Pathobiology of Stroke and Neurovascular Disorders

September 11-18, 2027

Director: Costantino Iadecola

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, USA

Co-Director: Arthur Liesz

Institute for Stroke and Dementia Research, LMU University Hospital, Munich, Germany

Faculty:

Stéphanie Debette, Paris Brain Institute, Paris, France

Louise McCullough, McGovern Medical School, Houston, USA

María Moro, Spanish National Centre for Cardiovascular Research (CNIC), Madrid, Spain

Mira Katan, University Hospital Basel, Switzerland

Lauren Sansing, Yale School of Medicine, New Haven, USA

Arthur Liesz, LMU University Hospital, Munich, Germany

Costantino Iadecola, Weill Cornell Medicine, New York, USA

Stroke and other neurovascular disorders remain among the leading causes of death and long-term disability worldwide. Over the past decade, major advances in vascular biology, neuroimmunology, genetics, imaging, and translational neuroscience have profoundly changed our understanding of how cerebrovascular diseases develop, evolve, interact with other pathologies, and recover. At the same time, emerging technologies ranging from spatial ‘omics to artificial intelligence are opening entirely new avenues for mechanistic discovery and personalized therapeutic approaches.

The present advanced course will provide participants with an integrated view of contemporary stroke research, spanning fundamental mechanisms of cerebrovascular dysfunction, ischemic and hemorrhagic brain injury, neuroimmune interactions, vascular risk factors, biomarker development, recovery and rehabilitation, and translational approaches from experimental models to clinical applications. The course will combine lectures by internationally recognized leaders in the field with ample time for interactive discussions focused on conceptual challenges, methodological approaches, and emerging technologies.

A major emphasis of the course will be the integration of traditionally separated disciplines — including vascular biology, immunology, neuropathology, systems neuroscience, imaging, and stroke medicine — into a modern framework of neurovascular disease research. Participants will gain exposure not only to established concepts, but also to unresolved questions, emerging trends, and future directions in the field.

The program is designed for basic scientists and clinician-scientist at all career stages in academia or industry, with interests in stroke pathobiology, neurovascular medicine, neuroimmunology, biomarker development and related disciplines.

María Moro

The immune-vascular axis and stroke

Stroke triggers a complex immune response that shapes not only acute brain injury but also long-term plasticity, repair, and cognitive recovery. Recent work identifies immuno-thrombosis, driven by neutrophil-platelet interactions, as a key link between vascular injury and persistent disruption of brain homeostasis. Beyond the acute lesion, this immune-vascular axis perturbs brain-wide homeostatic processes, including clearance and drainage, and extends to region-specific mechanisms of plasticity, such as hippocampal neurogenesis. These alterations are associated with cognitive deficits across stroke models, supporting a continuum in which immune and vascular dysfunction reshape the brain environment and influence endogenous plasticity and repair. Understanding these mechanisms may reveal new opportunities to promote recovery after stroke and limit long-term cognitive impairment.

Costantino Iadecola

Principles of cerebrovascular structure and function, mechanisms of ischemic brain injury: how does the brain die in stroke?

These lectures will review the fundamental principles of cerebrovascular structure and function and the mechanisms by which interruption of cerebral blood flow leads to brain injury. We will examine the organization of the cerebral circulation and the critical functions of the neurovasculature, focusing on mechanisms that match blood supply to metabolic demand, maintain blood-brain barrier integrity, facilitate the clearance of potentially toxic proteins, and support immune surveillance. The consequences of cerebral ischemia will then be discussed, including the concepts of ischemic core and penumbra and the temporal evolution of tissue injury driven by the ischemic cascade. These concepts will provide a framework for understanding therapeutic approaches to limit ischemic brain injury and foundational knowledge for subsequent lectures in the course.

Stroke and dementia: vascular contributions and interactions with neurodegenerative disease

The complex relationship between cerebrovascular disease and cognitive impairment will be the focus of these lectures. We will discuss how overt stroke and covert vascular brain injury contribute to cognitive decline, examining the roles of large infarcts, microvascular pathology (cerebral small vessel disease), white matter injury, cerebral microinfarcts, and microhemorrhages. We will then explore the growing recognition of the frequent coexistence of vascular pathologies with neurodegenerative diseases, including Alzheimer’s disease. Particular attention will be paid to the reciprocal interactions between neurovascular dysfunction and neurodegeneration, and to the role of impaired vascular clearance of amyloid-β and tau from the brain in this relationship. The clinical spectrum of post-stroke cognitive impairment and vascular cognitive impairment will be reviewed, together with opportunities for prevention through recognition and treatment of modifiable vascular risk factors.

