|Year : 2015 | Volume
| Issue : 1 | Page : 3-8
The collaterome: A novel conceptual framework of systems biology in cerebrovascular disorders
David S Liebeskind
Department of Neurology, Neurovascular Imaging Research Core; Comprehensive Stroke Center, Geffen School of Medicine, University of California, Los Angeles, California, USA
|Date of Submission||16-Apr-2015|
|Date of Acceptance||15-Jun-2015|
|Date of Web Publication||30-Sep-2015|
David S Liebeskind
Neurovascular Imaging Research Core, University of California; Department of Neurology, Neuroscience Research Building, 635 Charles E Young Drive South, Suite 225, Los Angeles, California 90095-7334
Source of Support: None, Conflict of Interest: None
The collaterome is the elaborate neurovascular architecture within the brain that regulates and determines the compensatory ability, response, and outcome of cerebrovascular pathophysiology. Based on the fundamental aspects of the cerebral collateral circulation, this model provides a conceptual framework or novel approach to cerebrovascular disorders that endorses systems biology rather than traditional reductionism. The nature of this holistic approach mirrors the innate or endogenous compensatory ability of collaterals, extending this concept to reconsider current approaches to cerebrovascular disorders. The distinction of asymptomatic and symptomatic physiology, and normal brain health versus cerebrovascular disease and the management of cerebrovascular disorders from diagnosis to therapeutic strategies may be reconsidered from this conceptual framework that builds upon established knowledge in the stroke literature.
Keywords: Collaterals, imaging, stroke
|How to cite this article:|
Liebeskind DS. The collaterome: A novel conceptual framework of systems biology in cerebrovascular disorders. Brain Circ 2015;1:3-8
| Introduction|| |
The collaterome is the elaborate neurovascular architecture within the brain that regulates and determines the compensatory ability, response, and outcome of cerebrovascular pathophysiology.  Based on the fundamental aspects of the cerebral collateral circulation, this model provides a conceptual framework or novel approach to cerebrovascular disorders that endorses systems biology rather than traditional reductionism. The structural and functional components of this model integrate vascular components of the cerebral circulation from arterial to venous beds and extend from microscopic to macroscopic elements, with features of the neurovascular unit that regulate the dynamic interaction between vessels and parenchyma. The nature of this holistic approach mirrors the innate or endogenous compensatory ability of collaterals, extending this concept to reconsider current approaches to cerebrovascular disorders. The distinction between asymptomatic and symptomatic physiology, normal brain health versus cerebrovascular disease and management of cerebrovascular disorders from diagnosis to therapeutic strategies may be reconsidered from this conceptual framework that builds upon established knowledge in the stroke literature.
| Systems Biology|| |
The collaterome provides a seminal application of systems biology to the field of stroke, coinciding with the marked transformation of other areas of medicine from the traditional reductionist basis of evidence-based medicine to holistic approaches that consider many other dimensions.  Systems biology emanated from the marked increase in biomedical data over the last decade, including clinical, genomic, and imaging variables that enable better understanding of specific disorders. Classical research paradigms of complex disorders such as cerebrovascular physiology tend to focus on singular elements at the genetic, molecular, structural, or functional levels that permit isolated analyses. Reductionism within the scientific method has focused attention on specific targets within most medical disciplines, from diagnosis to prevention and treatment. Examples within the stroke field include translational research paradigms bridging basic sciences and clinical trials in neuroprotection where specific molecular events have been the overwhelming focus of investigations on the ischemic cascade. Such an approach has followed a logical trajectory, yet experimental models and subsequent clinical trials failed to consider systems interactions such as the role of collateral perfusion as it relates to delivery of a potential neuroprotective agent.  As recapitulated by others, systems biology is complementary to and does not entirely replace the hypothesis-driven focus of reductionist investigations.  The simultaneous consideration of parallel interactions has been fueled by the availability of data and the use of advanced computational techniques.
