A study examining the effect of etanercept on inflammation in the brain

INTERVENTION: Participants in the study will be given either: 1. A 50mg once weekly subcutaneous injection of etanercept for 52 weeks 2. A subcutaneous injection of the placebo CONDITION: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD). ; Nervous System Diseases ; Alzheimer disease PRIMARY OUTCOME: Ascertain the change in microglial activation on [11C] (R)‐PK‐111‐95 PET scans from base‐line to the final imaging visit in the treatment group compared to the placebo group. The imaging related outcome measures (microglial activation and cortical amyloid load) will be done at the screening image visit and at the final imaging visit, one week before the end of the treatment period. INCLUSION CRITERIA: 1. Capacity to make an informed decision as to whether they would like to take part in this specific clinical research trial 2. Male or female aged between 50‐90 3. Minimum 7 years formal education 4. Be able to hear, read, write and perform study neuro‐psychological tests in English 5. Adequate visual and auditory acuity to allow neuro‐psychological testing, based on the research clinician’s judgement 6. Fulfil the NIA‐AA criteria for the diagnosis of MCI due to AD at the screening visit. Participants must have a MOCA score of 19 to 25 inclusive at screening, at the discretion of the Principal Investigator 7. Have a study partner who spends at least eight hours a month with the subject. The study partner may be a close friend or a neighbour and not necessarily a close relative, spouse, son or daughter, and should be present at all visits. Every effort should be made to ensure that the study partner will be the same throughout the study. If it beco SECONDARY OUTCOME: The neuro‐psychological testing related outcome measures will be done at base‐line, Visit (V) 1, and repeated at V3 (13 weeks into treatment period), V4, (26 weeks), V5 (39 weeks), V6, (52 weeks on treatment, end of treatment period). Procedures carried out: PET scans x 4; MRI scans x 2; CXR x 1; blood tests x 10; urine tests x 8; ECG x 1, and as required; optional LP x 1; study injection, sub‐cutaneous, x 53; physical examination x 8; neuro‐psychological testing x 6:; 1. Ascertain the change in the primary cognitive outcome measure, the Montreal Cognitive Assessment (MOCA) from baseline to final treatment visit; 2. Ascertain the change in cortical amyloid load on AMYVID PET scans from base‐line to the final imaging visit; Exploratory objectives:; 1. Ascertain the change in the first of the exploratory cognitive outcome measures, the Repeatable Battery for the Assessment of Neuro‐psychological Status, (RBANS), from baseline to final treatment visit; 2. Ascertain the change in the second of the exploratory cognitive outcome measures, the Free and Cued Recall Selective Reminding Test with Immediate Recall (FCSRT‐IR), from baseline to final treatment visit; 3. Ascertain the change in the Cornell Scale score from base‐line to final treatment visit; 4. Ascertain the change in the behavioural assessment the Apathy Inventory from baseline to final treatment visit; 5. Ascertain the change in the behavioural assessment the Apathy Clinicians Diagnostic Criteria from baseline to final treatment visit; 6. Ascertain the change in the levels of plasma markers of neuro‐inflammation (pro and anti‐inflammatory cytokines: IL‐1; IL‐6, TNF‐a, IFN‐?, IL‐4, IL‐10, IL‐12, IL‐13; CRP, and TGF‐ß). The neuro‐inflammatory markers for the neuro‐inflammatory explorative outcome measures will be taken at the two imaging visits and at V3, V4, and V5. ; 7. Study the relationship between the changes in the levels of plasma markers of neuro‐inflammation (IL‐1; IL‐6, TNF‐a, IFN‐?, IL‐4, IL‐10, IL‐12, IL‐13; CRP, TGF‐ß) and changes of microglial activation on PK1195 PET scan, and clinical outcomes; 8. Study the relationship between the changes in the levels of plasma markers of neuro‐inflammation (IL‐1; IL‐6, TNF‐a, IFN‐?, IL‐4, IL‐10, IL‐12, IL‐13; CRP, TGF‐ß) and changes of microglial activation on [11C] (R)‐PK‐111‐95 PET scan, the change in cortical amyloid load on AMYVID PET scans and clinical outcomes; 9. Examine the penetration of etanercept across the blood brain barrier in patients with mild cognitive impairment due to AD ; 10. Optional lumbar puncture to examine the effects of etanercept on inflammatory markers in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment due to AD, and the relationship with clinical outcomes. CSF will be collected from 4 to 10 patients at V4, +/‐ two weeks. Tests will be done on the cerebro‐spinal fluid samples to measure levels of etanercept, to determine cytokine levels (Cytokine assays using MESOSCALE elisa's), and possibly to determine levels of amyloid protein