Biopsychology, Global Edition, 11th Ed, Chapter 10 - Brain Damage and Neuroplasticity PDF

Chapter 10 Brain Damage and Neuroplasticity Can the Brain Recover from Damage? Michael Ventura/Alamy Stock Photo Chapter Overview and Learning Objectives Causes of Brain Damage LO 10.1 Describe different types of brain tumors and...

Chapter 10 Brain Damage and Neuroplasticity Can the Brain Recover from Damage? Michael Ventura/Alamy Stock Photo Chapter Overview and Learning Objectives Causes of Brain Damage LO 10.1 Describe different types of brain tumors and explain the difference between an encapsulated and an infiltrating brain tumor. LO 10.2 Describe differences between the two types of stroke: cerebral hemorrhage and cerebral ischemia. LO 10.3 Describe the two sorts of closed-head traumatic brain injuries (TBIs). LO 10.4 Describe two different types of infections of the brain. LO 10.5 Describe three different types of neurotoxins. LO 10.6 Discuss the symptoms of Down syndrome and what causes this disorder. LO 10.7 Explain the difference between apoptosis and necrosis. 258 M10_PINE1933_11_GE_C10.indd 258 22/01/2021 11:15  Brain Damage and Neuroplasticity 259 Neurological Diseases LO 10.8 Define epilepsy; describe four common types of seizures; and discuss some treatments for epilepsy. LO 10.9 Describe the symptoms of Parkinson’s disease and some ­treatments for this disorder. LO 10.10 Describe the symptoms of Huntington’s disease and explain its genetic basis. LO 10.11 Describe the symptoms of multiple sclerosis (MS) and its risk factors. LO 10.12 Describe the symptoms of Alzheimer’s disease and evaluate the amyloid hypothesis. Animal Models of Human LO 10.13 Describe the kindling model of epilepsy and explain the ways Neurological Diseases in which it models human epilepsy. LO 10.14 Describe the events that led to the discovery of the MPTP model of Parkinson’s disease, and evaluate the utility of this animal model. Responses to Nervous LO 10.15 Explain the various types of neural degeneration that ensue System Damage: following axotomy. Degeneration, LO 10.16 Compare neural regeneration within the CNS vs. the PNS. Regeneration, Reorganization, and LO 10.17 Describe three examples of cortical reorganization following Recovery damage to the brain, and discuss the mechanisms that might underlie such reorganization. LO 10.18 Describe the concept of “cognitive reserve,” and discuss the potential role of adult neurogenesis in recovery following CNS damage. Neuroplasticity and the LO 10.19 Discuss early work on neurotransplantation for the treatment Treatment of CNS Damage of CNS damage. LO 10.20 Discuss the methods and findings of modern research on neurotransplantation. LO 10.21 Discuss methods of promoting recovery from CNS damage through rehabilitative treatment. The study of human brain damage serves two purposes: It increases our understanding of the healthy brain, and it The Ironic Case of Professor P. serves as a basis for the development of new treatments. One night Professor P. sat at his desk staring at a drawing of the The first three modules of this chapter focus on brain dam- cranial nerves, much like the one in Appendix III of this book. As age itself, the fourth module focuses on the recovery and he mulled over the location and function of each cranial nerve reorganization of the brain after damage, and the fifth dis- (see Appendix IV), the painful truth became impossible for him cusses exciting new treatments that promote neuroplasticity. to deny. The irony of the situation was that Professor P. was a But first, the continuation of the ironic case of Professor P., neuroscientist, all too familiar with what he was experiencing. which you first encountered in Chapter 5, provides a per- His symptoms started subtly, with slight deficits in balance. sonal view of brain damage. Professor P. chalked up his occasional lurches to aging—after all, M10_PINE1933_11_GE_C10.indd 259 22/01/2021 11:15  260 Chapter 10 he thought to himself, he was past his prime. Similarly, his doctor didn’t seem to think that it was a problem, but Professor P. moni- Brain Tumors tored his symptoms nevertheless. Three years later, his balance LO 10.1 Describe different types of brain tumors and problems unabated, Professor P. started to worry. He was trying to explain the difference between an encapsulated talk on the phone but was having trouble hearing until he changed and an infiltrating brain tumor. the phone to his left ear. Professor P. was going deaf in his right ear. Professor P. made an appointment