 9-month PD mice, potentially linked to αSyn aggregation and ensuing impairments. The study conducted fMRI at a late PD stage; future research aims to explore the evolution of these deficits longitudinally. Correlation with C-FOS and CBF mapping bolstered the understanding of our BOLD-fMRI results, encouraging further investigation into sensory deficits and early PD biomarkers.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI)
Perception, Attention and Motor Behavior:
Perception: Visual 2
Physiology, Metabolism and Neurotransmission :
Neurophysiology of Imaging Signals
Keywords:
Blood
Cerebral Blood Flow
Degenerative Disease
Dopamine
fMRI CONTRAST MECHANISMS
FUNCTIONAL MRI
Vision
1|2Indicates the priority used for review
Provide references using author date format
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