Diffusion Kurtosis Imaging Detects Microstructural Alterations in Brain of α-Synuclein Overexpressing Transgenic Mouse Model of Parkinson’s Disease: A Pilot Study
- 484 Downloads
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.
KeywordsDiffusion kurtosis imaging α-Synuclein TNWT-61 Parkinson’s disease Transgenic mice TBSS
The transgenic mice were supplied for free by the QPS Austria GmbH, Grambach, Austria. The instruments for behavioral tests were kindly provided by Jiri Kucera, Environmental Measuring Systems, Brno, Czech Republic. The authors are grateful to Amy Chen and Heejae Chung for helping with English proof reading. This work was supported by the project “Employment of Newly Graduated Doctors of Science for Scientific Excellence” (CZ.1.07/2.3.00/30.0009) co-financed from the European Social Fund and the state budget of the Czech Republic and by the project “CEITEC - Central European Institute of Technology” (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund. This study was also financed from the SoMoPro II programme. The research leading to this invention has acquired a financial grant from the People Programme (Marie Curie action) of the Seventh Framework Programme of EU according to the REA Grant Agreement No. 291782. The research is further co-financed by the South-Moravian Region. The study reflects only the author’s views and that the Union is not liable for any use that may be made of the information contained therein.The MR research was also supported by MEYS CR (LO1212), the MR unit and the animal facility (CZ62760225) infrastructure by MEYS CR and EC (CZ.1.05/2.1.00/01.0017) and by ASCR (RVO:68081731).
Compliance with Ethical Standards
Conflict of interest
The authors declare no ethical or financial conflict of interest.
Human and Animal Rights and Informed Consent
All procedures involving experimental animals were performed in accordance with EU Directive no. 2010/63/EU and approved by the Animal Care Committee of the Faculty of Medicine, Masaryk University, Czech Republic, in compliance with Czech Animal Protection Act No. 246/1992.
- Blockx I, Verhoye M, Van Audekerke J, Bergwerf I, Kane JX, Delgado YPR, Veraart J, Jeurissen B, Raber K, von Horsten S, Ponsaerts P, Sijbers J, Leergaard TB, Van der Linden A (2012) Identification and characterization of Huntington related pathology: an in vivo DKI imaging study. NeuroImage 63(2):653–662CrossRefPubMedGoogle Scholar
- Delgado y Palacios R, Campo A, Henningsen K, Verhoye M, Poot D, Dijkstra J, Van Audekerke J, Benveniste H, Sijbers J, Wiborg O, Van der Linden A (2011) Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol Psychiatry 70(5):449–457CrossRefPubMedGoogle Scholar
- Falangola MF, Guilfoyle DN, Tabesh A, Hui ES, Nie X, Jensen JH, Gerum SV, Hu C, LaFrancois J, Collins HR, Helpern JA (2014) Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination. NMR Biomed 27(8):948–957CrossRefPubMedGoogle Scholar
- Kamagata K, Tomiyama H, Motoi Y, Kano M, Abe O, Ito K, Shimoji K, Suzuki M, Hori M, Nakanishi A, Kuwatsuru R, Sasai K, Aoki S, Hattori N (2013) Diffusional kurtosis imaging of cingulate fibers in Parkinson disease: comparison with conventional diffusion tensor imaging. Magn Reson Imaging 31(9):1501–1506CrossRefPubMedGoogle Scholar
- Kamagata K, Tomiyama H, Hatano T, Motoi Y, Abe O, Shimoji K, Kamiya K, Suzuki M, Hori M, Yoshida M, Hattori N, Aoki S (2014) A preliminary diffusional kurtosis imaging study of Parkinson disease: comparison with conventional diffusion tensor imaging. Neuroradiology 56(3):251–258CrossRefPubMedGoogle Scholar
- Leemans A, Jeurissen B, Sijbers J, Jones DK (2009) ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. In: 17th Annual Meeting of Intl Soc Mag Reson Med, Hawaii, USAGoogle Scholar
- Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
- Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(Suppl 1):S208–S219CrossRefPubMedGoogle Scholar
- Soria G, Aguilar E, Tudela R, Mullol J, Planas AM, Marin C (2011) In vivo magnetic resonance imaging characterization of bilateral structural changes in experimental Parkinson’s disease: a T2 relaxometry study combined with longitudinal diffusion tensor imaging and manganese-enhanced magnetic resonance imaging in the 6-hydroxydopamine rat model. Eur J Neurosci 33:1551–1560CrossRefPubMedGoogle Scholar