with his doctor, who A tumor, or neoplasm (literally, “new growth”), is a mass referred him to a specialist. After a cursory and poorly controlled of cells that grows independently of the rest of the body. hearing test, the specialist gave him good news. “You’re fine, About 20 percent of tumors found in the human brain Professor P.; lots of people experience a little hearing loss are meningiomas (see Figure 10.1)—tumors that grow when they reach middle age; don’t worry about it.” To this day, between the meninges, the three membranes that cover the Professor P. regrets that he did not insist on a second opinion. central nervous system. All meningiomas are encapsulated It was about a year later that Professor P. sat staring at the tumors—tumors that grow within their own membrane. illustration of the cranial nerves. By then, he had begun to experi- As a result, they are particularly easy to identify on a CT ence numbness on the right side of his mouth, he was having scan, they can influence the function of the brain only by problems swallowing, and his right tear ducts were not releasing the pressure they exert on surrounding tissue, and they are enough tears. He stared at the point where the auditory and almost always benign tumors—tumors that are surgically vestibular nerves come together to form cranial nerve VIII (the auditory-vestibular nerve). He knew it was there, and he knew removable with little risk of further growth in the body (see that it was large enough to be affecting cranial nerves V through Barresi, Caffo, & Tuccari, 2016). X as well. It was something slow-growing, perhaps a tumor? Was he going to die? Was his death going to be terrible and lingering? Journal Prompt 10.1 He didn’t see his doctor right away. A friend of his was Were you surprised that one of the authors of your text- conducting a brain MRI study, and Professor P. volunteered to book suffered significant brain damage? Why or why not? be a control subject, knowing that his problem would show up on the scan. It did: a large tumor sitting, as predicted, on the right cranial nerve VIII. Unfortunately, encapsulation is the exception rather Then, MRI in hand, Professor P. went back to his doctor, than the rule when it comes to brain tumors. Aside from who referred him to a neurologist, who in turn referred him to a meningiomas, most brain tumors are infiltrating. Infiltrating neurosurgeon. Several stressful weeks later, Professor P. found tumors are those that grow diffusely through surrounding himself on life support in the intensive care unit of his local hos- tissue. As a result, they are usually malignant tumors; that pital, tubes emanating seemingly from every part of his body. is, it is difficult to remove or destroy them completely, and During the 6-hour surgery, Professor P. had stopped breathing. any cancerous tissue that remains after surgery usually In the intensive care unit, near death and hallucinating from continues to grow. Gliomas (brain tumors that develop the morphine, Professor P. thought he heard his wife, Maggie, call- from glial cells) are infiltrating, rapidly growing, and ing for help, and he tried to go to her assistance. But one gentle unfortunately the most common form of malignant brain morphine-steeped professor was no match for five nurses intent on saving his life. They quickly turned up his medication, and the next time he regained consciousness, he was tied to the bed. Figure 10.1 A meningioma. Professor P.’s auditory-vestibular nerve was transected during his surgery, which has left him permanently deaf and without ves- tibular function on the right side. He was also left with partial hemi- facial paralysis, including serious blinking and tearing problems. Professor P. is still alive and much improved. Indeed, at the very moment that these words are being written, Professor P. is working on a forthcoming edition... If it has not yet occurred to you, I (JP) am Professor P., which is why this chapter has come to have special meaning for me. Causes of Brain Damage This module provides an introduction to six causes of brain damage: brain tumors, cerebrovascular disorders, closed- head injuries, infections of the brain, neurotoxins, and genetic factors. It concludes with a discussion of programmed cell death, which mediates many forms of brain damage. Living Art Enterprises/Science Source M10_PINE1933_11_GE_C10.indd 260 22/01/2021 11:15  Brain Damage and Neuroplasticity 261 tumors (see Broekman et al., 2018; Gusyatiner & Hegi, 2018; Figure 10.3 An MRI of Professor