Delta power robustly predicts cognitive function in Angelman syndrome

Ostrowski, Lauren M.; Spencer, Elizabeth R.; Bird, Lynne M.; Thibert, Ronald L.; Komorowski, Robert W.; Kramer, Mark A.; Chu, Catherine J.

doi:10.1002/acn3.51385

Cited by 28 publications

(33 citation statements)

References 58 publications

(125 reference statements)

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“…One potential explanation as to why we observed effects on EEG power spectral density (PSD) but no changes in behavioral performance is that the increase in delta power may not have substantial behavioral significance. However, we find this explanation unlikely in light of recent evidence from our laboratory illustrating reductions delta power with concomitant behavioral improvements [ 74 ] and a new report in humans with Angelman Syndrome [ 70 ]. A more likely explanation for the present data is that the IGF-2-induced delta power reduction was sub-threshold for behavioral change.…”

Section: Discussionmentioning

confidence: 60%

“…Novel data uncovered by this work illustrated that acute systemic administration of IGF-2 reduced delta spectral power in EEG, a theorized biomarker in AS. This was a very promising initial finding, considering newly published data linking delta power to improvements in the Bayley Cognitive Assessment [ 70 ], prompting the prediction that an effect of IGF-2 on EEG would translate to behavioral improvements. However, disappointingly, the overwhelming majority of metrics for motor abilities, coordination, and learning and memory were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition.…”

Section: Discussionmentioning

confidence: 89%

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Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

et al. 2021

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Background Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. Methods We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. Results Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. Limitations The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. Conclusions Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 89%

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

et al. 2021

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“…We note that delta rhythms are abnormal during wake and sleep in AS. 11 , 14 We focused on wake data because it was more widely available and more reliably identified. The final data set included wake recordings of mean duration 37.4 min (range: 1 min–6.5 hrs).…”

Section: Methodsmentioning

confidence: 99%

“…Power spectra were calculated using the Chronux toolbox. 17 Following the procedure in Ostrowski et al , 14 we analyzed only occipital and parietal electrodes, O1, O2, P3, Pz, and P4 referenced to a group average across those electrodes. There, it was shown that delta power estimates from the uncleaned posterior electrodes provided the best predictor of cognitive function as these electrodes are free of muscle artifacts and provide the largest amount of data from which to estimate delta power.…”

Section: Methodsmentioning

confidence: 99%

“…Delta power is highly elevated in AS subjects compared with typically developing individuals, 11–13 and in mouse models of AS compared with wild-type (WT) mice. 11 In addition, delta power correlates with genotype 12 and cognitive function, 14 , 15 where increased delta power correlates with more severely affected phenotypes. Therefore, delta power may present a useful biomarker for severity of disease and may provide a simple, non-invasive metric to track improvement in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome

Spencer

Shi

Komorowski

et al. 2022

Brain Communications

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Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A gene in neurons. Antisense oligonucleotide therapies are under development to reinstate UBE3A protein production. Non-invasive biomarkers to detect target engagement and treatment response are needed to support clinical trials. Delta power measured in the scalp EEG is a reliable biomarker for Angelman syndrome, but varies widely across individuals and throughout development, making detection of a treatment effect using single measurements challenging. We utilized a longitudinal dataset of 204 EEG recordings from 56 subjects with AS to develop a natural history model of delta (2-4 Hz) power, with predictors of age, elapsed time, and relative delta power at an initial recording. Using this model, we computed the sample and effect sizes needed to detect a treatment effect in a human clinical trial with 80% power. We applied the same model structure to a mouse model of Angelman syndrome (n = 41) to detect antisense oligonucleotide-mediated treatment effects on absolute delta activity and Ube3a expression. In humans, delta power at a second timepoint can be reliably predicted using the natural history model. In mice, a treatment effect can be detected after antisense oligonucleotide treatment targeting the Ube3a-antisense transcript through at least 8 weeks post-treatment (P < 1e-15). Deviations in delta power from the expected natural history correlated with Ube3a expression in the mouse model (P < 0.001). Deviations in delta power from a human natural history model in Angelman syndrome can detect antisense oligonucleotide mediated improvement in Ube3a expression in Angelman syndrome mice and may be relevant for human clinical trials.

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Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep

et al. 2022

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Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss‐of‐function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual disability, impaired speech and motor skills, epilepsy, and sleep disruptions. Multiple treatment strategies to re‐express functional neuronal UBE3A from the dormant paternal allele were successful in rodent models of AS and have now moved to early phase clinical trials in children. Developing reliable and objective AS biomarkers is essential to guide the design and execution of current and future clinical trials. Our prior work quantified short daytime electroencephalograms (EEGs) to define promising biomarkers for AS. Here, we asked whether overnight sleep is better suited to detect AS EEG biomarkers. We retrospectively analyzed EEGs from 12 overnight sleep studies from individuals with AS with age and sex‐matched Down syndrome and neurotypical controls, focusing on low frequency (2–4 Hz) delta rhythms and sleep spindles. Delta EEG rhythms were increased in individuals with AS during all stages of overnight sleep, but overnight sleep did not provide additional benefit over wake in the ability to detect increased delta. Abnormal sleep spindles were not reliably detected in EEGs from individuals with AS during overnight sleep, suggesting that delta rhythms represent a more reliable biomarker. Overall, we conclude that periods of wakefulness are sufficient, and perhaps ideal, to quantify delta EEG rhythms for use as AS biomarkers. Lay Summary Electroencephalography (EEG) is a safe and reliable way of measuring abnormal brain activity in Angelman syndrome. We found that low‐frequency “delta” EEG rhythms are increased in individuals with Angelman syndrome during all stages of overnight sleep. Delta rhythms can be used as a tool to measure improvement in future clinical trials.

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Delta power robustly predicts cognitive function in Angelman syndrome

Cited by 28 publications

References 58 publications

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome

Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep

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