Diffusion kurtosis imaging (DKI) is sensitive in detecting α-Synuclein (α-Syn) accumulation-associated microstructural changes at late stages of the pathology in α-Syn overexpressing TNWT-61 mice. The aim of this study was to perform DKI in young TNWT-61 mice when α-Syn starts to accumulate and to compare the imaging results with an analysis of motor and memory impairment and α-Syn levels. Three-month-old (3mo) and six-month-old (6mo) mice underwent DKI scanning using the Bruker Avance 9.4T magnetic resonance imaging system. Region of interest (ROI) analyses were performed in the gray matter; tract-based spatial statistics (TBSS) analyses were performed in the white matter. In the same mice, α-Syn expression was evaluated using quantitative immunofluorescence. Mean kurtosis (MK) was the best differentiator between TNWT-61 mice and wildtype (WT) mice. We found increases in MK in 3mo TNWT-61 mice in the striatum and thalamus but not in the substantia nigra (SN), hippocampus, or sensorimotor cortex, even though the immunoreactivity of human α-Syn was similar or even higher in the latter regions. Increases in MK in the SN were detected in 6mo mice. These findings indicate that α-Syn accumulation-associated changes may start in areas with a high density of dopaminergic nerve terminals. We also found TBSS changes in white matter only at 6mo, suggesting α-Syn accumulation-associated changes start in the gray matter and later progress to the white matter. MK is able to detect microstructural changes induced by α-Syn overexpression in TNWT-61 mice and could be a useful clinical tool for detecting early-stage Parkinson's disease in human patients.

• Keywords
• Animal model, Diffusion kurtosis imaging, MRI, Parkinson’s disease, Striatum, Substantia nigra, TNWT-61, Thalamus, Transgenic mice,
• MeSH
• alpha-Synuclein genetics   metabolism   MeSH
• Diffusion Magnetic Resonance Imaging * MeSH
• Disease Models, Animal MeSH
• Motor Skills physiology   MeSH
• Brain diagnostic imaging   metabolism   MeSH
• Mice MeSH
• Memory physiology   MeSH
• Parkinson Disease diagnostic imaging   genetics   metabolism   MeSH
• Motor Activity physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• alpha-Synuclein MeSH
• Snca protein, mouse MeSH Browser

Diffusion kurtosis imaging (DKI) by measuring non-Gaussian diffusion allows an accurate estimation of the distribution of water molecule displacement and may correctly characterize microstructural brain changes caused by neurodegeneration. The aim of this study was to evaluate the ability of DKI to detect changes induced by α-synuclein (α-syn) accumulation in α-syn over-expressing transgenic mice (TNWT-61) in both gray matter (GM) and white matter (WM) using region of interest (ROI) and tract-based spatial statistics analyses, respectively, and to explore the relationship between α-syn accumulation and DKI metrics in our regions of interest. Fourteen-month-old TNWT-61 mice and wild-type (WT) littermates underwent in vivo DKI scanning using the Bruker Avance 9.4 Tesla magnetic resonance imaging system. ROI analysis in the GM regions substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus and tract-based spatial statistics analysis in WM were performed. Immunohistochemistry for α-syn was performed in TNWT-61 mice and correlated with DKI findings. We found increased kurtosis and decreased diffusivity values in GM regions such as the thalamus and sensorimotor cortex, and in WM regions such as the external and internal capsule, mamillothalamic tract, anterior commissure, cingulum, and corpus callosum in TNWT-61 mice as compared to WT mice. Furthermore, we report for the first time that α-syn accumulation is positively correlated with kurtosis and negatively correlated with diffusivity in the thalamus. The study provides evidence of an association between the amount of α-syn and the magnitude of DKI metric changes in the ROIs, with the potential of improving the clinical diagnosis of Parkinson's disease. We propose diffusion kurtosis imaging as a sensitive method for detecting human α-synuclein accumulation-induced changes in brain tissue, which may be reflective of Parkinson disease stage. Boxplots show the averaged mean kurtosis (orange) and mean diffusivity (blue) under the results of the analysis (*p < 0.05) in brains of wild-type (WT) and α-synuclein over-expressing (TNWT-61) mice. This approach might represent a novel biomarker for the early diagnosis of Parkinson's disease. Read the Editorial Highlight for this article on page 1117.

• Keywords
• Parkinson's disease, TBSS, TNWT-61, diffusion kurtosis imaging, mean kurtosis, transgenic mice, α-syn,
• Publication type
• Journal Article MeSH

Evidence suggests that accumulation and aggregation of α-synuclein contribute to the pathogenesis of Parkinson's disease (PD). The aim of this study was to evaluate whether diffusion kurtosis imaging (DKI) will provide a sensitive tool for differentiating between α-synuclein-overexpressing transgenic mouse model of PD (TNWT-61) and wild-type (WT) littermates. This experiment was designed as a proof-of-concept study and forms a part of a complex protocol and ongoing translational research. Nine-month-old TNWT-61 mice and age-matched WT littermates underwent behavioral tests to monitor motor impairment and MRI scanning using 9.4 Tesla system in vivo. Tract-based spatial statistics (TBSS) and the DKI protocol were used to compare the whole brain white matter of TNWT-61 and WT mice. In addition, region of interest (ROI) analysis was performed in gray matter regions such as substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus known to show higher accumulation of α-synuclein. For the ROI analysis, both DKI (6 b-values) protocol and conventional (2 b-values) diffusion tensor imaging (cDTI) protocol were used. TNWT-61 mice showed significant impairment of motor coordination. With the DKI protocol, mean, axial, and radial kurtosis were found to be significantly elevated, whereas mean and radial diffusivity were decreased in the TNWT-61 group compared to that in the WT controls with both TBSS and ROI analysis. With the cDTI protocol, the ROI analysis showed decrease in all diffusivity parameters in TNWT-61 mice. The current study provides evidence that DKI by providing both kurtosis and diffusivity parameters gives unique information that is complementary to cDTI for in vivo detection of pathological changes that underlie PD-like symptomatology in TNWT-61 mouse model of PD. This result is a crucial step in search for a candidate diagnostic biomarker with translational potential and relevance for human studies.

• Keywords
• Diffusion kurtosis imaging, Parkinson’s disease, TBSS, TNWT-61, Transgenic mice, α-Synuclein,
• MeSH
• alpha-Synuclein metabolism   MeSH
• Diffusion Magnetic Resonance Imaging methods   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Brain metabolism   pathology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Parkinson Disease metabolism   pathology   MeSH
• Pilot Projects MeSH
• Motor Activity MeSH
• Diffusion Tensor Imaging methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• alpha-Synuclein MeSH
• SNCA protein, human MeSH Browser