P.’s acoustic neuroma, Laug, Glasgow, & Deneen, 2018). the very one that he took to his doctor. The arrow indicates About 10 percent of brain tumors do not originate in the tumor. the brain. They grow from infiltrating cells that are carried to the brain by the bloodstream from some other part of the body. These tumors are called metastatic tumors (metas- tasis refers to the transmission of disease from one organ to another)—see Alarcón & Tavazoie (2016); Cheung and Ewald (2016). Many metastatic brain tumors originate as cancers of the lungs. Figure 10.2 illustrates the ravages of metastasis. Currently, the chance of recovering from a cancer that has already attacked two or more separate sites is slim. Fortunately, my (JP) tumor was encapsulated. Encapsulated tumors that grow on cranial nerve VIII are referred to as acoustic neuromas (neuromas are tumors that grow on nerves or tracts). Figure 10.3 is an MRI scan of my acoustic neuroma, the same scan that I took to my doctor. Strokes LO 10.2 Describe differences between the two types of stroke: cerebral hemorrhage and cerebral ischemia. Strokes are sudden-onset cerebrovascular disorders that cause brain damage. In the United States, stroke is the fifth leading cause of death, the major cause of neurological dysfunction, and a leading cause of adult disability (see John Pinel Figure 10.2 Multiple metastatic brain tumors. The col- ored areas indicate the location of the larger metastatic brain tumors in this patient. Feigin et al., 2016; Prabhakaran, Ruff, & Bernstein, 2015). The symptoms of a stroke depend on the area of the brain affected, but common consequences of stroke are amnesia, aphasia (language difficulties), psychiatric disorders, dementia, paralysis, and coma (see Ferro, Caeiro, & Figueira, 2016; Mok et al., 2017). The area of dead or dying tissue produced by a stroke is called an infarct. Surrounding the infarct is a dysfunc- tional area called the penumbra. The tissue in the penum- bra may recover or die in the ensuing days, depending on a variety of factors. Accordingly, the primary goal of treatment following stroke is to save the penumbra (see Baron, 2018; Evans et al., 2017). There are two major types of strokes: those resulting from cerebral hemorrhage and those resulting from cerebral ischemia (pronounced “iss-KEEM-ee-a”). CEREBRAL HEMORRHAGE. Cerebral hemorrhage (bleeding in the brain) occurs when a cerebral blood ves- sel ruptures and blood seeps into the surrounding neural tissue and damages it (see Bulters et al., 2018; Carpenter et al., 2016). Bursting aneurysms are a common cause of intracerebral hemorrhage. An aneurysm is a pathological balloonlike dilation that forms in the wall of an artery at a point where the elasticity of the artery wall is defective SMC Images/Photodisc/GettyImages (see Etminan & Rinkel, 2016). Although aneurysms of the M10_PINE1933_11_GE_C10.indd 261 22/01/2021 11:15  262 Chapter 10 Second, ischemia-induced brain damage does not occur Figure 10.4 An angiogram that illustrates narrowing of one carotid artery (see arrow), a major pathway of blood to equally in all parts of the brain—particularly suscepti- the brain. ble are neurons in certain areas of the hippocampus (see Schmidt-Kastner, 2015). Paradoxically, glutamate, the brain’s most prevalent excitatory neurotransmitter, plays a major role in ischemia- induced brain damage (see Chisholm & Sohrabji, 2015; Parsons & Raymond, 2014). Here is how this mechanism is thought to work (see Lai, Zhang, & Wang, 2014; Leng et al., 2014). After a blood vessel becomes blocked, many of the blood-deprived neurons become overactive and release excessive quantities of glutamate. The glutamate in turn overactivates glutamate receptors in the membranes of postsynaptic neurons; the glutamate receptors most involved in this reaction are the NMDA (N-methyl-D- aspartate) receptors. As a result, large numbers of Na+ and Ca2+ ions enter the postsynaptic neurons. The excessive internal concentrations of Na+ and Ca2+ ions in postsynap- tic neurons affect them in two ways: They trigger the release of excessive amounts of glutamate from the neurons, thus spreading the toxic cascade to yet other neurons; and they trigger a sequence of internal reactions that ultimately kill the postsynaptic neurons. See Figure 10.5. An implication of the discovery that excessive gluta- mate release causes much of the brain damage associated ZEPHYR/SPL/Science Photo Library/Alamy Stock Photo with stroke is the possibility of preventing stroke-related brain are particularly