Acute Brain Impairment

Scientific Discoveries and Translational Research

Philip V Peplow, Svetlana A Dambinova, Thomas A Gennarelli, Bridget Martinez

• Publisher: Royal Society of Chemistry
• Year: 2017
• eBook ISBN: 9781788013376
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Biochemistry

A rise in the number of young and old patients suffering from a stroke or traumatic brain injury has led to the need for better drug development and treatment, as well as diagnosis and prevention of ischemic stroke and traumatic brain injury. This book provides a comprehensive overview of scientific advancements in these areas.

Chapters provide the latest knowledge in neuroscience, biotechnology, and personalized medicine applicable to acute brain injuries. Development of neuroprotective drugs is treated in detail. Chemical biomarkers for detection, imaging and preventative strategies are covered to provide medicinal chemists with a broad view of translational aspects of the field.

This book will be useful to postgraduate students and researchers in medicinal chemistry and pharmacology as well as specialists in the acute brain injury field.

CHAPTER 1

Transient Ischemic Attack, Traumatic Brain Injury, and Ischemic Stroke: Risk Factors and Treatments

PHILIP V. PEPLOW^* AND JACQUELINE J. T. LIAW

Department of Anatomy, University of Otago, Dunedin, New Zealand

^*Email: [email protected]

1.1 Introduction

The overall burden of stroke in the number of people affected is increasing, especially in the younger age groups and in lower-to-middle-income countries.^1–3 Despite some improvements in stroke prevention and management in high-income countries, the growth and aging of the global population is leading to a rise in the number of young and old patients with stroke. Closely related to this is the increasing number of people, including young children, who are overweight or obese.⁴ Obesity is a risk factor for stroke on account of it leading to atherosclerosis, which promotes thrombosis and obstruction to the flow of blood.⁵ Moreover, there is an increasing prevalence of hypertension, which also leads to atherosclerosis, and this in turn can lead to blockage of small blood vessels in the brain, causing stroke.^6–8

In people experiencing a transient ischemic attack (TIA), the incidence of subsequent stroke is as high as 11% over the next 7 days and 24–29% over the following 5 years.⁹ Unlike a stroke, the symptoms of a TIA can resolve within a few minutes or within 24 hours. However, brain injury may still occur in a TIA lasting only a few minutes.¹⁰ A strong association has been shown between traumatic brain injury (TBI) and later development of ischemic stroke, which remained significant even after several potential confounders, such as vascular risk factors and comorbidities, were taken into consideration. The association was similar in magnitude to that of hypertension, which is the leading stroke risk factor.^8,11

1.2 Definition of TIA, TBI, and Stroke

Early definitions of stroke and TIA focused on the duration of symptoms and signs. More recently, using clinical observation and modern brain imaging, it has been shown that the duration and reversibility of brain ischemia are variable. While brain tissue deprived of needed nutrients undergoes irreversible damage (infarction) in most individuals, in some patients it can survive for a considerable period of time, which may be several hours or even, rarely, days. In 2009, an expert committee of the American Heart Association/American Stroke Association (AHA/ASA) published a scientific statement defining TIA as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction.¹² The word ‘transient’ indicates a lack of permanence. However, modern brain imaging has shown that many patients in whom symptoms and signs of brain ischemia are clinically transient have evidence of brain infarction. Similarly, ischemia may produce symptoms and signs that are prolonged (and would qualify as strokes in older definitions) and yet no permanent brain infarction has occurred. In 2013, the AHA/ASA published a scientific statement defining ischemic stroke as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. Stroke caused by intracerebral hemorrhage was defined as rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma. Likewise, stroke caused by subarachnoid hemorrhage was defined as rapidly developing clinical signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space between the arachnoid membrane and the pia mater of the brain or spinal cord, which is not caused by trauma.¹³ TBI has been defined as a non-degenerative, non-congenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness.¹⁴ It usually results from a violent blow or jolt to the head or body. The resulting brain damage can be focal or diffuse. A focal TBI is usually caused by sudden contact; diffuse injury is more likely to be caused by an acceleration/deceleration trauma. The severity of TBI is determined by the nature, speed, and location of the impact, and by complications such as hypotension, intracranial hemorrhage, or increased intracranial pressure. These complications may cause secondary injury hours or even days after the trauma.¹⁵

1.3 Incidence of TIA, TBI, and Stroke

Precise estimates of the incidence and prevalence of TIAs are difficult to determine because of varying criteria used in epidemiological studies to identify TIA. Failure of recognition by both the public and health professionals of the transitory focal neurological symptoms associated with TIAs may also lead to significant underestimates. Given these limitations, the incidence of TIA in the United States has been estimated to be 200 000–500 000 per year, with a population prevalence of 2.3%, which equated to 5 million individuals in 1999.^12,16 TIA incidence markedly increases with age and varies by race–ethnicity. The prevalence rate varies depending on the age distribution of the study population. The Cardiovascular Health Study estimated a prevalence of TIA in men of 2.7% for 65–69 years of age and 3.6% for 75–79 years of age. For women, TIA prevalence was 1.6% for 65–69 years of age and 4.1% for 75–79 years of age.¹⁷ In the Atherosclerosis Risk in Communities Study, the overall prevalence of TIAs among adults 45–64 years of age was 0.4%.¹⁸ Among patients who present with stroke, the prevalence of prior TIA may range from 7% to 40% depending on how TIA is defined, which stroke subtypes are evaluated, and whether the study is a population-based series or a hospital-based series. Variability in the use of brain imaging and the type of diagnostic imaging used can also affect estimates of the incidence and prevalence of TIAs. For example, a revision of the TIA definition to include the absence of changes on magnetic resonance imaging could lead to a decrease in the incidence of TIAs by 33% and a resultant 7% increase in the number of cases labeled as stroke.¹⁹