Mira Katan

The quest for stroke biomarkers and personalized stroke therapies

Stroke is a heterogeneous disorder with distinct etiologies, pathophysiological trajectories, and outcomes. Yet clinical decisions still rely largely on population-based rather than individualized approaches. Circulating blood-based biomarkers offer a minimally invasive and repeatable means of capturing the molecular processes underlying cerebrovascular disease, and thus hold considerable promise for precision stroke medicine.

The lectures will first provide a conceptual framework distinguishing diagnostic, prognostic, etiological, and predictive biomarkers, and outline how circulating markers reflect key pathways such as neuroglial injury, inflammation, neuroendocrine stress, hemostasis, and cardiovascular dysfunction. The translational trajectory of a biomarker will then be addressed. It extends from high-throughput discovery approaches through validation in large multicenter cohorts to evaluation in interventional trials. Common methodological pitfalls along the way, including pre-analytical variability, confounding, and insufficient external validation, will be highlighted.

Drawing on data from prospective biomarker cohorts and biomarker-guided randomized trials in secondary prevention, the lectures will illustrate how blood-based biomarkers may refine etiological classification, improve risk stratification, and inform individualized therapy.

Arthur Liesz

Stroke: types, causes, epidemiology, and global burden of disease

This introductory lecture will provide a common framework for the course by reviewing the clinical and epidemiological landscape of stroke. We will first discuss the major stroke types – ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage – and their underlying causes, including large artery atherosclerosis, cardioembolism, cerebral small vessel disease, and less common etiologies, together with current approaches to etiological classification. We will then examine the global burden of stroke, which remains a leading cause of death and a major cause of acquired long-term disability in adults, with attention to differences across world regions, sexes, and age groups. Historical trends will be reviewed, contrasting the decline in age-standardized incidence and mortality in high-income countries with the rising absolute number of stroke patients and survivors driven by population aging and the growing burden in low- and middle-income countries. Finally, we will outline the milestones that have shaped modern stroke care, from organized stroke unit care to intravenous thrombolysis and endovascular thrombectomy, and highlight the unmet needs that motivate the research topics addressed throughout the course.

Stroke recovery and rehabilitation: mechanisms of repair and opportunities for intervention

The biological mechanisms underlying spontaneous recovery after stroke and the current state of rehabilitation strategies will be the main focus of this lecture. We will discuss how the injured brain reorganizes in the days to months after stroke, including the concept of a time-limited sensitive period of heightened plasticity, and the cellular and molecular processes that support repair, such as axonal sprouting, synaptic and circuit remodeling, angiogenesis, and neurogenesis. Particular attention will be paid to the emerging role of the immune system as a determinant of recovery, examining how microglia, infiltrating monocytes, and lymphocytes contribute to both tissue repair and secondary injury, and how systemic factors – including post-stroke infections, immunosuppression, gut–brain interactions, and comorbidities – shape long-term outcome. We will then review rehabilitation approaches, from the timing, intensity, and dose of motor training to adjunct strategies such as non-invasive brain stimulation, vagus nerve stimulation, robotics, and pharmacological enhancement of plasticity. Finally, we will discuss the challenges of translating recovery-promoting interventions from experimental models to clinical trials, and the opportunity to target repair processes well beyond the acute treatment window.

Assessment of brain damage, neuroplasticity, and recovery: imaging and functional outcomes from bench to bedside

This lecture will address how brain injury, neuroplasticity, and functional recovery after stroke can be measured in experimental models and in patients. We will first review approaches to quantify tissue damage, from histological and stereological methods to in vivo magnetic resonance imaging, and discuss how lesion size and location relate – or fail to relate – to functional deficits. We will then examine imaging technologies that capture the dynamic processes of injury and repair, including diffusion imaging and tractography of white matter integrity, functional MRI and connectivity analyses of network reorganization, positron emission tomography of neuroinflammation, intravital microscopy, and whole-brain tissue clearing with light-sheet microscopy. The second part of the lecture will focus on the assessment of functional outcome, covering sensorimotor, cognitive, and affective behavioral tests in rodents, their sensitivity in the acute and chronic phases, and common methodological pitfalls such as compensatory strategies, testing bias, and insufficient follow-up. Finally, we will discuss strategies to align preclinical outcome measures with clinical scales and trial endpoints, a key requirement for improving the predictive value of experimental stroke research.