problematic, aneurysms can occur in brain damage by blocking the glutaminergic cascade. any part of the body. Aneurysms can be congenital (pres- Some clinical trials have shown that NMDA-receptor ent at birth) or can result from exposure to vascular poi- antagonists are effective following acute ischemic stroke. sons or infection (see Caranci et al., 2013). Individuals at ­However, to be effective they need to be administered risk of aneurysms should make every effort to avoid ciga- almost immediately after the stroke. This makes them rette smoking, alcohol consumption, and hypertension (see impractical in most human clinical situations (see Leng Brown & Broderick, 2014). et al., 2014). That being said, two other sorts of treatments CEREBRAL ISCHEMIA. Cerebral ischemia is a disruption have been shown to be effective for stroke (see Levy & of the blood supply to an area of the brain. The three main Mokin, 2017): The administration of a tissue plasminogen causes of cerebral ischemia are thrombosis, embolism, and activator (a drug that breaks down blood clots) or an endo- arteriosclerosis. In thrombosis, a plug called a thrombus is vascular therapy (the surgical removal of a thrombus or formed and blocks blood flow at the site of its formation. embolus from an artery). Administration of these treat- A thrombus may be composed of a blood clot, fat, oil, an air ments within a few hours after the onset of ischemic stroke bubble, tumor cells, or any combination thereof. Embolism can lead to better recovery (see Algra & Wermer, 2017; is similar, except that the plug, called an embolus in this Dong et al., 2018; Ginsberg, 2016; Mokin, Rojas, & Levy, case, is carried by the blood from a larger vessel, where it 2016; Law & Levine, 2015). was formed, to a smaller one, where it becomes lodged; in essence, an embolus is just a thrombus that has taken a trip. Traumatic Brain Injuries In arteriosclerosis, the walls of blood vessels thicken and LO 10.3 Describe the two sorts of closed-head the channels narrow, usually as the result of fat deposits; traumatic brain injuries (TBIs). this narrowing can eventually lead to complete blockage of the blood vessels. The angiogram in Figure 10.4 illustrates About 50–60 million people experience some form of partial blockage of one carotid artery. traumatic brain injury (TBI) each year; and about 50 p­ ercent Ischemia-induced brain damage has two important of us will experience a TBI at least once in our lives (see properties. First, it takes a while to develop. Soon after Mollayeva, Mollayeva, & Colantonio, 2018). For the brain a temporary cerebral ischemic episode, there usually is to be seriously damaged by a TBI, it is not necessary for little or no evidence of brain damage; however, substan- the skull to be penetrated (i.e., a penetrating TBI). In fact, tial neuron loss can often be detected a day or two later. any blow to the head should be treated with extreme M10_PINE1933_11_GE_C10.indd 262 22/01/2021 11:15  Brain Damage and Neuroplasticity 263 occur when the brain slams Figure 10.5 The cascade of events by which the ischemia-induced release of glutamate kills neurons. against the inside of the skull. As Figure 10.6 illustrates, blood from such injuries can accumulate in the 1 Blood vessel becomes blocked. subdural space—the space between the dura mater and arachnoid 2 Neurons that are affected by the ischemia release membrane—and severely distort the surrounding neural tissue. Blockage Such a “puddle” of blood is known excessive glutamate. as a subdural hematoma (see Shi Glutamate et al., 2019). It may surprise you to learn 3 Excessive glutamate binds to NMDA that contusions frequently occur on the side of the brain opposite receptors, thus the side struck by a blow. The rea- Na+ triggering an son for such so-called contrecoup Ca2+ excessive influx of injuries is that the blow causes the Na+ and Ca2+ ions brain to strike the inside of the skull into postsynaptic on the other side of the head. neurons. When there is a disturbance of consciousness following a blow to the head and there is no NMDA evidence of a contusion or other receptor structural damage, the diagnosis is mild TBI (mTBI). Most TBIs are mTBIs (see Mollayeva, Mollayeva, & Colantonio, 2018). mTBIs were once called concussions. However, Degeneration the term “concussion” is no lon- 4 The excessive influx of Na+ and Ca2+ ions ger deemed appropriate because it was associated with the mis- eventually kills postsynaptic taken assumption that its effects neurons, but first it triggers