TSPO PET as a Measure of Post-stroke Brain Inflammation: a Natural History Cohort
Condition: Stroke, Ischemic; Inflammatory Response; Stroke, Acute
MeSH terms: Infectious Encephalitis; Stroke; Ischemic Stroke; Encephalitis; Inflammation
Study type: Interventional

Summary: 
      DESIGN: exploratory, prospective, natural history, imaging cohort study

      BACKGROUND: Stroke causes a strong inflammatory response in the brain which is thought to
      contribute to permanent brain damage in stroke patients. To develop new therapies targeting
      inflammation we need to better understand how inflammation affects the injured brain tissue
      and how it relates to neurological deficits that directly affect the patients' quality of
      life.

      AIMS: To track the extent and location of inflammation in the brain after stroke over a
      period of 90 days. The study will explore whether the most inflamed areas in the brain
      undergo the most damage after stroke and correspond to the cognitive and neurological
      deficits experienced by stroke patients.

      METHODS: The study involves an initial screening visit and 2 study imaging visits at days 15
      and 90 after the stroke episode. Patients will undergo:

        1. Two 90-minute brain imaging sessions using Positron Emission Tomography (PET) (involves
           injection of safe radiotracers which attach to brain immune cell markers TSPOs and light
           up the inflamed areas in the brain),

        2. Two 45-90 minute Magnetic Resonance Imaging (MRI) scanning sessions (include
           administration of safe chemical contrast agent Gadolinium),

        3. Physical and neurological examinations (vital signs, assessments of mobility and
           cognitive functioning),

        4. Blood testing (routine measurements, blood inflammation markers, and genetic testing for
           TSPO marker).

      Venous cannula will be inserted into the forearm for the duration of the scans.

      POPULATION: 15- 25 patients (recruitment will cease once 15 patients have completed the
      study)

      ELIGIBILITY: Male and female stroke patients, aged 18-85, with a recent (within last 10 days)
      ischemic stroke of moderate severity, able and willing to provide informed consent

      LOCATION: Patients will be recruited at the Charing Cross Hospital, Imperial College
      Healthcare NHS Trust, and study scans will be performed by Invicro Centre for Imaging
      Sciences, Hammersmith Hospital

      DURATION: 18 months FUNDED BY: Biogen Idec Ltd
    

Detailed description: 
      Stroke is a leading cause of mortality and serious long-term disability. There is a
      substantial unmet medical need for new therapies that can improve outcomes in acute stroke.

      Experimental and pathologic data suggest that peri-infarct inflammation contributes to
      secondary injury after brain ischemia and that blocking inflammation could reduce the volume
      of brain infarction and improve clinical outcome.

      In a recently completed phase 2 placebo-controlled clinical trial, the administration of
      natalizumab (a potent inhibitor of leukocyte transmigration through the blood -brain barrier
      [BBB]) in the hyperacute phase of ischemic stroke was associated with beneficial effects in
      measures of functional outcome, but did not affect the rate of infarct volume growth during a
      90-day assessment period. This apparent discrepancy between the lack of effect of
      anti-inflammatory therapy on lesion size and a substantial beneficial effect on functional
      outcome in ischemic stroke patients has raised further questions about the manifestation of
      neuroinflammation, its pathophysiological role and its relation to patients' functional
      outcome in stroke patients.

      The purpose of this imaging study is to characterize the subacute and longstanding extent of
      upregulation of the neuroinflammation marker TSPO on glial cells at two time points after
      stroke. The study will also explore the correlation of TSPO upregulation with measures of
      stroke severity and post-stroke functional outcomes.

      The objectives of this study are:

        -  To characterize TSPO glial expression in specific regions of interest defined on
           correlative brain MRI (ROIs; infarct, peri-infarct, thalamus) in the subacute (day 15+7)
           and chronic (day 90+/-7) phases after an ischemic stroke;

        -  To determine the magnitude and variability of TSPO uptake at these ROIs during the
           assessment period;

        -  To describe changes in TSPO expression between 15 and 90 days

        -  To explore the relationship between TSPO uptake, blood and infarct volume, and measures
           of Wallerian degeneration,

        -  To characterize post-stroke TSPO glial expression in relation to measures of stroke
           severity (infarct size, volume and location; NIHSS) and functional outcome (mRS,BI,
           depression scale, MoCA)

        -  To characterize post-stroke TSPO glial expression in relation to systemic inflammatory
           markers in blood

      The endpoints that relate to these objectives are:

        -  PET-derived measures of TSPO radiotracer uptake in the infarct and peri-infarct areas at
           day 15 and day 90 after a stroke

        -  PET-derived measures of TSPO radiotracer uptake in ROIs distant from the infarct area
           (e.g. thalamus, hippocampi, amygdalae and midbrain) at day 15 and day 90 after a stroke

        -  Correlation of PET-derived measures with clinical and imaging measures of stroke
           severity (stroke volume, size and NIHSS) and functional outcome (mRS Barthel index,
           MoCA, depression, ) at day 15 and day 90

        -  Correlation of infarct volume and MRI measures of white matter tract injury determined
           from DTI MRI with measures of thalamic TSPO uptake (time-activity curve; measures of
           mean and max TSPO uptake on summed image sets fromTSPO PET

        -  Correlation of PET derived measures with inflammatory markers in the blood (e.g.
           cytokines)

      This is an exploratory, prospective, natural history, imaging cohort study. The recruiting
      site will be Imperial College Healthcare NHS Trust. All study scans will be performed by
      Invicro, Hammersmith Hospital

      Between 15 and 25 subjects, with recruitment ending when 15 participants have completed all
      study procedures.

      Subjects aged 18-85 with a supratentorial ischemic stroke of moderate severity as measured by
      NIHSS >4 and evidence of infarction on clinical brain scan at time of stroke:

      Subjects will participate in this study for approximately 90 days. No treatment will be
      started as part of the trial
    

Intervention name(s): Brain Imaging
Intervention type(s): Diagnostic Test
Intervention description(s): The study involves an initial screening visit and 2 study imaging visits at days 15 and 90 after the stroke episode.Patients will undergo:
Two 90-minute brain imaging sessions using Positron Emission Tomography (PET) (involves injection of safe radiotracers which attach to brain immune cell markers TSPOs and light up the inflamed areas in the brain),
Two 45-90 minute Magnetic Resonance Imaging (MRI) scanning sessions (include administration of safe chemical contrast agent Gadolinium),
Physical and neurological examinations (vital signs, assessments of mobility and cognitive functioning),
Blood testing (routine measurements, blood inflammation markers, and genetic testing for TSPO marker).
Venous cannula will be inserted into the forearm for the duration of the scans.
Other intervention name(s): Magnetic Resonance Imaging (MRI); Positron Emission Tomography (PET-CT)
Intervention model: Single Group Assignment
Intervention model description: Exploratory, prospective, natural history, imaging cohort study
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: TSPO; MRI; PET; Stroke; Brain inflammation