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The phase coherence of the neurovascular unit is reduced in Huntington's disease.

Published version
Peer-reviewed

Repository DOI


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Authors

Bjerkan, Juliane 
Kobal, Jan 
Lancaster, Gemma 
Šešok, Sanja 
Meglič, Bernard 

Abstract

Huntington's disease is a neurodegenerative disorder in which neuronal death leads to chorea and cognitive decline. Individuals with ≥40 cytosine-adenine-guanine repeats on the interesting transcript 15 gene develop Huntington's disease due to a mutated huntingtin protein. While the associated structural and molecular changes are well characterized, the alterations in neurovascular function that lead to the symptoms are not yet fully understood. Recently, the neurovascular unit has gained attention as a key player in neurodegenerative diseases. The mutant huntingtin protein is known to be present in the major parts of the neurovascular unit in individuals with Huntington's disease. However, a non-invasive assessment of neurovascular unit function in Huntington's disease has not yet been performed. Here, we investigate neurovascular interactions in presymptomatic (N = 13) and symptomatic (N = 15) Huntington's disease participants compared to healthy controls (N = 36). To assess the dynamics of oxygen transport to the brain, functional near-infrared spectroscopy, ECG and respiration effort were recorded. Simultaneously, neuronal activity was assessed using EEG. The resultant time series were analysed using methods for discerning time-resolved multiscale dynamics, such as wavelet transform power and wavelet phase coherence. Neurovascular phase coherence in the interval around 0.1 Hz is significantly reduced in both Huntington's disease groups. The presymptomatic Huntington's disease group has a lower power of oxygenation oscillations compared to controls. The spatial coherence of the oxygenation oscillations is lower in the symptomatic Huntington's disease group compared to the controls. The EEG phase coherence, especially in the α band, is reduced in both Huntington's disease groups and, to a significantly greater extent, in the symptomatic group. Our results show a reduced efficiency of the neurovascular unit in Huntington's disease both in the presymptomatic and symptomatic stages of the disease. The vasculature is already significantly impaired in the presymptomatic stage of the disease, resulting in reduced cerebral blood flow control. The results indicate vascular remodelling, which is most likely a compensatory mechanism. In contrast, the declines in α and γ coherence indicate a gradual deterioration of neuronal activity. The results raise the question of whether functional changes in the vasculature precede the functional changes in neuronal activity, which requires further investigation. The observation of altered dynamics paves the way for a simple method to monitor the progression of Huntington's disease non-invasively and evaluate the efficacy of treatments.

Description

Acknowledgements: We would like to thank all patients and control participants for their participation—without them, this study would not have been possible. We are grateful to Franci Benko, research nurse at the Department of Neurology, University Medical Centre Ljubljana, for his invaluable help in organizing and carrying out the measurements. We also thank Fajko Bajrović for his support with the clinical part of the study and Boštjan Dolenc for the automated analysis which was used for initial checks. J.B. would like to thank Trevor Crawford, Benediktas Valys, Joe Rowland Adams and Charlie Mpetha for helpful discussions and Sam McCormack for guidance with programming. The High-End Computing facility at Lancaster University was used for data analysis. Figure 1 and the graphical abstract were created using BioRender.com.


Funder: Sir John Fisher Foundation; doi: https://doi.org/10.13039/100011314

Keywords

brain oxygenation, multiscale oscillatory analysis, neurovascular unit, phase coherence, time–frequency analysis

Journal Title

Brain Commun

Conference Name

Journal ISSN

2632-1297
2632-1297

Volume Title

6

Publisher

Oxford University Press (OUP)
Sponsorship
Engineering and Physical Sciences Research Council (EP/M006298/1)
Slovenian Research Agency (P20232)
Engineering and Physical Sciences Research Council (EP/100999X1, EP/M006298/1, 517133, 642563)
Action Medical Research (GN1963)