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Interferon-alpha induced changes in NODDI predispose to the development of fatigue

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Version 2 2023-06-12, 08:48
Version 1 2023-06-09, 09:38
journal contribution
posted on 2023-06-12, 08:48 authored by Nicholas DowellNicholas Dowell, Samira BouyagoubSamira Bouyagoub, J Tibble, V Voon, Mara Cercignani, Neil Harrison
Interferon-alpha (IFN-a) is an important mediator of antiviral immune responses. It is also used clinically in the treatment of hepatitis-C infection. Though effective, IFN-a-based therapies can often impair mood, motivation and cognition, which when severe can appear indistinguishable from major depression. In susceptible patients, fatigue and motivational impairment emerge early and have been linked to changes in basal ganglia (striatal) metabolism, neurochemistry and microstructural integrity. Here we use neurite orientation dispersion and density imaging (NODDI) modeling of multi-shell diffusion MRI to investigate whether changes in orientation dispersion index (ODI) or neurite density index (NDI) can predict the later emergence of IFN-a-induced fatigue. Eighteen patients initiating IFN-a based treatment for hepatitis-C underwent diffusion MRI and blood sampling at baseline and 4 hours after their first IFN-a injection. They were then followed up with regular psychological assessments for 12 weeks of treatment. IFN-a injection stimulated an acute inflammatory cytokine response and evoked acute fatigue that peaked between 4 and 12 weeks of treatment. Within the brain, IFN-a induced an acute increase in NDI in patients that experienced a simultaneous increase in IFN-a-induced fatigue but not patients that did not. Acute changes in striatal microstructure additionally predicted the continued development of fatigue but not mood symptoms 4 and 8 weeks later into treatment. Our findings highlight the value of NODDI as a potential in vivo biomarker of the central effects of peripheral inflammation. We highlight the exquisite sensitivity of the striatum to IFN-a and further implicate striatal perturbation in IFN-a-induced fatigue.

Funding

Mechanisms of Human Sickness; G0043; WELLCOME TRUST; 093881/Z/10/Z

History

Publication status

  • Published

File Version

  • Published version

Journal

Neuroscience

ISSN

0306-4522

Publisher

Elsevier

Volume

403

Page range

111-117

Department affiliated with

  • BSMS Neuroscience Publications

Research groups affiliated with

  • Sackler Centre for Consciousness Science Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-05

First Open Access (FOA) Date

2018-07-03

First Compliant Deposit (FCD) Date

2018-01-05

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