Current Developments in Stroke

Stroke, the third most-common cause of mortality after cancer and heart disease in developed countries, is one of the most common causes of cognitive impairment and vascular dementia. Stroke pathogenesis and its consequences are not completely elucidated, with various factors and biological mechanisms probably having a role. After age, hypertension is the leading modifiable cardiovascular risk factor for ischaemic/haemorrhagic stroke, small vessel disease predisposing to lacunar infarction, cerebral white matter lesions (cWML), and cerebral microbleeds. Primary stroke prevention, involving hypertension therapy and blood pressure (BP) control is now standard. At the same time, elevated post-stroke BP levels increase the risk of recurrent stroke, with recent trials suggesting that BP reduction with combinations of hypertension therapy reduces stroke recurrence. This chapter reviews the evidence on hypertension as a stroke risk factor and the part played by hypertension therapy in first/recurrent stroke prevention.

Cerebrovascular disease is predicted to remain the second leading cause of mortality reaching almost eight million annual deaths by 2030. Cerebral arteries are innervated and are therefore potential targets for autonomic nervous system dysfunction. In particular, a dynamic baroreflex mediated sympathetic modulation of cerebral blood flow has been demonstrated, confirming the role that the autonomic nervous system exerts on cerebral flow regulation. Moreover, it has been shown that the vagus nerve may influence neuro-inflammation therefore producing an inflammatory mediated vascular damage in case of dysfunction. Dynamic interactions between cerebral blood flow and the autonomic nervous system activity are therefore important and can be analyzed by studying the rhythms that characterize both cerebral blood flow, blood pressure and heart rate. With this regard, variability analysis performed together with techniques that investigate cerebral blood flow distribution and together with functional evaluation of the brain could provide new insight on the role played by the autonomic nervous system in the progression of cerebral vascular disease.

Local and systemic inflammatory responses have been shown to play an important role in post-stroke damage. Recent studies suggest that the innate immune cells contribute to stroke-induced brain injury by activating an inflammatory response that further increases local ischemic damage. Innate immune signaling, via Toll-like receptors (TLRs), has been shown to be involved in several neuropathological processes. This chapter summarizes the current knowledge concerning the involvement of TLRs in acute ischemic brain injury. In particular, the therapeutic role of TLR2 and TLR4 antagonists will be discussed. Moreover, since TLR3 stimulation could play a beneficial role through the production of anti-inflammatory molecules, including I type interferons (IFNs), the potential benefits of TLR3 agonist administration to counteract stroke-related inflammation will be also focused.

Vitamin K antagonists such as warfarin and acenocumarol are the most widely used oral anticoagulants. Their clinical indications include both stroke prevention and prophylaxis and treatment of venous thromboembolism. Intracerebral hemorrhage (ICH) is the most important side effect of anticoagulant therapy accounting for almost 20% of all ICH. Non vitamin K anticoagulants or direct oral anticoagulants (DOACs) have been recently introduced in clinical practice due to their practical advantages over VKA. They are at least as effective as warfarin in the management of thromboembolic diseases and in the thromboprophylaxis of non-valvular atrial fibrillation, moreover, they have a more favorable safety profile. The present chapter will focus on vitamin K antagonists and DOACs mechanisms of action, on their pharmacokinetics and pharmacodynamics, and on the relative risk of bleeding during treatment.

Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. The assessment of collateral status in acute stroke patients may improve patient selection and maximize benefit-to-risk ratio of acute recanalization therapies. The systematic assessment of collaterals in experimental stroke models may be used as a “stratification factor” in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals during acute ischemic stroke may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in terms of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute (even pre-hospital) phase of ischemic stroke, prior to recanalization therapies.

