Quantitative Electroencephalographic Biomarkers in Preclinical and Human Studies of Huntington’s Disease: Are They Fit-for-Purpose for Treatment Development?

Leuchter, Michael K.; Donzis, Elissa J.; Cepeda, Carlos; Hunter, Aimee M.; Estrada‐Sánchez, Ana María; Cook, Ian A.; Levine, Michael S.; Leuchter, Andrew F.

doi:10.3389/fneur.2017.00091

Cited by 19 publications

(16 citation statements)

References 53 publications

(130 reference statements)

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“…Studies evaluating brain activity through quantitative electroencephalography also have revealed changes in the lower frequency bands in zQ175 and R6/2 mice (Fisher et al 2013;Kantor et al 2013). Collectively, these results further support the claim that changes in lower frequency bands (theta and alpha) may serve as a putative biomarker for HD progression (Leuchter et al 2017).…”

Section: Discussionsupporting

confidence: 70%

Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice

Estrada‐Sánchez

Blake

Barton

et al. 2019

Journal of Neurophysiology

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Abnormal communication between cerebral cortex and striatum plays a major role in the motor symptoms of Huntington’s disease (HD), a neurodegenerative disorder caused by a mutation of the huntingtin gene ( mHTT). Because cortex is the main driver of striatal processing, we recorded local field potential (LFP) activity simultaneously in primary motor cortex (M1) and dorsal striatum (DS) in BACHD mice, a full-length HD gene model, and in a conditional BACHD/Emx-1 Cre (BE) model in which mHTT is suppressed in cortical efferents, while mice freely explored a plus-shaped maze beginning at 20 wk of age. Relative to wild-type (WT) controls, BACHD mice were just as active across >40 wk of testing but became progressively less likely to turn into a perpendicular arm as they approached the choice point of the maze, a sign of HD motor inflexibility. BE mice, in contrast, turned as freely as WT throughout testing. Although BE mice did not exactly match WT in LFP activity, the reduction in alpha (8–13 Hz), beta (13–30 Hz), and low-gamma (30–50 Hz) power that occurred in M1 of turning-impaired BACHD mice was reversed. No reversal occurred in DS. In fact, BE mice showed further reductions in DS theta (4–8 Hz), beta, and low-gamma power relative to the BACHD model. Coherence analysis indicated a dysregulation of corticostriatal information flow in both BACHD and BE mice. Collectively, our results suggest that mHTT in cortical outputs drives the dysregulation of select cortical frequencies that accompany the loss of behavioral flexibility in HD. NEW & NOTEWORTHY BACHD mice, a full-length genetic model of Huntington’s disease (HD), express aberrant local field potential (LFP) activity in primary motor cortex (M1) along with decreased probability of turning into a perpendicular arm of a plus-shaped maze, a motor inflexibility phenotype. Suppression of the mutant huntingtin gene in cortical output neurons prevents decline in turning and improves alpha, beta, and low-gamma activity in M1. Our results implicate cortical networks in the search for therapeutic strategies to alleviate HD motor signs.

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Section: Discussionsupporting

confidence: 70%

Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice

Estrada‐Sánchez

Blake

Barton

et al. 2019

Journal of Neurophysiology

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“…EEG measures the summarized electrical activity of cortical and subcortical neurons, providing a very sensitive tool to detect brain dysfunction (Leuchter et al, 2017; Meghdadi et al, 2021), including theta power increases in several human PrDs (Franko et al, 2016). Analyses of EEG spectral frequency distributions revealed a pronounced and progressive increase in the theta band (5-10 Hz) relative to other frequencies (0-50 Hz) that reached statistical significance at 18 weeks post-injection (WPI) (Fig 1C).…”

Section: Resultsmentioning

confidence: 99%

Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

Kaczmarczyk

Schleif

Dittrich

et al. 2021

Preprint

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Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific brain regions and cell types. This selectivity may arise from cells possessing varying capacities to regain proteostasis when stressed by cytotoxic protein conformers. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite having a normal outward appearance. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated a sharply reduced synthesis of ribosomal and mitochondrial components, 2) excitatory neurons showed increased expression of cytoskeletal genes, and 3) inhibitory neurons revealed reduced expression of circadian rhythm network genes. Further assessment for the role of circadian rhythms using a jet lag paradigm modestly exacerbated disease. These data demonstrate that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types. Therapeutic strategies may need to target multiple pathways, each in specific populations of cells, early in the disease process.

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“…In response to a homeostatic challenge, the R6/2 line did show deficits in recovery sleep (Fisher et al, ). The increase in sleep fragmentation is commonly associated with the sleep disturbances observed in HD patients (e.g., Goodman et al, ) and there is growing appreciation that quantitative EEG may serve as a biomarker for HD (Leuchter et al, ; Odish, Johnsen, van Someren, Roos, & van Dijk, ).…”

Section: Resultsmentioning

confidence: 99%

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Smarr

Cutler

Loh

et al. 2019

J of Neuroscience Research

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Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock‐in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

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Quantitative Electroencephalographic Biomarkers in Preclinical and Human Studies of Huntington’s Disease: Are They Fit-for-Purpose for Treatment Development?

Cited by 19 publications

References 53 publications

Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice

Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice

Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

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