Brain abnormalities can vary by age, sex in juvenile Batten
Differences in brain activity seen for male, female mice in response to sound
Brain abnormalities in juvenile Batten disease can vary according to biological sex and age, a new study in mice has found.
The research, which focused on brain activity in response to sound, found that female Batten mice had brain activity abnormalities that were evident at an early age and persisted into late adulthood. In male mice, these abnormalities were also present at an early age; however, as the mice got older, their brain activity became more normal, the data showed.
According to the researchers, uncovering these differences has shed light on how juvenile Batten disease affects the brain.
“These findings provide a foundation to characterize sex- and disease progression-specific sensory processing deficits [and] uncover underlying neural mechanisms,” the scientists wrote.
Their study, “Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease,” was published in the Journal of Neurodevelopmental Disorders by researchers from the University of Rochester Medical Center in New York.
Juvenile Batten disease, also called CLN3 disease, usually manifests in childhood, with symptoms that include vision problems, seizures, and cognitive issues. Previous studies have suggested that CLN3 disease tends to manifest differently based on biological sex. Specifically, female patients tend to have a later age at symptom onset, but also faster disease progression, than their male counterparts.
The reasons behind these sex-based differences are poorly understood, and the fact that the disease causes vision and cognitive problems early on can make it difficult to assess brain activity in people with CLN3. To learn more about how the disease affects the brain, researchers conducted a series of experiments in a mouse model of juvenile Batten.
“Because vision and cognition decline early, it is hard for scientists to track how the disease progresses and develop reliable treatments using standard tests,” Yanya Ding, PhD, first author of the study at the University of Rochester, said in a university news story. “Being able to successfully track brain functions in mice gives us a model that could transform how we study possible treatments and therapeutics for this devastating disease.”
Scientists used noninvasive EEG to measure electrical activity in brain
The researchers used electroencephalography (EEG) — a noninvasive test that measures electrical activity in the brain — to track a measure called mismatch negativity or MMN. In this experimental paradigm, the mice were played a series of beeps, where most of the beeps were the same but some were different. MMN is measured by looking at how the brain’s activity changes when it hears a beep that’s different than all the others.
According to the team, “EEG recordings using the auditory duration MMN paradigm provide a valuable approach for characterizing age and sex-dependent differences in auditory processing.”
In healthy mice, MMN measurements were “robust and stable” at all time points assessed, the researchers reported. In female Batten mice, MMN defects were observed across all ages studied, whereas in male Batten mice, MMN defects were evident at early ages but became less pronounced as the mice aged.
By showing how Batten disease progresses differently in males and females, this research could help guide more personalized therapies and improve the timing of interventions for better outcomes.
The differences “likely stem from sex-specific patterns of disease progression,” the researchers wrote, adding that these findings “underscore the importance of accounting for sex differences” when studying juvenile Batten disease. The scientists speculated that understanding the mechanisms that lead to MMN improvements in male mice may open up new avenues for treating Batten disease.
These findings also lend support to the idea that MMN may be useful as a biomarker to track the progression of Batten disease in humans, the scientists noted. The team further suggested that MMN might prove useful to track in trials of investigational Batten treatments.
Kuan Hong Wang, PhD, professor of neuroscience at the university and cosenior author of the new study, said the findings “highlight the importance of tracking brain function over time and support the use of this EEG-based method as a valuable tool for monitoring disease progression and testing new treatments.”
“By showing how Batten disease progresses differently in males and females, this research could help guide more personalized therapies and improve the timing of interventions for better outcomes,” Wang added.
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