The nature of current stroke research and practice is largely reductionist, offering a logical sequence of hypothesis-driven investigations or medical decisions. This reductionist approach is characterized by the focus on specific targets or dominant factors, maintenance of homeostasis, risk factor modification, and additive treatment strategies. For example, ischemic stroke therapies have only indirectly addressed the key pathophysiology, or ischemia, by targeting clots in the setting of acute ischemic stroke. Clearly, some individuals may suffer the equivalent embolic occlusion of a vessel, yet collateral status is sufficient to completely offset ischemia.  Ischemia can be ameliorated by alternative means, such as improving collateral perfusion, yet thrombolysis and mechanical clot extraction via thrombectomy are prioritized rather than altering collateral perfusion. In fact, many clinicians have questioned the need to measure perfusion despite the fact that baseline and subsequent changes to hypoperfusion or ischemic severity are the principal determinants of outcomes. Homeostasis, or stable regulation of specific variables, has dogged numerous therapeutic strategies in stroke. Hyperglycemia in acute stroke has been repeatedly linked with worse outcomes, yet correction of serum glucose may not demonstrate the expected benefit in outcomes. Similarly, elevated blood pressure in acute ischemic or hemorrhagic stroke has been a major focus, yet normalization of blood pressure has yet to demonstrate an equivalent improvement in outcomes. From a systems biology perspective, the explanation lies in the distinction of homeodynamics from homeostasis.  Homeodynamics reflects the constantly changing, and often complex interactions between physiologic processes that maintain equilibrium. The value of a specific variable such as serum glucose or blood pressure may not reflect the underlying complexity of the system. In the chronic phase of cerebrovascular disorders, therapeutic and preventive strategies often focus on such parameters that seemingly mitigate risk. We target specific blood pressure values, serum lipid levels, or glycosylated hemoglobin measures to reduce risk without considering the dynamic interplay or homeodynamics that stabilize these values. Finally, we address these isolated factors in additive fashion, by individually approaching separate risk factors and not considering interactions or overlap between systems. For example, regular physical exercise may simultaneously alter blood pressure and biochemical parameters that serve as targets for stroke risk reduction. These reductionist practices in stroke research studies or in routine clinical practice have also influenced our overall understanding of cerebrovascular disorders. Multidimensional data analyses are more likely to accurately model cerebrovascular disorders rather than assuming that the effects of multiple interventions are additive rather than nonlinear. In some cases, opposing effects may even obliterate the expected results.
Systems biology is a relatively new area, with only marginal consideration in the field of stroke. In the last decade or so, increasing use of advanced imaging, laboratory assays, and the routine collection of common data elements in stroke provide a cogent basis to apply such concepts to investigations in this area. The role of collateral circulation in the brain is perhaps the most telling example of how such an approach may be appreciated. Collaterals remove the focus in acute stroke from the clot, to consider alternative blood flow pathways and the complex dynamics of the arterial and venous circulation. In brief, consideration of collaterals and the evolutionary development of this endogenous protective response force our consideration of numerous potential mechanisms beyond the simplest means of reversing ischemia (i.e., clot removal). This search to understand the more complex pathophysiology of collaterals and recognition that there are numerous biological interactions and dynamics beyond our current measurement schemes or biomarkers serve as a model for the implementation of systems biology. This rationale supports the terminology of the collaterome rather than other potential "-omic" iterations that have flourished in the last several years. Selecting or focusing on an individual aspect of systems biology may seem counterintuitive or reductionist at first glance, yet other -omic perspectives such as the genome, proteome, or the connectome are even more selectively focused on a particular facet of these disorders. 
The manifestations of systems biology and the collaterome in cerebrovascular disorders may be considered with respect to the context, and temporal and spatial features of many investigations or questions. An understanding of systems biology in cerebrovascular disorders must be comprehensive and include all potential elements. For instance, consideration of hemodynamics in the brain cannot focus solely on arterial delivery of blood without including other determinants of blood flow, such as downstream resistance due to tissue pressure or capillary and venous characteristics. Temporal resolution or the variability with respect to time must be included, as the brain response to a vascular event widely varies across individuals due to collaterals, and the pace of sequelae, such as infarct growth, may change over time, in nonlinear fashion. Finally, the spatial distribution or topography of functional changes and lesion evolution is almost never considered. Complex patterns of either ischemic or hemorrhagic lesion evolution in the brain remain poorly understood. For example, the pivotal determinants of hematoma growth or pace are largely unknown but likely have to do with the context of other systemic factors, the changing nature of other variables, and the spatial orientation in the brain. Arterial blood pressure, lesion location, spatial features including the nature of adjacent tissue, and even venous hemodynamics may be influential in addition to many other factors.