involved no long-term damage the excessive release of glutamate from them, thus (see Grasso & Landi, 2016; Moye spreading the toxic & Pradhan, 2017; Zetterberg & cascade. Blennow, 2016). This has not turned out to be the case. For example, there is now substantial evidence that the effects of mTBIs can last many years and that the effects of repeated mTBIs can accumulate (see Carman et al., 2015). caution, particularly when confusion, sensorimotor dis- Chronic traumatic encephalopathy (CTE) is the turbances, or loss of consciousness ensues. Brain injuries dementia (general intellectual deterioration) and cerebral produced by blows that do not penetrate the skull are scarring often observed in boxers, rugby players, American called closed-head TBIs. football players (see Figure 10.7), and other individuals who There are several types of closed-head TBIs. Contusions have experienced repeated mTBIs (see Azad et al., 2016; are closed-head TBIs that involve damage to the cerebral Maroon et al., 2015; Smith et al., 2019; Underwood, 2015a). circulatory system. Such damage produces internal For example, there have been reports that most (approxi- hemorrhaging, which in turn produces a localized collection mately 90 percent) former American football players, and of blood in the brain—in other words, a bruised brain. many former recreational American football players, meet It is paradoxical that the very hardness of the skull, the diagnostic criteria for chronic traumatic encephalopathy which protects the brain from penetrating injuries, is the (Mez et al., 2017). The case of Junior Seau is particularly major factor in the development of contusions. Contusions tragic (Azad et al., 2016). M10_PINE1933_11_GE_C10.indd 263 22/01/2021 11:15  264 Chapter 10 The Case of Junior Seau Figure 10.7 The NFL has acknowledged that there is a connection between playing football and chronic traumatic encephalopathy (CTE). Junior Seau was an all-star linebacker in the National Football League (NFL) for 20 years. He was known for his hard-hitting, aggressive play. Although Seau never complained about head injuries to his coaches or medical staff, his family members reported that he had suffered many mTBIs. When he came home from games, he often experienced severe headaches and would go straight to his darkened bedroom. But, according to his ex-wife, “he always bounced back and kept on playing.” He was a warrior. After Seau’s retirement from the NFL in 2010, his fam- ily and friends noticed several disturbing behavioral changes: heavy consumption of alcohol, reckless business and financial decisions, and gambling. Most disturbing were his frequent vio- lent outbursts that were completely out of character for him and were often directed at friends and family—the very people who were trying to help him. On May 2, 2012, at the age of 43, Junior Seau shot him- self. He left no note—no explanation. Seau’s family donated his brain to the American National Institutes for Health (NIH) for study. A detailed autopsy of Seau’s brain revealed that he met criteria for a diagnosis of chronic traumatic encephalopathy. epa european pressphoto agency b.v./Alamy Stock Photo Figure 10.6 A CT scan of a subdural hematoma. Notice BACTERIAL INFECTIONS. When bacteria infect the that the hematoma has displaced the left lateral ventricle. brain, they often lead to the formation of cerebral abscesses— pockets of pus in the brain. Bacteria are also the major cause of meningitis (inflammation of the meninges), which is fatal in 30 percent of adults (see Castelblanco, Lee, & Hasbun, Hematoma 2014). Penicillin and other antibiotics sometimes eliminate bacterial infections of the brain, but they cannot reverse brain damage that has already been produced. Syphilis is one bacterial brain infection you have likely heard about (see Berger & Dean, 2014). Syphilis bacte- ria are passed from infected to noninfected individuals through contact with genital sores. The infecting bacte- ria then go into a dormant stage for several years before Left lateral they become virulent and attack many parts of the body, ventricle including the brain. The syndrome of mental illness and dementia that results from a syphilitic infection is called general paresis. VIRAL INFECTIONS. There are two types of viral infec- tions of the nervous system: those that have a particular Scott Camazine/Alamy Images affinity for neural tissue and those that attack neural tissue but have no greater affinity for it than for other tissues. Infections of the Brain Rabies, which