TY - JOUR
T1 - Validating visual evoked potentials as a preclinical, quantitative biomarker for remyelination efficacy
AU - Cordano, Christian
AU - Sin, Jung H.
AU - Timmons, Garrett
AU - Yiu, Hao H.
AU - Stebbins, Karin
AU - Guglielmetti, Caroline
AU - Cruz-Herranz, Andres
AU - Xin, Wendy
AU - Lorrain, Daniel
AU - Chan, Jonah R.
AU - Green, Ari J.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease - and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.
AB - Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease - and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.
KW - clemastine
KW - demyelination
KW - remyelination
KW - visual evoked potential
UR - http://www.scopus.com/inward/record.url?scp=85136586221&partnerID=8YFLogxK
U2 - 10.1093/brain/awac207
DO - 10.1093/brain/awac207
M3 - Article
C2 - 35678509
AN - SCOPUS:85136586221
SN - 0006-8950
VL - 145
SP - 3943
EP - 3952
JO - Brain
JF - Brain
IS - 11
ER -