The systems biology of the collaterome provides a different perspective to almost every aspect of cerebrovascular disorders, from pathophysiology and our definitions of disease and pursuit of research questions at translational phases, to diagnostic techniques such as imaging and the role of specific therapeutic interventions. The remainder of this article elaborates on such manifestations and potential implications for future understanding and management of cerebrovascular disorders. The collaterome or systems biology approach complements the careful, reductionist, hypothesis-driven methods that have become so familiar, while modernizing and potentially simplifying the consideration of big data in stroke. Reductionist strategies best address biomedical derangements that are dominated by one factor, unlike the heterogeneity and complexity of potentially chronic disorders such as stroke. This perspective may require the use of analytical methods that integrate such dynamics, including use of large datasets, advanced computational techniques, and methods that consider both temporal and spatial changes. Serial imaging may chronicle the wide degree of variability in collateral status among individuals. Multiple parameters may be simultaneously probed, such as the voxel-based changes on magnetic resonance imaging (MRI) or the hemodynamic variables at a specific point in the vasculature with computation fluid dynamics. The consideration of numerous parameters at once may be difficult at first, as we have become accustomed to searching for one dominant factor, such as the apparent diffusion coefficient value or Tmax perfusion value. At a higher level, this approach endorses the personalization or individualization of approaches, in line with precision medicine. , Complex datasets may indicate divergent responses to the same therapeutic intervention in individuals with the same disorder. Context, timing, and spatial features will likely be important. Predicting the biological response of an individual, as in the case of collateral status, may be determined more reliably from individual data rather than from a population-based approach. Even endpoints may require revision, as describing the entire outcome of an individual based on a singular variable such as angiographic reperfusion grade or a dichotomized modified Rankin scale score of disability may fail to differentiate important dimensions. The informatics, previously unavailable in cerebrovascular disorders, requires and enables a transformation that may now apply systems biology in a logical framework.
| Pathophysiology|| |
The consideration of collaterals in stroke has recently changed and broadened our perspective on stroke and vascular pathophysiology in the brain. Although the protective and potentially beneficial nature of collateral circulation was recognized for centuries, the reductionist nature of stroke research over the last several decades placed overwhelming attention on isolated aspects of pathophysiology. In acute ischemic stroke, a litany of failed clinical trials investigated the isolated role of specific neuroprotective agents without consideration of other concomitant pathophysiology in the brain. Neuroprotective agents have also not been considered with regard to their potential impact on vascular elements, such as endothelia. Even with respect to revascularization, a one-size-fits-all approach has grappled with the marked variability in response of an isolated middle cerebral artery occlusion to recanalization when the timing or spatial distribution of ischemic injury and subsequent reperfusion are not considered. For intracranial atherosclerotic disease, simplistic measures such as the degree of arterial luminal stenosis or narrowing have yielded limited insight on the pathophysiology or rational treatment of this disorder, whereas the role of perfusion, emboli, and ischemic tolerance in downstream tissue offer many other system aspects to consider. Oddly, we have adapted a very pragmatic approach with respect to the underlying pathophysiology, assuming that ischemic symptoms become manifest and clearly demarcate the exact time of stroke onset or that "fixing" the obvious lesion such as a stenosis or occlusion should promptly reverse the entire problem. In general, we have prioritized the elusive goals of delivering curative treatments before better understanding the underlying disorders.
Context of disease has been poorly addressed in cerebrovascular disorders. Pathophysiology in the clinical realm is empirically defined by findings on laboratory or imaging studies when individuals come to attention due to neurological complaints or symptoms. In those scenarios, we often attribute biological significance to the most obvious findings without considering an array of slightly more subtle and complex interactions. For years, isolated gene mutations have been blamed without considering genome-wide patterns and the more recent consideration of the exome.  Our ability to detect abnormalities has shaped our definition of pathophysiology. Even when such capabilities exist, as with routine neuroimaging techniques, the context of disease sways our understanding. For instance, MRI is readily obtained in symptomatic individuals, yet similar pathophysiology would be ignored in the chronic "asymptomatic" phase. Biological events during such phases would be artificially deemed physiology, in clear distinction with pathophysiology. As we have learned from the dynamic nature of collateral circulation and resultant perfusion, these biological events may be affected by numerous factors and vary widely in spatial and temporal features. In order to best understand such disorders, imaging surveillance or other measures are necessary to avoid selection biases, as we image only those individuals that we deem "patients" due to the failure or relative compromise of collaterals.