is usually transmitted through the bite of a rabid animal, is a well-known example of a virus that LO 10.4 Describe two different types of infections has a particular affinity for the nervous system. The fits of of the brain. rage caused by the virus’s effects on the brain increase the An invasion of the brain by microorganisms is a brain infection, probability that rabid animals that normally attack by bit- and the resulting inflammation is called encephalitis. ing (e.g., dogs, cats, raccoons, bats, and mice) will spread There are two common types of brain infections: bacterial the disorder. Although the effects of the rabies virus on the infections and viral infections. brain are almost always lethal (see Schnell et al., 2010), the M10_PINE1933_11_GE_C10.indd 264 22/01/2021 11:15  Brain Damage and Neuroplasticity 265 virus does have one redeeming feature: It does not usually Genetic Factors attack the brain for at least a month after it has been con- tracted, thus allowing time for preventive vaccination. LO 10.6 Discuss the symptoms of Down syndrome and The mumps and herpes viruses are common examples what causes this disorder. of viruses that can attack the nervous system but have no Some neuropsychological diseases of genetic origin are special affinity for it. Although these viruses sometimes caused by abnormal recessive genes that are passed from spread into the brain, they typically attack other tissues of parent to offspring. (In Chapter 2, you learned about the body. one such disorder, phenylketonuria, or PKU.) Inherited Viruses may play a far greater role in neuropsychologi- neuropsychological disorders are rarely associated with cal disorders than is currently thought. Their involvement dominant genes because dominant genes that disturb in the etiology (cause) of disorders is often difficult to rec- neuro­psychological function tend to be eliminated from the ognize because they can lie dormant for many years before gene pool—individuals who carry one usually have major producing symptoms (see Miller, Schnell, & Rall, 2016). survival and reproductive disadvantages. In contrast, indi- viduals who inherit one abnormal recessive gene do not develop the disorder, and the gene is passed on to future Neurotoxins generations. Genetic accident is another major cause of neuropsy- LO 10.5 Describe three different types of neurotoxins. chological disorders of genetic origin. Down syndrome, The nervous system can be damaged by exposure to any which occurs in about 0.15 percent of births, is such a dis- one of a variety of toxic chemicals—chemicals that can enter order. The genetic accident associated with Down syndrome general circulation from the gastrointestinal tract, from the occurs in the mother during ovulation, when an extra chro- lungs, or through the skin. For example, heavy metals such mosome 21 is created in the egg. Thus, when the egg is fer- as mercury and lead (see Chen, 2013a; Hare et al., 2015; tilized, there are three chromosome 21s, rather than two, Tshala-Katumbay et al., 2015) can accumulate in the brain in the zygote (see Dekker et al., 2015). The consequences and permanently damage it, producing a toxic psychosis tend to be characteristic disfigurement, intellectual disabil- (chronic mental illness produced by a neurotoxin). Have you ity, early-onset Alzheimer’s disease (a type of dementia), and ever wondered why Alice in Wonderland’s Mad Hatter was a other troublesome medical complications. “mad hatter” and not a “mad” something else? In 18th- and There was great optimism among professionals who 19th-century England, hat makers commonly developed study and treat neuropsychological disorders when the toxic psychosis from the mercury employed in the prepara- human genome was documented at the beginning of this tion of the felt used to make hats. In a similar vein, the word century. Inherited factors play major roles in virtually all crackpot originally referred to the toxic psychosis observed in neuropsychological disorders, and it seemed that the offend- some people in England—primarily the poor—who steeped ing genes would soon be identified and effective treatments their tea in cracked ceramic pots with lead cores. developed to target them. This has not happened, for two Sometimes, the very drugs used to treat neurological or reasons (see Maurano et al., 2012). First, numerous loci psychiatric disorders prove to be toxic. For example, some on human chromosomes have been associated with each of the antipsychotic drugs introduced in the early 1950s