The penumbra is an area of living brain tissue immediately surrounding the necrotic core of an ischemic or thrombolytic stroke. The penumbra may remain viable several hours post-stroke due to blood flow from collateral arteries. Thus, this area of peri-infarct tissue is a therapeutic target for post- stroke and neuroprotective treatment modalities. Due to the fact that the ratio of viable to non-viable tissue decreases with time, Factor Xa and Factor II inhibitors such as enoxaparin and thrombolytics such as recombinant tissue plasminogen activator (r-tPA) must be administered immediately for optimal, synergistic treatment outcomes. The Broderick Lab is the first to study penumbral brain neurochemistry after causal acute ischemic stroke (AIS) by middle cerebral artery occlusion (MCAO) in vivo, as well as to comprehend the effects of enoxaparin (Lovenox®) and reperfusion via in vivo biochip nanotheranostics actually imaging the penumbra and its surrounding tissue intravascularly. Indeed, using Neuromolecular Imaging (NMI) with BRODERICK PROBE® nanobiosensors, animals were studied as their own control and each side of the brain was imaged in vivo, online, and in real time. NMI is a technology that uniquely images the baseline state of subjects before a disease state occurs, thereby establishing an intra-subject control model. In the same subject, with no gliosis, both the infarcted and peri-infarcted regions were imaged before, during, and after enoxaparin administration. Such imaging is available only with NMI nanobiosensor technology. In fact, with this new NMI nanobiosensor technology, the specificity of comparing baselines during drug and disease states is high because of the ability of NMI to compare baselines in thousands of previous studies of prescient and non-prescient mammals in vivo. Concurrently, Dual Laser Doppler Flowmetry (DLDF) was used to monitor cerebral blood perfusion. The results of this study demonstrate that, using intra-subject studies online (a) NMI profiles for dorsal striatum in basal ganglia are baseline values, ipsilaterally and contralaterally. (b) Diminished cerebral blood perfusion from AIS produces a significant increase of DA and 5-HT neurotransmitter concentrations, as well as associated metabolites and precursors, in motor neurons. (c) Enoxaparin alleviates oxygen deficiency by enhancing blood perfusion and reduces DA-induced brain trauma, enabling brain repair and regeneration. (d) Enoxaparin increases 5-HT release from motor neurons within the ipsilateral, lesioned hemisphere, as well as in the contralateral, non-lesioned hemisphere, particularly during the reperfusion stage. This serotonergic effect demonstrates the potential use of enoxaparin as an antidepressant, which would be clinically relevant for treating the depression that oftentimes is comorbid with AIS. (e) The area of post-stroke infarcts is significantly reduced upon reperfusion; and (f) Cerebral blood perfusion is augmented in a compensatory manner by both enoxaparin therapy and reperfusion within both hemispheres, particularly the contralateral hemisphere. Thus, this research demonstrates the efficacy of enoxaparin in preserving the viability of the penumbra in stroke victims and supports consideration of the combined use of enoxaparin with r-TPA in standard stroke treatment protocols in order to harness the brain’s intrinsic repair system. Moreover, these studies demonstrate the power of NMI nanotechnology in conjunction with BRODERICK PROBE® theranostic nanobiosensors to reliably study the intricacies of stroke in order to develop further neuroprotective treatments and allow personalized medicine to be realized.

Normalization of magnetic resonance images with a given reference is a common preprocessing task which is rarely discussed. We review and address this question for a specific neuro-imaging problem of practical huge interest. We investigate the influence of the location of region of interest used for normalization of perfusion maps obtained with perfusion magnetic resonance imaging in the framework of the study of acute stroke. We demonstrate that a slice by slice normalization based on the whole hemisphere strategy optimally reduces the variability of the predictive value of the different perfusion maps. Interestingly, this is obtained for all the tested perfusion maps both from numerical simulation of perfusion MRI and from perfusion maps of real patients through a Neyman-Pearson detection strategy. These are important results to ease the quantitative assessment of stroke lesion from perfusion MRI on cohorts of patients. The proposed methodology could easily be transposed to other medical imaging problems where normalization of images is necessary.

The pathogenesis of ischemic stroke remains unknown but a better knowledge of its pathogenetic mechanism may help us in identifying more effective therapies to reduce the the disease burden. Family and twin studies support the role of genetic factors in stroke pathophysiology. A number of monogenic conditions presenting with stroke have been described. They account for only a small proportion of strokes, but it is believed they are underestimated and the study of these diseases may provide insight in the pathogenic pathways of stroke, given also the existence of animal models in which examine disease mechanisms. However, in most cases, stroke is believed to be a multifactorial disorder. A number of genetic association studies using the candidate gene approach have failed in demonstrating reliable associations between stroke and genetic variants. Although several molecular variants resulted from GWAS strongly associated with ischemic stroke risk, they account for only a small part of the risk of ischemic stroke. Moreover, the pathogenic significance of many of these genetic variants has yet to be determined by functional studies so that the significance of these findings in clinical practice has been limited. Interestingly, the studies conducted so far demonstrated that the majority of the identified genetic variants found were associated with specific stroke subtypes, supporting the hypothesis that distinct genetic architecture and pathophysiological mechanisms underlie specific stroke subtypes.

Cryptogenic ischemic stroke defines the situation where the cause of the thromboembolic event is not evident. Atrial fibrillation (AF) is a possible cause of cryptogenic stroke, even if asymptomatic. AF is the most common arrhythmia, and its incidence increases with age. AF is associated with an increased risk of ischemic stroke and systemic embolism, independent of the type of AF and also of the symptoms caused by the arrhythmia. The thromboembolic risk is associated to some clinical variables like age, hypertension, heart failure, diabetes, previous stroke, vascular diseases and gender. The mechanism of thrombosis in AF is complex, and comprises blood stasis in the left atrial appendage, but also atrial and endothelial damage, alteration of the extracellular matrix, and activation of humoral factors with prothrombotic significance.