Local spatial or structural features are also assumed to be most influential, in contrast to adjacent or peripheral events. For instance, in acute ischemic stroke the location and structure of a clot causing an occlusion of an artery in the brain has been implicitly deemed as more important than the corresponding remote and often redundant collateral anastomoses that deliver blood flow to offset such arterial blockage. In analogous fashion, seemingly remote structural elements from an artery, at the capillary interface, blood-brain barrier (BBB), adjacent tissue, and local venous outflow routes are often ignored. Emphasis is placed on the delivery of oxygenated arterial blood to the brain without much consideration for the downstream resistance and compensatory mechanisms that balance blood flow in a particular vascular distribution. For venous disorders, the exquisite redundancy and capacitance of neighboring veins permits remarkable compensation for obstructive disorders such as cerebral venous thrombosis. This extensive capacity to balance or offset venous blood flow abnormalities keeps many patients from becoming symptomatic or focusing the attention of clinicians until quite severe. It is this for this reason that isolated cortical vein thromboses of single draining veins are not prioritized as a diagnostic or therapeutic challenge, despite the fact that entities such as thrombosis of the vein of Labbé can have devastating consequences if untreated. Alternatively, when an arteriovenous malformation is identified, the complex architectural or structural features fascinate us, yet we are perplexed by the actual hemodynamic or functional effects of these lesions.
The functional regulatory elements of the collaterome are only poorly understood. Via extrapolation from other circulatory beds, we now recognize that FSS is a key variable in the balance between atherosclerosis (low FSS) and arteriogenesis (high FSS) in the cerebral circulation. Rather than describing this FSS homeostasis as stable under normal conditions, it is more likely that there is continual balance between these forces or homeodynamics at every point in the circulatory bed. For instance, low FSS may cause focal atherosclerotic plaque development, yet this deformation of the lumen causes the jet of blood flow to exert high FSS on an adjacent vessel wall, leading to vascular remodeling and aneurysmal outgrowth. A cycle of events may ensue where there is constant balancing of these opposing vascular forces. The resultant vascular structure or anatomy may reflect a pseudostable balance of such homeodynamics. Overall regulatory control of the cerebral circulation is typically ascribed to autoregulation at the arteriolar level, yet we are learning that such regulation may actually be maintained at the microvascular level by pericytes and complex interactions of the neurovascular unit with adjacent cellular elements.  We may infer from these examples that a vibrant interplay at many levels of the cerebral circulation continually regulates blood flow with tissue demands in the brain, rather than the existence of a carefully poised or static balance of various forces.
| Concept of 'Cerebrovascular Disease'|| |
The ongoing homeodynamics of the collaterome or systems interactions of neurovascular elements in the brain suggest that our current definitions of cerebrovascular disease are solely a relative state of imbalance in these continual physiologic events. In routine clinical practice, we most commonly define disease based on the presence of symptoms, yet imaging of the brain has revealed alternative definitions. For instance, individuals that remain asymptomatic are deemed healthy despite the fact that MRI may reveal established microvascular infarcts that we term "silent strokes." Another example of this paradox is the scenario of asymptomatic carotid atherosclerosis. Clearly, carotid occlusion due to atherosclerotic plaque progression is a manifestation of disease, yet individuals with such lesions would be defined as normal until neuroimaging is acquired. In many of these cases, it is solely the extent of collateral circulation or the capacity of the collaterome that distinguishes health from disease, utilizing these definitions. Defining or proving a healthy state or normalcy is likely more difficult than differentiating asymptomatic versus symptomatic states. Symptomatic status, however, often depends on the judgment of a clinician or even on the tolerance of an individual to specific neurological manifestations.
The systems biology criteria of context, timing, and spatial dimension also have relevance in our definitions and measurement of disease. Population estimates or the epidemiology of cerebrovascular disease are undoubtedly influenced by our biases. Most commonly, we refrain from the screening or surveillance of entire populations due to the potential cost of imaging studies, deferring to clinical definitions of disease based on symptomatic histories. We utilize selection criteria for therapeutic studies in cerebrovascular disorders and paradoxically place little attention on screening or the nature of which individuals were excluded from study. Most recent trials in cerebrovascular disorders have limited data on screening logs.  This contextual limitation is compounded by the changing nature of symptoms over time from acute to chronic and back again. Collaterals and other compensatory factors influence these dynamic manifestations, dictating when an individual may become diseased or return to normal. The most extreme examples of collateral sustenance and fluctuations in stroke have mesmerized clinicians, observing the rapid resolution of potentially devastating neurological disabilities or the Lazarus effect of hemodynamics in acute stroke.  Once again, it is the imaging of the underlying biology that helps us distinguish disease severity, therapeutic windows, and the relatively arbitrary definitions of stroke from transient ischemic attacks. Imaging and other biomarkers may clearly help us better understand the temporal evolution of cerebrovascular disorders.