Approximately 795 000 strokes occur each year in the United States.²⁰ In total, 10–20% of patients have a stroke within 90 days following a TIA, and in up to 50% of these patients the stroke occurs within 24–48 hours.²¹ In 2000, there were 167 661 deaths in the United States attributable to stroke, which was nearly 24% of stroke patients.²² The AHA/ASA reported that among non-Hispanic blacks, the relative risk of stroke is four-times higher than among whites at 35–54 years of age and three-times higher at 55–64 years of age. Among Hispanics and American Indians/Alaska natives, the relative risk is about 1.3-times higher than in whites at 35–64 and 45–54 years of age, respectively.^22,23 Ischemic stroke accounts for 87% of all strokes and can be divided into two main types: thrombotic and embolic. Thrombotic disease accounts for about 60% of acute ischemic strokes.²⁴ It is estimated that 14–30% of ischemic strokes are cardioembolic in origin.^25,26 The incidence of cardioembolic strokes increases with age.²⁵

TBI is the greatest cause of mortality and disability in young adults in modern Western societies. In the United States, 1.6 million people sustain a TBI each year, approximately 50 000 people die from a TBI, and 125 000 people are disabled 1 year after injury. However, the exact facts and figures on the incidence, prevalence, and long-term consequences of TBI are uncertain, and it is likely the incidence figures have to be multiplied by 5 or even 10 in order to include every unregistered patient.¹⁵ TBI is strongly associated with several neurological disorders 6 months or more after injury.²⁷ Seizures are associated with most types of TBI. About 25% of patients with brain contusions or hematomas and about 50% of patients with penetrating head injuries will develop seizures within the first 24 hours of the injury.¹⁵

1.4 Risk Factors for TIA and Stroke

1.4.1 Age

The most important of the non-modifiable risk factors associated with stroke is age. Stroke is most prevalent among the elderly and the majority of strokes occur in those aged >65 years.²⁶ Age-related risk also increases for TIA, except for those in the oldest category (≥85 years), where it may decrease slightly.²⁸

1.4.2 Gender

Men are at greater risk of stroke, with the incidence rate being 1.25-times higher than in women.²⁹ Some differences between the genders have also been noted for stroke subtype. Men have about a fourfold greater age-adjusted incidence rate of ischemic stroke due to large vessel atherosclerosis than women, which may account for their higher rate of undergoing carotid endarterectomy.³⁰

1.4.3 Race...

Table of contents

• Cover
• Title
• Copyright
• Preface
• Dedication
• Contents
• Chapter 1 Transient Ischemic Attack, Traumatic Brain Injury, and Ischemic Stroke: Risk Factors and Treatments
• Chapter 2 Inflammatory Changes in Cerebral Ischemic Injury: Cellular and Molecular Involvement
• Chapter 3 Biomarkers of Acute Brain Injury and Surrogate Endpoints in Traumatic Brain Injury and Stroke Translational Studies
• Chapter 4 Difficulties of Translating Outcomes from Animal Studies to Clinical Trials
• Chapter 5 Neuroprotective Therapies for Ischemic Stroke
• Chapter 6 The Molecular Neuroprotective Strategies in Cerebral Ischemia: An Insight into Emerging Treatments for Oxidative Stress
• Chapter 7 Identification of MicroRNAs as Targets for Treatment of Ischemic Stroke
• Chapter 8 Combined Drug–Diagnostic Test Co-development for Predicting and Preventing Brain Impairments
• Chapter 9 Advances in Diagnostics and Treatment of Neurotoxicity after Sports-related Injuries
• Chapter 10 Functional Predictors for Prognosis and Recovery after Mild Traumatic Brain Injury
• Chapter 11 Predictors for Prognosis and Recovery from Unconsciousness Due to Brain Trauma
• Chapter 12 Neurotoxicity in Spinal Cord Impairments
• Chapter 13 Advanced Approaches in Stem Cell Therapy for Stroke and Traumatic Brain Injury
• Chapter 14 Testing and Mechanisms of Neuroprotective Agents for Cerebral Ischemic Injury in Clinical Trials, 2010–2016
• Chapter 15 Difficulties in Clinical Trials to Treat Traumatic Brain Injury and Stroke
• Chapter 16 Challenges in Using Biomarkers in Central Nervous System Applications
• Chapter 17 Resolving Difficult Case Scenarios by Incorporating Stroke Biomarkers in Clinical Decision-making
• Chapter 18 Development of Novel Test Platforms for the Assessment of Brain Injury
• Chapter 19 Advancements and Challenges in Hyperacute Stroke Translational Research
• Subject Index