AF is often asymptomatic or “silent”, as demonstrated in many clinical situations. Silent AF may be a frequent cause of otherwise unexplained stroke. The association between stroke and silent AF was demonstrated in many trials, especially in patients with an implanted device, like pacemakers, implantable cardiac defibrillators (ICD) and cardiac resynchronisation therapy (CRT) devices, where a reliable report of the arrhythmia is available. The best system to discover if a patient with cryptogenic stroke has AF is the continuous monitoring with an implantable loop recorder. However, the temporal relationship between AF and stroke is not often evident, so that the decision to prevent thromboembolisms in patients with silent AF should be based on the evaluation of risk with the appropriate score index. In the secondary prevention of stroke and transient ischemic attack (TIA), however, anticoagulation is generally indicated if a silent AF is demonstrated.

Following an ischemic insult, the early damage associated with the energy defect gives rise to molecular events, which may occur even during reperfusion to sustain a progression of the damage in the ensuing hours or days. Neuroprotection refers to interventions that are supposed to beneficially interfere with the maturation of the ischemic damage. The post-ischemic molecular events embrace a huge variety of mechanisms. Each mechanism is entangled with others, to configure a pathogenic process that has the characteristics of a near-chaotic phenomenon. To add to the complexity, the ischemic process includes both mechanisms that fuel the pathogenic process promoting cell death, and mechanisms reflecting the effort of the organism to oppose the process.

Interventions aimed to oppose the maturation process activate brain repair and epigenetic mechanisms to promote survival pathways. Examples of potential neuroprotective approaches are: pre- and post-conditioning, hypothermia, and a number of drugs. All the treatments, however, that were proven to be effective in animal models, failed in clinical trials. No unique explanation accounts for the gap between laboratory animal and clinical studies.

The major aim of acute stroke treatment is to save the hypoperfused cerebral parenchyma in order to minimize residual disability. Early recanalization of occluded arteries with thrombolytic therapy is the most efficient procedure for protecting the brain parenchyma which is not yet infarcted.

Intravenous administration of Alteplase (recombinant tissue-type plasminogen activator – rtPA) has proven to be effective in reducing disability at 90 and 180 days after stroke in patients treated within 4.5 hours from symptoms onset.

Recently, striking results have been provided by the endovascular treatment, unless in a selected population. The use of the stent-retrievers or direct thrombus aspiration is now a good option for acute stroke treatment giving the opportunity of an effective multimodal therapeutic approach.

Promoting tissue plasticity is a very important therapeutic approach to reduce post-stroke disability. The neurological damage occurring after stroke indeed is a consequence of disrupted brain connectivity circuits due to cellular degeneration and impairment of plasticity processes. Axonal degeneration is also invariably seen in remote brain structures that have neuroanatomical links to the ischemic area. Recovery from stroke is thus very much depending on the possibility to develop treatments able to halt the neurodegenerative process and to foster adaptive tissue plasticity. Due to the intricacy of the systems involved, therapies that foster endogenous repair processes in a spatially and time targeted manner are required. We here discuss the physiology of recovery processes occurring after stroke and the main strategies to foster compensatory neuronal networks aiming to reduce stroke-related disability.

Stroke is one of the main cause of chronic disability in industrialized countries and, in 2010, it was among the top eighteen diseases that most frequently lead to “years lived with disability”. All the quoted conditions decreased between 1990 and 2010, with the exception of the age-standardized rates for stroke. Caring addressed to post-stroke patients involves multiple challenges, due to stroke causes a wide range of impairments, among them motor skills deficits are the most common, even if should be enumerated other areas of impairment such as sensory, visual, swallowing, cognitive and language related. Rehabilitation provides the possibility of reducing the burden of disability and, nowadays, one of the most exciting areas of stroke research is the prospect to increase rehabilitation effectiveness, influence neurological recovery and, subsequently, impact clinical outcomes. In recent years, following the spreading of studies regarding neuroplasticity, innovative rehabilitative approaches have been based on reasonable and intriguing theoretical assumptions. The restorative methods represent significant tools for stroke rehabilitation; nevertheless, they become meaningless if not integrated within the context of a rigorously personalized care plan. A comprehensive rehabilitation plan should begin as soon as the stroke occurs. Management must be directed toward preventing functional deterioration, restoring lost abilities and functions, gaining compensatory strategies, suggesting environmental changes, increasing participation and consequently achieving the highest quality of life after the brain damage. The grade to which a rehabilitation program meets the challenge of improving dignity and independence of stroke survivors is assessable through the adoption of a systematic approach that relates the diseased-state and disability to outcomes of care. The following can be considered as stroke rehabilitation strongholds: (1) to provide a consistent rehabilitation plan throughout the acute, sub-acute, and chronic phases: stroke rehabilitation is a dynamic pathway starting following the symptoms onset and accompanying the patient in the care pathway until his going back to community; (2) to set goals based on the prediction of the single cases evolution (short, medium and long-term goals) and design an appropriate pathway: the first step for a well-conceived rehabilitation management is to establish appropriate setting addressed to the patient; (3) to provide a comprehensive, coordinated, interdisciplinary approach: since the strokes clinical manifestations are multidimensional, rehabilitation is best realized through the coordinated and well harmonized actions among the whole members of a specialized team; (4) to build up a tailored rehabilitative treatment.