constitute countries with a low, low-middle, and middle SDI in 2016. The graphs depict absolute numbers as well as a distribution of the bulk of global stroke burden to developing countries (based on JOHNSON et al. 2019). Emmrich, J. V., Knauss, S., Endres, M., Current advances, challenges, and opportunities in stroke research, management, and care NAL-live 2021.2, v1.0, doi:10.34714/leopoldina_NAL-live_0002_01000 3 Tab. 1 Most common symptoms of acute stroke Sudden onset of: · Numbness (half-sided) · Weakness (half-sided) · Confusion · Difficulty speaking · Vision loss · Dizziness · Imbalance · Severe headache Prognosis In high-income countries, 10 % to 25 % of stroke patients die within a month, up to a third by the end of year one, and more than half within five years after the initial stroke (LUENGO-FERNANDEZ et al. 2013, SENNFÄLT et al. 2019). Prognosis is even worse for people who experience haemorrhagic strokes, as the 1-month mortality approaches 40 %, indicating the need for improved therapeutic approaches (ASCH et al. 2010). About 50 % to 70 % of stroke survivors regain functional independence. However, 15 % to 30 % suffer from permanent disabilities (particularly hemiparesis, aphasia, sensory loss, spasticity, and an inability to walk unassisted or perform activities of daily living), and about one fifth requires institutional care in a nursing home at 3 months after onset (ROGER et al. 2011). Only about 50 % of working-aged adults return to paid employment within 6 to 12 months after stroke (DANIEL et al. 2009). Aetiology and Risk Factors More than 90 % of the overall burden of stroke is attributable to modifiable risk factors, including metabolic risk factors (such as high systolic blood pressure, a high body mass index, high fasting plasma glucose, high total cholesterol, low glomerular filtration rate, and atrial fibrillation) and behavioural risk factors (including smoking, an unhealthy diet, and low physical activity) indicating that preventive programmes aimed at modifying metabolic and behavioural risk factors could lead to a major reduction in global stroke burden (FEIGIN et al. 2016b). Recently, it has become clear that psychosocial factors, including psychosocial stress and depression, also significantly contribute to cerebrovascular risk (HOUSE et al. 2001, SALAYCIK et al. 2007). Strikingly, air pollution has emerged as an additional major modifiable risk factor being attributable to around one-third of the global stroke burden, especially in low- and middle-income countries (FEIGIN et al. 2016b). Hypertensive vascular disease resulting from chronic, increased blood pressure is the most common cause of bleeding into the brain (CORDONNIER et al. 2018); embolisms, mostly from the heart, and large and small vessel thromboses are the most common causes of ischaemic stroke (BOGOUSSLAVSKY et al. 2018). Pathophysiology The brain requires a permanent supply of glucose and oxygen to function properly. Although the brain constitutes only 1 % to 2 % of total body mass, it receives 15 % of the resting cardiac blood output and accounts for 20 % of the total body oxygen consumption (FROSCH et al. 2010). The brain is one of the most oxygen-sensitive organs in the body. Here oxygen is used almost entirely for the oxidative metabolism of glucose, which, under normal physiological conditions, is almost the only substrate for the brain’s energy metabolism (CLARKE and SKOLOFF 1999). Oxygen deprivation of the brain may occur through several mechanisms: (i) ischaemia, an either permanent or transient restriction in blood flow, or (ii) hypoxia, a deprivation of adequate oxygen supply caused by low partial pressure of oxygen or a decreased oxygen-carrying capacity of the blood. In addition, haemorrhage results in mechanical damage to brain tissue associated with the mass effect (ARONOWSKI and ZHAO 2011). Following a reduction in blood flow, the survival of the at-risk tissue depends on factors such as duration of the ischaemia, extent of flow reduction, and presence of collateral circulation (FROSCH et al. 2010) or, in the case of a haemorrhage, haemorrhage volume and intracranial pressure. Emmrich, J. V., Knauss, S., Endres, M., Current advances, challenges, and opportunities in stroke research, management, and care NAL-live 2021.2, v1.0, doi:10.34714/leopoldina_NAL-live_0002_01000 4 The Ischaemic Penumbra In the late 1970s, ASTRUP et al. (1977) recognised that after the onset of focal brain ischaemia in baboon brains, measurements of neuronal activity revealed regions that were electrically silent but had not yet undergone irreversible cell death. Blood supply deficiency is severe at the core of an ischaemic stroke, causing irreversible membrane failure and rapid cell death. This infarct core is surrounded by a peripheral zone, the so-called penumbra (Latin: ‘half-shade’) where blood flow deficits are milder and electrical excitability of neurons is lost without causing morphological damage. Strikingly, when cerebral blood is increased, the ability to fire action potentials in these areas is completely restored. But after prolonged ischaemia, widespread cell death ensues. Today, clinical imaging techniques, such as positron emission tomography (PET), allow for real-time visualisation of these areas of ‘stunned’ brain that can be therapeutically salvaged in theory. This discovery has