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| Name | Class |
|---|---|
| Empa, Swiss Federal Laboratories for Materials Science and Technology | OTHER |
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Stroke remains a major health burden worldwide. Many patients are severely disabled and stay in need of care. Mechanical thrombectomy has dramatically improved outcomes for stroke patients with large vessel occlusions, yet 40-50% of patients with successful recanalization remain severely disabled despite successful recanalization, a scenario called "futile recanalization". One of the causes for this lack of treatment effect is capillary obstruction, or "no reflow", potentially resulting from activated neutrophils and micrometer-sized blood clots. To address this issue, we employ digital holotomographic and atomic force microscopy to investigate the structural and chemical characteristics of blood and clot material in stroke patients and individuals at high risk of developing a stroke. Our study elucidates the association of activated neutrophils and microclots with stroke risk, and may be associated with clinical outcome, stroke ethology and reperfusion failure in patients with stroke. Leveraging label-free microscopy tools, could potentially lead to the discovery of new biomarkers for individualized stroke treatment and prevention, ultimately offering rapid identification of at risk patients and improving clinical outcomes
Background:
Stroke remains a major health burden worldwide. Many patients are severely disabled and stay in need of care. Since introducing mechanical thrombectomy as a therapeutic option, clinical outcome has drastically improved over the last few years. However, despite successful macrovascular reperfusion (recanalization), patients with stroke still have a significant risk (about 40-50%) of remaining severely disabled, a scenario called "futile recanalization". One of the causes for this lack of treatment effect is capillary obstruction, or "no reflow", potentially resulting from activated neutrophils and micrometer-sized blood clots. Previous work in rodent stroke models demonstrated that removal of these capillary stalls indeed improves reperfusion and recovery after stroke. However, there is a lack of knowledge regarding the role of neutrophils or microclots in patients with stroke, and their potential to indicate reperfusion failure.
Aim:
The goal of our study is to search for activated neutrophils and microclots in peripheral blood samples from patients with stroke. We anticipate that neutrophil and microclot characteristics such as size, shape, or surface structure may indicate stroke risk, and may be associated with clinical outcome, stroke ethology and reperfusion failure in patients with stroke. Our goal is to improve the prediction of stroke risk and treatment success.
Methodology:
We plan to prospectively include 500 patients with acute and chronic stroke, as well as a control group. We have teamed up with biophysicists from the Swiss Federal Laboratories for Materials Science (EMPA) using the novel microscopic tools 3D rotational digital tomography (DHTM) to achieve an unprecedented resolution of less than 10 μm for detection of altered neutrophil phenotypes and microclots in peripheral blood samples. Furthermore, in patients undergoing mechanical thrombectomy, retrieved clots will be analyzed with high-density micro-computertomography (micro-CT). Quantity, mechanical and structural properties of microclots and neutrophils will be correlated with risk of reperfusion failure, stroke recurrence and clinical recovery. Analyses of clots from patients with large vessel occlusion will be used to derive risk of reperfusion failure along with most likely source of the clot, and thus, most likely stroke etiology.
