TY - JOUR

T1 - No detectable effect on visual responses using functional mri in a rodent model of a-synuclein expression

AU - Østergaard, Freja Gam

AU - Skoven, Christian Stald

AU - Wade, Alex R.

AU - Siebner, Hartwig R.

AU - Laursen, Bettina

AU - Christensen, Kenneth Vielsted

AU - Dyrby, Tim B.

N1 - Funding Information: This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant 641805. H.R.S. holds a five-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen, which is sponsored by the Lundbeck Foundation Grant R186-2015-2138. Publisher Copyright: © 2021 Østergaard et al.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, a-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. a-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wild-type a-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wild-type a-synuclein alter functional activity in the visual system. A total of 16 rats were injected with either AAV-a-synuclein (n = 7) or AAV-null (n = 9) in the substantia nigra pars compacta (SNc) of the left hemisphere. The expression of a-synuclein was validated by a motor assay and post-mortem immunohistochemistry. Five months after the introduction of the AAV-vector, fMRI showed robust blood oxygen level-dependent (BOLD) responses to light stimulation in the visual systems of both control and AAV-a-synuclein animals. However, our results demonstrate that the expression of AAV-a-synuclein does not affect functional activation of the visual system. This negative finding suggests that fMRI-based read-outs of visual responses may not be a sensi-tive biomarker for PD.

AB - Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, a-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. a-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wild-type a-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wild-type a-synuclein alter functional activity in the visual system. A total of 16 rats were injected with either AAV-a-synuclein (n = 7) or AAV-null (n = 9) in the substantia nigra pars compacta (SNc) of the left hemisphere. The expression of a-synuclein was validated by a motor assay and post-mortem immunohistochemistry. Five months after the introduction of the AAV-vector, fMRI showed robust blood oxygen level-dependent (BOLD) responses to light stimulation in the visual systems of both control and AAV-a-synuclein animals. However, our results demonstrate that the expression of AAV-a-synuclein does not affect functional activation of the visual system. This negative finding suggests that fMRI-based read-outs of visual responses may not be a sensi-tive biomarker for PD.

KW - A-synuclein

KW - FMRI

KW - Rat

KW - Superior colliculus

KW - Vision

U2 - 10.1523/ENEURO.0516-20.2021

DO - 10.1523/ENEURO.0516-20.2021

M3 - Journal article

C2 - 33958374

AN - SCOPUS:85106177435

VL - 8

SP - 1

EP - 9

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 3

M1 - ENEURO.0516-20.2021

ER -