pro- disorder—not just one or two. Second, about 90 percent duced effects of distressing scope. By the late 1950s, m­ illions of the chromosomal loci involved in neuropsychological of patients with schizophrenia were being maintained on disorders did not involve protein-coding genes; rather, the these drugs. However, after several years of treatment, loci were in poorly understood sections of the DNA. about 5 percent of the patients developed a motor disor- der called tardive dyskinesia (TD)—see Cloud, Zutshi, Programmed Cell Death and Factor (2014). Its primary symptoms are involuntary LO 10.7 Explain the difference between apoptosis smacking and sucking movements of the lips, thrusting and and necrosis. rolling of the tongue, lateral jaw movements, and puffing of the cheeks. Recall that neurons and other cells have genetic programs Some neurotoxins are endogenous (produced by the for destroying themselves by a process called apoptosis patient’s own body). For example, the body can produce (pronounced “A-poe-toe-sis”). Apoptosis plays a critical antibodies that attack particular components of the nervous role in early development by eliminating extra neurons. system (see Melzer, Meuth, & Wiendl, 2012). Stress hor- It also plays a role in brain damage. Indeed, all of the six mones, such as cortisol, are also believed to produce neuro- causes of brain damage that have been discussed in this toxic effects (see Lupien et al., 2018). Likewise, as you have chapter (tumors, cerebrovascular disorders, closed-head just learned from the discussion of glutamate and ischemic TBIs, infections, toxins, and genetic factors) produce neural stroke, the excessive release of certain neurotransmitters can damage, in part, by activating apoptotic programs of self- also damage the brain. destruction (see Viscomi & Molinari, 2014). M10_PINE1933_11_GE_C10.indd 265 22/01/2021 11:15  266 Chapter 10 It was once assumed that the death of neurons follow- or, more accurately, by spontaneously recurring epileptic ing brain damage was totally necrotic—necrosis is passive seizures—you might think that the task of diagnosing epi- cell death resulting from injury. It now seems that if cells lepsy would be an easy one. But you would be wrong. The are not damaged too severely, they will attempt to mar- task is made difficult by the diversity and complexity of epi- shal enough resources to destroy themselves via apopto- leptic seizures. You are probably familiar with seizures that sis. However, cell death is not an either–or situation: Some take the form of convulsions (motor seizures); these often dying cells display signs of both necrosis and apoptosis (see involve tremors (clonus), rigidity (tonus), and loss of both Zhou & Yuan, 2014). balance and consciousness. But most seizures do not take It is easy to understand why apoptotic mechanisms this form; instead, they involve subtle changes of thought, have evolved: Apoptosis is clearly more adaptive than mood, or behavior that are not easily distinguishable from necrosis. In necrosis, the damaged neuron swells and breaks normal ongoing activity. apart, beginning in the axons and dendrites and ending in There are many causes of epilepsy. Viruses, neuro- the cell body. This fragmentation leads to inflammation, toxins, tumors, and blows to the head can all cause epi- which can damage other cells in the vicinity. Necrotic cell lepsy, and more than 30 different faulty genes have been death is quick—it is typically complete in a few hours. In linked to it, as well as many different epigenetic mechanisms contrast, apoptotic cell death is slow, typically requiring a (see Chapter 2; see Boison, 2016; Chen et al., 2017). Many day or two. Apoptosis of a neuron proceeds gradually, start- cases of epilepsy are associated with faults at inhibitory ing with shrinkage of the cell body. Then, as parts of the synapses (e.g., GABAergic synapses)—synapses that are neuron die, the resulting debris is packaged in vesicles—a normally responsible for preventing excessive excitatory process known as blebbing (one of my (SB) favorite words). activity in the brain; this, in turn, leads to synchronous fir- As a result, there is no inflammation, and damage to nearby ing of neurons and ultimately seizures (see Ben-Ari, 2017; cells is kept to a minimum. Di Cristo et al., 2018; Moore et al., 2017; Trevelyan, 2016). Dysfunctional activity in astrocytes is also implicated in the development of seizures (see Almad & Maragakis, 2018; Bedner & Steinhäuser, 2016; Robel & Sontheimer, Neurological