Potential Significance:
Current diagnostic tools are insufficient to predict response to treatment, clot source or stroke recurrence risk. Our project has the potential to discover new, clinically applicable biomarkers identifying patients at risk within a few hours, enabling individualized stroke treatment and prevention.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control Group | Patients without previous documented stroke |
| |
| Chronic Stroke Group | Patients with previous stroke ≥1year ago |
| |
| Acute Stroke No Therapy Group | Patients with acute stroke, but without intravenous thrombolysis or mechanical thrombectomy |
| |
| Acute Stroke IVT only Group | Patients with acute stroke and intravenous thrombolysis |
| |
| Acute Stroke MT-Group | Patients with acute stroke and mechanical thrombectomy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 3D rotational digital tomography | Diagnostic Test | DHTM is label-free and records the phase shift of low-energy light passing through the specimen on a transparent surface with minimal perturbation. DHTM measures the refractive index (RI) and computes the refractive index gradient (RIG), unveiling optical heterogeneity in cells. We will analyze blood samples for the detection of altered neutrophil phenotypes and microclots. |
| Measure | Description | Time Frame |
|---|---|---|
| Quantification and characterization of microclots | 3D rotational digital tomography and atomic force microscopy imaging outcome measurements:
| First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year |
| Quantification and characterization of neutrophils | 3D rotational digital tomography and atomic force microscopy image morphological outcome measurements:
| First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year |
| Evaluation of reperfusion failure in patients with large vessel occlusion and mechanical thrombectomy | Defined by successfull macrovascular reperfusion (TICI >=2c) and insufficient microvascular reperfusion with the outcome measurment (yes/no) Successfull macrovasular reperfusion is defined according to the mTICI score 2c or 3. Microvascular reperfusion success will be evaluated with thresholds were used to discriminate between microvascular hypoperfusion and reperfusion, calculated from perfusion images obtained on computed tomography (CTP) or magnetic resonance perfusion imaging (MRP). | <24 hours in patients with mechanical thrombectomy |
| Measure | Description | Time Frame |
|---|---|---|
| Change in National Institute of Health Score Scale (NIHSS) | will be assessed using National Institutes of Health Stroke Scale (NIHSS) NIHSS 13 assessed functional domains Range 0-42, higher score indicates severe impairment | First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year |
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Inclusion Criteria:
Patients without acute stroke CS or CSG
Patients with acute stroke (AS-noTx, AS-IVT, AS-MT):
Exclusion Criteria:
All groups:
Acute Stroke no Therapy
• Acute treatment with IVT or with MT
Acute Stroke IVT-Group • Acute treatment with MT or without IVT
Acute Stroke MT-Group
• Acute treatment without MT
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Patients without acute stroke (Control Group and chronic Stroke Group) will be recruited at the neurovascular ambulatory of the University Hospital Zurich
Patient with acute stroke will be included at the stroke unit of the University Hospital Zurich.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lukas Otto, Dr. med. | Contact | +41 43 253 13 01 | lukasbastian.otto@usz.ch | |
| Susanne Wegener, Prof. | Contact | +41 44 255 10 78 | susanne.wegener@usz.ch |
| Name | Affiliation | Role |
|---|---|---|
| Susanne Wegener, Prof. | University Hospital Zurich, department Neurology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Zurich | Recruiting | Zurich | Canton of Zurich | 8091 | Switzerland |
Will be decided upon reasonable request
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| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D018625 | Microscopy, Atomic Force |
| ID | Term |
|---|---|
| D020527 | Microscopy, Scanning Probe |
| D008853 | Microscopy |
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
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Blood sampling
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| Atomic Force Microscopy | Diagnostic Test | The atomic force microscope (AFM) is widely used in materials science and has found many applications in biological sciences but has been limited in use in vision science. The AFM can be used to image the topography of soft biological materials in their native environments. We will analyze blood samples for the detection of altered neutrophil phenotypes and microclots |
|
| Micro-Computertomography | Diagnostic Test | Micro-CT is a 3D imaging technique utilizing X-rays to see inside an object, slice by slice. Micro-CT, also called microtomography or micro computed tomography, is similar to hospital CT or "CAT" scan imaging but on a small scale with greatly increased resolution. Samples can be imaged with pixel sizes as small as 100 nanometers and objects can be scanned as large as 200 millimeters in diameter. We will use micro-CT to analyze blood clots from patients with large vessel occlusion. |
|
| Degree of disability or dependence assessed by the modified ranking scale (mRS) |
will be assessed using modified Rankin Scale (mRS) mRS Range: (0-6) 0 = no symptoms, 6 = death, higher score indicates severe impairment |
| First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year |
| Assessment Quality of Life using European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) | EQ-5D-5L Evaluation of 5 different aspects of health with likert scale (1-5) MOBILITY SELF-CARE USUAL ACTIVITIES PAIN / DISCOMFORT ANXIETY / DEPRESSION Each domain is scored individually, higher values indicate higher impairment of quality of life | 365 days |
| Incidence of new cardiovascular disease | Stroke, heart attack, brain bleeding | 365 days |
| All-cause mortality | Mortality | 365 days |
| D009422 |
| Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D003933 | Diagnosis |
| D008919 | Investigative Techniques |