| Imaging|| |
The imaging of collaterals has disclosed this more extensive model or view of cerebrovascular disorders by demonstrating endogenous and often more elaborate mechanisms that have evolved to balance vascular lesions in the brain. The routine use of imaging with computerized tomography (CT) or MRI in stroke to detail the nature of lesions in the brain has provided an avenue to probe multiple other facets of vascular pathophysiology. Multimodal CT and MRI, including noninvasive angiography, perfusion imaging, and other depictions of brain parenchyma have been integrated into the regular management of individuals with cerebrovascular disorders. Serial imaging of such individuals into the chronic phase has elucidated the temporal evolution of various pathophysiology and disease mechanisms. As a result, subtle correlates on imaging, both local and remote, to the vascular lesion have been uncovered. The relative ease of multimodal CT and MRI have thereby enabled the study of increasingly larger populations and over wider time epochs.
Unlike the hypothesis-driven requirements of an imaging trial in stroke, large-scale surveillance of patients in clinical practice with routine CT or MRI has enabled discovery of other pathophysiology or mechanisms that may be important from a systems biology perspective. As an example, the BBB leakage of contrast at the vascular borderzones or collateral anastomoses apparent on fluid-attenuated inversion recovery (FLAIR) in acute ischemic stroke provides insight on collateral status and potential arteriogenesis.  The increased fluid shear stress (FSS) at these collateral anastomoses may cause vascular remodeling and enhanced permeability of the BBB. Imaging of the collaterome or such fortuitous investigations of systems biology in stroke enable such discovery that may complement and inform subsequent hypothesis-driven and more reductionist studies that focus on this imaging finding. Other types of routine imaging in cerebrovascular disorders may also yield previously unknown data due to the application of advanced postprocessing techniques. For example, conventional angiography is often used to depict luminal changes in the arterial circulation of the brain, yet postprocessing of the time series data may yield key information on the resultant perfusion in the downstream territory. PerfAngio postprocessing may thereby enhance the value of routinely acquired imaging.  Similarly, the mapping of specific perfusion territories in the brain may be made possible on CT or MRI techniques that capitalize on the labeling of the proximal arterial inflow circuit. Even at the local level of an arterial lesion such as a stenosis or occlusion, computational fluid dynamics may illustrate the multiple dimensions of blood flow changes in adjacent vascular segments due to the local geometry or structure of the vessel.  Although many of these techniques are not necessarily focused on the imaging of collaterals per se, they incorporate collateral perfusion and utilize the holistic approach of the collaterome to consider other potential pathophysiology beyond the obvious arterial lesion. The resultant mechanisms disclosed may offer novel therapeutic opportunities, as well.
| Therapeutic Considerations|| |
Implementing a more comprehensive approach of the collaterome that reflects such perspective on the context, timing and spatial features of cerebrovascular disorders may expand our treatment of stroke. As described above, imaging surveillance becomes pivotal in delineating the presence of disease and relative changes over time. Stroke prevention could truly be implemented at the earliest stages possible rather than the current paradigm where clinicians rely on the development of symptoms to alter treatment. This commonly adopted strategy is effectively reactive rather than preventive. Imaging may establish the extent of neurovascular lesions and associated downstream changes in brain parenchyma. Perhaps most importantly, serial imaging in conjunction with paired neurological evaluation may discern subtle changes suggestive of disease evolution or, alternatively, stability. The chronic imaging of such lesions may actually dissuade clinicians from overzealously attempting to treat every vascular lesion, as minimal changes over time may assure relative stability. The imaging of intracranial atherosclerotic disease in Asia serves as a great example where "severe" or highly stenotic arterial lesions are noted to have exuberant associated collaterals with relatively minimal lesion growth and robust flow compensation. , Even after procedural interventions, monitoring lesions such as restenosis in context of clinical findings may be important. In sum, imaging of the brain and vasculature provides a survey that may guide further risk factor identification or disclose a set of aspects to consider in the stroke prevention of an individual patient. Precision stroke medicine may address the unique pattern of risk factors identified in a specific individual.