María Moro

Modelling stroke: Which models should I use? White and gray matter? A practical approach

No single experimental model can fully replicate the complexity and heterogeneity of human stroke, yet the choice of model profoundly shapes our understanding of disease mechanisms and therapeutic opportunities. This lecture will provide a practical overview of the most widely used experimental models of cerebral ischemia, highlighting their strengths, limitations, and translational relevance. We will compare focal ischemia models, including transient and permanent middle cerebral artery occlusion, thromboembolic stroke, and photothrombosis, and discuss their suitability for investigating ischemic injury, reperfusion, neuroinflammation, and recovery. We will also address the differential vulnerability of gray and white matter, the challenges of reproducing white matter injury in experimental settings, and the implications of species-specific differences in brain structure. We will further explore models of global cerebral hypoperfusion, particularly chronic cerebral blood flow reduction induced by carotid artery stenosis, which provide valuable insights into white matter damage, neurovascular dysfunction, and cognitive impairment. Finally, we will discuss practical considerations for model selection, experimental design, relevant comorbidities, and the assessment of structural and functional outcomes. Together, these concepts will provide a framework for selecting the most appropriate experimental model for the specific biological question, ultimately improving the reproducibility and translational potential of preclinical stroke research.

The immunology of stroke, microbiota, thromboinflammation, systemic influences

Stroke is increasingly recognised as a systemic immunovascular disorder rather than an isolated cerebral event. After ischaemia, resident and recruited immune cells mount complex responses that can amplify neurovascular injury but also contribute to resolving inflammation and tissue repair. This lecture will explore the dynamic interplay between immunity, thrombosis, and peripheral organs, drawing on experimental and clinical evidence that highlights the central role of neutrophils and their extracellular traps (NETs). NET-mediated thromboinflammation contributes to thrombus stability, resistance to thrombolysis, and microvascular obstruction, while strategies targeting NET formation or degradation and innate immune signalling offer promising therapeutic opportunities. The microbiota-gut-brain axis is another important component of stroke pathophysiology, with bidirectional interactions involving intestinal dysbiosis, impaired gut barrier integrity, bacterial translocation, and systemic immune dysregulation that may influence brain injury, infectious complications, and recovery. Furthermore, systemic influences, particularly circadian rhythms and individual differences in immune regulation, profoundly shape neutrophil responses, collateral circulation, and stroke outcomes. Recent experimental and clinical findings illustrate how the timing and systemic immune environment of an ischemic event can determine its severity and potentially influence therapeutic efficacy. Together, these insights support a paradigm shift towards understanding stroke as a whole-body disease, opening new avenues for immunomodulatory, anti-thromboinflammatory, and personalized therapeutic strategies that complement conventional reperfusion treatments.

Assessment of brain damage, neuroplasticity, and recovery: Imaging and functional outcomes from bench to bedside

This lecture will address how brain injury, neuroplasticity, and functional recovery after stroke can be measured in experimental models and in patients. We will first review approaches to quantify tissue damage, from histological and stereological methods to in vivo magnetic resonance imaging, and discuss how lesion size and location relate – or fail to relate – to functional deficits. We will then examine imaging technologies that capture the dynamic processes of injury and repair, including diffusion imaging and tractography of white-matter integrity, functional MRI and connectivity analyses of network reorganization, positron emission tomography of neuroinflammation, intravital microscopy, and whole-brain tissue clearing with light-sheet microscopy. The second part of the lecture will focus on assessing functional outcome, covering sensorimotor, cognitive, and affective behavioural tests in rodents, their sensitivity in the acute and chronic phases, and common methodological pitfalls, such as compensatory strategies, testing bias, and insufficient follow-up. Finally, we will discuss strategies to align preclinical outcome measures with clinical scales and trial endpoints, a key requirement for improving the predictive value of experimental stroke research.