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MD WP2 Peripheral immunomarker validation in treatment resistant depression

MD WP2 Peripheral immunomarker validation in treatment resistant depression. Ed Bullmore, Jonathan Cavanagh, Phil Cowen Wayne Drevets , Neil Harrison, Carmine Pariante. Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer’s Disease. Structural MRI

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MD WP2 Peripheral immunomarker validation in treatment resistant depression

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  1. MD WP2 Peripheral immunomarker validation in treatment resistant depression Ed Bullmore, Jonathan Cavanagh, Phil Cowen Wayne Drevets, Neil Harrison, Carmine Pariante Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer’s Disease

  2. Structural MRI - multi-component relaxometry(e.g. (mc)DESPOT) - 15 mins quantify T1 and T2 relaxation times - quantitative magnetization transfer (qMT) - 20mins - multi-compartment models of diffusion imaging data (NODDI) - 17 mins Functional MRI - multi-echo echoplanar imaging data at rest - 9 mins - emotional processing task - 10 mins - reward related processing - 10 mins Structural Image - 6mins Total: - 90 mins Overview: Proposed MR Imaging Sequences • Key deliverable WP2: Mechanistically validated peripheral immune markers and related neuroimaging markers of central inflammation and brain structure and function in patients with treatment-resistant depression (MD WP2)

  3. Structural MRI mcDESPOT15 mins CAM/GLA/KCL/OXF/SUS qMT20 mins CAM/GLA/KCL/OXF/SUS NODDI 17 minsCAM/GLA/KCL/OXF/SUS Functional MRI multi-echo9minsCAM/GLA/KCL/OXF/SUS Emotion10 minsCAM/GLA/KCL/OXF/SUS Reward 10 minsCAM/GLA/KCL/OXF/SUS MPRAGE/SPGR 6 minsCAM/GLA/KCL/OXF/SUS Total: 90 minutes Implementation: Proposed MR Imaging Sequences • Guy Williams (CAM) - modify MPM (nick weiskopf) for qMT • John McLean (GLA) - implement qMT, mcDESPOT, NODDI, meEPI (with assistance Gareth Barker KCL) • Gareth Barker (KCL) - transfer mcDESPOT, qMT, meEPI to GLA • Stuart Clare (OXF) - transfer mcDESPOT to CAM, SUS • Mara Cercignani (SUS) - transfer qMT OXF, assist CAM qMT

  4. 1) 5 Healthy Participants 18-50 years, right-handed, no personal history of psychiatric or neurological disorder, no personal history of substance misuse disorder, no currently prescribed medication other than oral contraception, no contraindications to MRI, not pregnant, non-smokers. 2) Refrain from caffeine on day of scanning & alcohol 24hrs prior to scan 2) One participant recruited in each centre (scanned at own centre 1st) 3) Train between sites plus taxi from station (plane Glasgow) 4) Reimbursement: £30/40/50/60/70 Total £250 plus travel 5) If a participant fails to complete – ethics to recruit a further participant (max 10) 6) Total Scanning duration 75mins – suggest book 90 minutes 7) After scanning all sequences to be transferred to Sussex Post processing 1) Signal to noise & contrast to noise analyses 2) Decision on whether any sequence/ site needs to be excluded dependent on these analyses Travelling Heads

  5. Evidence for sequence selection: fMRI reward processing outcome A fixation choice + 4s 4s outcome 4s 4s choice 4s cue Observed choices (%) B cue Time (s) 4s cue 4s GAIN Δ Punishment PE Δ Reward PE LOSS

  6. Baseline vs 24h T1 Evidence for sequence selection: (mc)DESPOT T2

  7. Mild inflammation High dose Interferon Evidence for sequence selection: qMT (BSSFP) 4Hrs post ≠1 IFN (Hepatitis C) Typhoid vaccine ΔIL-6 = pending Depression ΔIL-6 = 1.8 pg/mL Harrison et al. In preparation 3Hrs post Typhoid vaccine Inflam. challenge Typhoid vaccine ΔIL-6 = 2.4 pg/mL Depression ΔIL-6 = 1.8 pg/mL Harrison et al. Biol. Psychiatry 2014

  8. Fractional isotropy Orientation dispersion Evidence for sequence selection: NODDI Mild inflammation (Typhoid vaccine) Orientation dispersion Main effect inflammation Correlation with fatigue

  9. > Evidence for sequence selection: fMRI emotional faces Amygdala reactivity to sad versus neutral faces predicts increase in depressive symptoms (HAMD) at 4 weeks – High dose IFN (Hepatitis C) Cg25 reactivity to sad versus neutral faces correlates with mood change (POMS) - Mild Inflammation (Typhoid)

  10. Hepatitis-C patients IFN-2a 180μg/wk – 4 wks Wait list control lose win

  11. Placebo – 0.9% Saline 0.8ng/kg Endotoxin fMRI 2 hrs after injection

  12. Primary sample assessment sites (and lead roles) • Cambridge (coordination) • KCL • Brighton (MRI) • Oxford (clinical) • Glasgow (immunophenotyping) • Secondary sample assessment site • KCL (PET, CSF) • Key industry inputs • Janssen (Drevets) – prior data, protocol design • Lundbeck (Moeller) – CSF proteomics Operations Primary sample Stage 2 baseline N=40 Secondary sample N=20 Reporting Stage 2 Follow-up N=40 Study set-up Protocol, ethics Multicentre standards Primary sample Stage 1 Baseline N=40 Interim analysis Stage 1 Follow-up N=40 Jan 2017 Jan 2015 Jan 2016

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