An individualized approach is also increasingly used in acute stroke, where the presence of proximal arterial occlusion is only the initial step before the more influential determination of the collateral profile of a given person. Once again, this may not require elaborate or detailed characterization of specific collateral arterial routes, as the profile may be variable defined or inferred based on the pattern of collateral perfusion to the territory. The Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study trialists concretized the relative profiles of a favorable or target mismatch and the unfavorable or malignant profile. ,, These relative patterns have been variably defined with multimodal CT and MRI in the most recent endovascular trials in acute ischemic stroke, demonstrating that the overall balance of collateral status or state of the collaterome is the essential element that ensured the success of these trials. ,,
Understanding the influential role of the collaterome has advanced revascularization in acute ischemic stroke or even in intracranial atherosclerotic disease. In future strategies, collateral status may not solely guide the decision to intervene or not, as such information may also inform how aggressive to be with specific treatments or, alternatively, to simultaneously implement concomitant collateral therapeutic strategies. A systems biology approach would advocate the use of multiple treatments rather than solely focusing on select therapeutic options. There is a glaring need to address therapeutic opportunities and hemodynamic management of many stroke patients beyond the acute phase in the intensive care unit and later timepoints. Complementary neuroprotective approaches may also be entertained, yet the limiting factor has been the research model traditionally used to establish our evidence-based treatments. Trialing one treatment at a time, from preclinical studies to randomized controlled trials (RCTs), will not advance such combined approaches, as the focus remains on a singular intervention while attempting to control for everything else. Paradoxically, these RCTs have not controlled for a wide range of factors or variables. In fact it is more likely this false assumption of control and failure to consider the systems biology that has flawed many prior studies. For these reasons, novel research paradigms are necessary to effectively address the complexity of acute on chronic disorders such as cerebrovascular disease.
Future research paradigms
The vast majority of translational research efforts in stroke have been devoted to the development of novel treatments based on careful selection of optimal subjects and an intensive focus on the response to one particular therapeutic intervention at a time, while attempting to control for all potential confounders. This idealized model of clinical investigations cannot envelop the extensive array of variables that may influence potential outcomes, given the complex nature of stroke pathophysiology. Investigators with this reductionist approach, however, leveraged the dominant role of revascularization in both acute and chronic cerebrovascular disorders. Intravenous thrombolysis and, more recently, endovascular therapy offer treatment options that alter the natural history of ischemic injury. The recent breakthrough in revascularization success with endovascular therapy for acute ischemic stroke capped many years of failed clinical trials, defining an important juncture to reconsider our research strategies. ,, Following the success of intravenous thrombolysis, these endovascular trials further extended the time window for revascularization in acute ischemic stroke, within which a reasonable clinical outcome may be achieved. Nevertheless, treatment within any of these early few hours after stroke onset or the relative pace of intervention does not guarantee a particular outcome in a given patient. Delineating the extent of collateral perfusion and potential for benefit following therapeutic intervention may be quickly surveyed with routine multimodal CT or MRI, irrespective of time from onset of symptoms. This imaging selection approach was not possible until recent advancements in endovascular therapy techniques yielded higher rates of revascularization. Such technology may be used to answer many elusive research questions beyond a simple go or no-go decision for revascularization. Similarly, the imaging or clinical outcomes of revascularization may be described as a continuum and not as a dichotomous measure of success.
A remarkable growth in data will likely ensue from the large-scale implementation of revascularization options for acute stroke in the community and the rapid dissemination of clinical and imaging expertise. Big data in stroke offer the capacity to explore the systems biology of the collaterome, identifying critical interactions at the structural and functional level and, importantly, enabling subsequent hypothesis-driven investigations. Without such data as in the past, the generation of hypotheses and validation methods were unavailable. Routine collection of data is therefore critical for such efforts, arguing for the systematic archival of the most practical clinical, laboratory, and imaging data already available in our clinics and hospitals. Serial or repeated evaluations over time in an individual patient will allow the proper contextual and temporal dimensions to be explored, whereas imaging in particular will allow us to probe the spatial relationships of the collaterome in the brain. These approaches are already underway with respect to the genomics of cerebrovascular disorders and will likely soon implement the imaging dimensions. Digital archival for most types of data, including source images from multimodal CT or MRI, permits future investigators to build upon prior investigations rather than starting from scratch. The increasing collaborations from around the world also facilitate the dissemination of scientific techniques, knowledge, and a broader understanding of cerebrovascular disorders in various contexts.
| Conclusions|| |
Recent scientific and technological advances that leverage big data offer the potential to explore numerous dimensions of acute and cerebrovascular disorders. The -mics or systems biology of cerebrovascular disorders provides a novel framework to investigate and refine our field, based on insight from the collaterome.
