Abstract
In vivo functional and structural brain imaging of synucleinopathies in humans have provided a rich new understanding of the affected networks across the cortex and subcortex. Despite this progress, the temporal relationship between α-synuclein (α-syn) pathology and the functional and structural changes occurring in the brain is not well understood. Here, we examine the temporal relationship between locomotor ability, brain microstructure, functional brain activity, and α-syn pathology by longitudinally conducting rotarod, diffusion magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), and sensory-evoked fMRI on 20 mice injected with α-syn fibrils and 20 PBS-injected mice at three timepoints (10 males and 10 females per group). Intramuscular injection of α-syn fibrils in the hindlimb of M83+/- mice leads to progressive α-syn pathology along the spinal cord, brainstem, and midbrain by 16 weeks post-injection. Our results suggest that peripheral injection of α-syn has acute systemic effects on the central nervous system such that structural and resting-state functional activity changes occur in the brain by four weeks post-injection, well before α-syn pathology reaches the brain. At 12 weeks post-injection, a separate and distinct pattern of structural and sensory-evoked functional brain activity changes was observed that are co-localized with previously reported regions of α-syn pathology and immune activation. Microstructural changes in the pons at 12 weeks post-injection were found to predict survival time and preceded measurable locomotor deficits. This study provides preliminary evidence for diffusion and fMRI markers linked to the progression of synuclein pathology and has translational importance for understanding synucleinopathies in humans.SIGNIFICANCE STATEMENT α-Synuclein (α-syn) pathology plays a critical role in neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The longitudinal effects of α-syn pathology on locomotion, brain microstructure, and functional brain activity are not well understood. Using high field imaging, we show preliminary evidence that peripheral injection of α-syn fibrils induces unique patterns of functional and structural changes that occur at different temporal stages of α-syn pathology progression. Our results challenge existing assumptions that α-syn pathology must precede changes in brain structure and function. Additionally, we show preliminary evidence that diffusion and functional magnetic resonance imaging (fMRI) are capable of resolving such changes and thus should be explored further as markers of disease progression.
Highlights
Intracellular aggregation of a-synuclein (a-syn) has been associated with a group of diseases known as synucleinopathies, which include Parkinson’s disease, multiple system atrophy, and Lewy body dementia
Intramuscular injection of a-syn fibrils in M831/2 mice induces microstructural changes at four and 12 weeks post-injection diffusion MRI (dMRI) is an in vivo imaging technique for measuring microstructural differences between M831/À mice intramuscularly inoculated with a-syn fibrils and phosphate-buffered saline (PBS) control mice
Four weeks post-injection, the mice injected with a-syn fibrils had reduced fractional anisotropy (p, 0.05; false discovery rate (FDR) corrected) in the cerebellum, vermis, anterior medulla, posterior medulla, and somatosensory cortex compared with PBS control mice (Fig. 3D).The Cohen’s d for these effects were calculated to be 1.74, 1.87, 1.03, 1.18, and 1.90, which correspond to very large, very large, large, large, and very large effect sizes, respectively (Sullivan and Feinn, 2012)
Summary
Intracellular aggregation of a-synuclein (a-syn) has been associated with a group of diseases known as synucleinopathies, which include Parkinson’s disease, multiple system atrophy, and Lewy body dementia. We used this seeded model of synucleinopathy to examine the progressive changes in the microstructural degeneration and functional activation of brain circuits in the context of progressive induction of a-syn pathology in the neuroaxis. This is a relevant question since brain microstructure and functional activation are established longitudinal markers of progression in patients with Parkinson’s disease (Burciu et al, 2016; Archer et al, 2019)
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