Changes in brain activity with tominersen in early-manifest Huntington’s disease

Abstract

It is unknown whether alterations in EEG brain activity caused by Huntington’s disease may be responsive to huntingtin-lowering treatment. We analysed EEG recordings of 46 patients (mean age = 47.02 years; standard deviation = 10.19 years; 18 female) with early-manifest Stage 1 Huntington’s disease receiving the huntingtin-lowering antisense oligonucleotide tominersen for 4 months or receiving placebo as well as 39 healthy volunteers (mean age = 44.48 years; standard deviation = 12.94; 22 female) not receiving treatment. Patients on tominersen showed increased resting-state activity within a 4–8 Hz frequency range compared with patients receiving placebo (cluster-based permutation test, P < 0.05). The responsive frequency range overlapped with EEG activity that was strongly reduced in Huntington’s disease compared with healthy controls (cluster-based permutation test, P < 0.05). The underlying mechanisms of the observed treatment-related increase are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment. Hawellek et al. report that patients with Huntington’s disease treated with the huntingtin-lowering antisense oligonucleotide tominersen exhibited increased EEG power in the theta/alpha frequency range. The underlying mechanisms of the observed changes are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment.

Machine learning of brain-specific biomarkers from EEG

“…log power, eq. 7) and a common choice in clinical biomarker studies (Frohlich et al, 2019; Hawellek et al, 2022; Janz et al, 2022). Beyond classical EEG metrics, here, we adapted the Wavelet approach to further derive advanced representations for state-of-the-art ML methods developed for EEG (Figure 1a,Figure 1b).…”

“…A recent body of literature estimated spectral EEG features (power, phase interactions, power envelope correlations) from complex Morlet wavelets (Forsyth et al, 2018; Frohlich, Miller, et al, 2019; Frohlich, Reiter, et al, 2019; Hawellek et al, 2022; Hipp et al, 2021) with a logarithmic frequency grid and log-linear scaling of spectral smoothness (Hipp et al, 2012). This approach takes into account prior knowledge about lognormal scaling of brain structure and function (Buzsáki & Mizuseki, 2014), leading to fewer and spectrally wider Wavelets with increasing frequency and log-frequency integration over orders of magnitudes (octaves) rather than frequencies.…”

“…log power, eq. 8 in methods) and a common choice in clinical biomarker studies (Frohlich, Miller, et al, 2019;Hawellek et al, 2022;Janz et al, 2022).…”

A perspective on oligonucleotide therapy: Approaches to patient customization

“…It occurs due to CAG repeat expansions in exon 1 of the huntingtin gene, resulting in a polyglutamine’s pathogenic expansion. Tominersen is an ASO, presently in clinical trials, that targets the huntingtin gene mRNA and decreases gene expression, hampering protein production ( Lane et al, 2018 ; Hawellek et al, 2022 ). • Alzheimer Disease (AD): AD is the most common and devastating neurodegenerative disorder associated with causative proteins tau and amyloid beta.…”

“…It occurs due to CAG repeat expansions in exon 1 of the huntingtin gene, resulting in a polyglutamine’s pathogenic expansion. Tominersen is an ASO, presently in clinical trials, that targets the huntingtin gene mRNA and decreases gene expression, hampering protein production ( Lane et al, 2018 ; Hawellek et al, 2022 ).…”