Financial support and sponsorship
NIH-National Institute of Neurological Disorders and Stroke awards (NIH/NINDS) K24NS072272, R13NS089280.
Conflicts of interest
Scientific consultant regarding trial design and conduct to Stryker (modest) and Covidien (modest).
| References|| |
Liebeskind DS. Imaging the collaterome: A stroke renaissance. Curr Opin Neurol 2015;28:1-3.
Ahn AC, Tewari M, Poon CS, Phillips RS. The limits of reductionism in medicine: Could systems biology offer an alternative? PLoS Med 2006;3:e208.
Liebeskind DS. Neuroprotection from the collateral perspective. IDrugs 2005;8:222-8.
Liebeskind DS. Collateral circulation. Stroke 2003;34:2279-84.
Lloyd D, Aon MA, Cortassa S. Why homeodynamics, not homeostasis? ScientificWorldJournal 2001;1:133-45.
Ning M, Lo EH. Opportunities and challenges in omics. Transl Stroke Res 2010;1:233-7.
Feldmann E, Liebeskind DS. Developing precision stroke imaging. Front Neurol 2014;5:29.
Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793-5.
Cole JW, Stine OC, Liu X, Pratap A, Cheng Y, Tallon LJ, et al
. Rare variants in ischemic stroke: An exome pilot study. PLoS One 2012;7:e35591.
Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al
. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 2014;508:55-60.
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al
. MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.
Liebeskind DS, Kim D, Starkman S, Changizi K, Ohanian AG, Jahan R, et al
. Collateral failure? Late mechanical thrombectomy after failed intravenous thrombolysis. J Neuroimaging 2010;20: 78-82.
Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 2004;35(Suppl 1):2659-61.
Scalzo F, Nour M, Liebeskind DS. Data science of stroke imaging and enlightenment of the penumbra. Front Neurol 2015;6:8.
Leng X, Scalzo F, Ip HL, Johnson M, Fong AK, Fan FS, et al
. Computational fluid dynamics modeling of symptomatic intracranial atherosclerosis may predict risk of stroke recurrence. PLoS One 2014;9:e97531.
Zou WX, Leung TW, Yu SC, Wong EH, Leung SF, Soo YO, et al
. Angiographic features, collaterals, and infarct topography of symptomatic occlusive radiation vasculopathy: A case-referent study. Stroke 2013;44:401-6.
Lau AY, Wong EH, Wong A, Mok VC, Leung TW, Wong KS. Significance of good collateral compensation in symptomatic intracranial atherosclerosis. Cerebrovasc Dis 2012;33:517-24.
Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG, et al
. DEFUSE 2 study investigators. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): A prospective cohort study. Lancet Neurol 2012;11:860-7.
Mlynash M, Lansberg MG, De Silva DA, Lee J, Christensen S, Straka M, et al
. DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: Insights from the DEFUSE-EPITHET pooled data set. Stroke 2011;42:1270-5.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, et al
. DEFUSE Investigators. Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-17.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al
. EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-18.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al
. ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-30.
|This article has been cited by|
||Cerebral watershed infarcts may be induced by hemodynamic changes in blood flow
| ||Jingfei Shi,Ran Meng,Sanjay Konakondla,Yuchuan Ding,Yunxia Duan,Di Wu,Bincheng Wang,Yinghao Luo,Xunming Ji |
| ||Neurological Research. 2017; 39(6): 538 |
|[Pubmed] | [DOI]|
||Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing
| ||Fengwu Li,Xiaokun Geng,Hajra Khan,John T. Pendy Jr.,Changya Peng,Xiaorong Li,Jose A. Rafols,Yuchuan Ding |
| ||Frontiers in Cellular Neuroscience. 2017; 11 |
|[Pubmed] | [DOI]|
||Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke
| ||Xiaokun Geng,Fengwu Li,James Yip,Changya Peng,Omar Elmadhoun,Jiamei Shen,Xunming Ji,Yuchuan Ding |
| ||Molecular Neurobiology. 2016; |
|[Pubmed] | [DOI]|