Translational endophenotypes (neuromarkers) in neurodevelopmental disorders: From mouse to man in CLN3 (Batten) disease
11/3/22, 11:20 AM - 11/3/22, 11:50 AM (Europe/Amsterdam) (30 minutes)
Prof. John J. Foxe
Director of the Ernest J. Del Monte Institute for Neuroscience, Professor and Chair of the Department of Neuroscience University of Rochester School of Medicine and Dentistry, New York
Director of the Ernest J. Del Monte Institute for Neuroscience, Professor and Chair of the Department of Neuroscience University of Rochester School of Medicine and Dentistry, New York

Foxe is an Irish Neuroscientist with a history of basic research into the neurophysiology of multisensory integration

and attention. He works to translate new understanding generated in his basic research program to advance understanding of

the neuropathology of a number of neurodevelopmental conditions. Emphasis is placed on the identification of endophenotypes

(neuromarkers) of disease, in linking these biomarkers to the underlying genotype, and in associating these markers with clinical

manifestations. He has worked extensively in neurodevelopmental disorders such as Autism, Rett Syndrome, and other rare

diseases of neurodevelopment, successfully gathering large-scale neuroimaging and neurophysiological datasets from these

vulnerable and often difficult-to-test populations. He is Editor-in-Chief of The European Journal of Neuroscience, the official journal of

the Federation of European Neuroscience Societies (FENS). He has published over 320 peer-reviewed papers (H-Index = 99).

The Neuronal Ceroid Lipofuscinoses (NCLs) are a group of autosomal recessive neurodevelopmental lysosomal storage

disorders that involve intracellular accumulation of ceroid lipofuscin. Clinical features include vision loss, seizures, motor decline, and

progressive dementia. Batten Disease is one of the most common NCLs, and results from mutations in the CLN3 gene on chromosome

16. Individuals with Batten/CLN3 disease show progressive decline of cognitive functioning and verbal intellectual abilities across

childhood. The neuropathologic bases of this decline are not yet well understood and objective neurologic biomarkers (neuromarkers)

of disease progression are not currently available. There is a critical need for such markers to provide more sensitive outcome measures

against which to test the effectiveness of therapeutic approaches currently in development, and to aide in the objective staging of disease

progression. We have taken a translational approach to development of reliable neuromarkers for persons with Batten disease, by using

near-identical electrophysiological approaches in a mouse model of CLN3 disease. In both humans and mice, we have interrogated

auditory sensory memory capabilities, specifically for the feature of “duration” processing, a critical cue in speech perception.


Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked

mismatch negativity (MMN) of the auditory evoked potential (AEP) would be a marker of progressive cortical deficits in this population,

with potential applicability as a brain-based biomarker in clinical trials. An additional design feature employed three stimulation rates (fast:

2.2Hz, medium: 1.1Hz, slow: 0.55Hz), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness

of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. By manipulating presentation rate, the

strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. We

also hypothesized that duration-evoked MMN deficits in CLN3 would be more severe at slower presentation rates, resulting from greater

demand on the sensory memory system.


Data from individuals with CLN3 disease (N=21; ages 6-28 years) showed robust MMN responses (i.e., intact auditory sensory memory

processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN

was not detectable in CLN3 relative to neurotypical controls (N=41; ages 6-26 years). These results reveal emerging deficits in this

critical auditory perceptual system in individuals with CLN3 disease. We also present equivalent MMN data from CLN3 mice that show

a remarkably similar electrophysiological pattern in the animal model, providing a clear high-throughput target against which to test new

therapeutic approaches, using a neuromarker that has high translational relevance.