Imaging the surviving penumbra and recovery after stroke

In the UK, stroke is the third cause of death and first cause of acquired disability, despite some degree of recovery in most survivors. Acutely reopening the blood vessel with thrombolysis salvages some tissue from infarction and improves outcome but does not always result in sufficient recovery. This may be due to death of brain cells in and inflammation of the salvaged tissue, in spite, or even perhaps because, of restoring blood flow. These lesions might prevent normal function of the remaining healthy cells to resume. Better understanding these processes might lead to novel approaches for treatment, in order to improve outcome after stroke. In this programme of research, we will use novel imaging techniques to tackle these issues in acute stroke patients.

Stroke is the third leading cause of death and the first of severe disability in the UK. Outcome after ischaemic stroke is a complex function of damage (the infarct) and plasticity, so limiting the former and promoting the latter are key goals. In middle cerebral artery (MCA) stroke - the most frequent subtype - the main determinant of clinical outcome is whether, and how extensively, the penumbra (i.e. the functionally impaired but viable ischaemic tissue) progresses to or escapes infarction. This underpins the rationale for early recanalization using thrombolysis in MCA stroke. However, not all patients with stable recanalization enjoy satisfactory functional outcome. In this four-year programme, we propose to study two cellular processes known from animal work to develop in the surviving penumbra and that may impede recovery, namely selective neuronal loss (SNL) and microglia activation. We will also assess whether they are related, and whether they dampen network activation. Understanding them may lead to novel therapeutic approaches aiming to both maximise benefits from thrombolysis and improve outcome in ineligible patients.

We will study MCA stroke patients longitudinally, combining cutting-edge imaging techniques with relevant clinical and behavioural scales. Eligible patients will be those with presence of penumbra on acute-stage diffusion/perfusion MR, and subsequent recanalization on transcranial Dopplers. Two to three weeks later, they will undergo PET using validated and selective ligands to provide quantitative measures of neuronal integrity and microglial inflammation. We will test two main hypotheses, firstly that the severity of initial ischaemia determines the degree of subsequent SNL in the surviving penumbra, and secondly that clinical recovery is worse with greater degrees of SNL. We will also address whether microglial activation affects the surviving penumbra, whether this is proportional to the degree of initial hypoperfusion and/or selective neuronal loss, and whether it is beneficial or harmful to recovery.

In the second part of the study, a second sample of otherwise similar patients fulfilling the same inclusion criteria will undergo serial fMRI from two weeks onward, using tasks that they can do, and a subset will also undergo a PET study of neuronal integrity. We will assess whether SNL interferes with functional activation, and whether the latter gradually resumes in the surviving penumbra to support clinical recovery.

These ?proof-of-principle? studies are meant to forerun larger-scale trials, potentially leading to randomized trials of interventions aiming to curb any detrimental processes occurring in the salvaged penumbra.