Diseases 2016). In other cases of epilepsy, inflammatory processes seem to be responsible for seizure activity (see Marchi, The preceding module focused on some of the causes of Granata, & Janigro, 2014). human brain damage. This module considers five diseases The diagnosis of epilepsy rests heavily on evidence associated with brain damage: epilepsy, Parkinson’s disease, from electroencephalography (EEG). The value of scalp Huntington’s disease, multiple sclerosis, and Alzheimer’s electroencephalography in confirming suspected cases disease. of epilepsy stems from the fact that seizures are associ- ated with bursts of high-amplitude EEG spikes, which Epilepsy are often apparent in the scalp EEG during a seizure (see Figure 10.8), and from the fact that individual spikes often LO 10.8 Define epilepsy; describe four common types punctuate the scalp EEG between epileptic seizures (see of seizures; and discuss some treatments for Bragatti et al., 2014). epilepsy. Some individuals with epilepsy experience pecu- The primary symptom of epilepsy is the epileptic seizure, liar psychological changes just before a seizure. These but not all persons who suffer seizures are considered to changes, called epileptic auras, may take many different have epilepsy. Sometimes, an otherwise healthy person forms—for example, a bad smell, a specific thought, a may have one seizure and never have another—such a vague feeling of familiarity, a hallucination, or a tightness one-time seizure could be triggered by exposure to a con- of the chest. Epileptic auras are important for two reasons. vulsive toxin or by a high fever. The diagnosis of epilepsy First, the nature of the auras provides clues concerning the is applied to only those patients whose seizures are repeatedly generated by their own chronic Figure 10.8 Cortical EEG recording of an epileptic seizure. Notice that the trace brain dysfunction. About 0.8 is characterized by epileptic spikes (sudden, high amplitude EEG signals that accom- percent of the population are pany epileptic seizures). diagnosed with epilepsy at some point in their lives (see Fiest et al., 2017). Because epilepsy is charac- EEG at the onset of a tonic-clonic seizure terized by epileptic seizures— M10_PINE1933_11_GE_C10.indd 266 22/01/2021 11:15  Brain Damage and Neuroplasticity 267 location of the epileptic focus. Second, epileptic auras can warn the patient of an impending convulsion (see Lohse The Subtlety of Complex et al., 2015). Seizures: Two Cases Once an individual has been diagnosed with epilepsy, it is common to assign the type of seizures they experience A doctor received a call from his hospital informing him that he to one of two general categories—focal seizures or generalized was needed to perform an emergency operation. A few hours after the surgery, he returned home feeling dazed and confused. seizures—and then to one of their respective subcategories He had performed the operation, a very difficult one, with his (see Falco-Walter, Scheffer, & Fisher, 2018). The various sei- usual competence, but afterward he had said and done things zure types are so different from one another that epilepsy that seemed peculiar to his colleagues. The next day he had no is best viewed not as a single disease but as a number of memory of the surgery or the related events. different, but related, diseases. While attending a concert, a young music teacher suddenly FOCAL SEIZURES. A focal seizure is a seizure that does jumped up from his seat, walked down the aisle onto the stage, not involve the entire brain. The epileptic neurons at a focus circled the piano twice, jumped to the floor, and hopped up the begin to discharge together in bursts, and it is this synchro- aisle out of the exit. He did not regain full consciousness until nous firing (see Figure 10.9) that produces epileptic spik- he was on his way home. This was not the first time that he had ing in the EEG. The synchronous activity tends to spread to had such a seizure: He often found himself on a bus with no other areas of the brain—but, in the case of focal seizures, idea where he was going or how he got there. not to the entire brain. The specific behavioral symptoms of a focal epileptic seizure depend on where the disrup- tive discharges begin and into what structures they spread. In 2017, the International League Against Epilepsy Because focal seizures do not involve the entire brain, they (ILEA)—the group responsible for defining the diagnostic are often not accompanied by a total loss of consciousness criteria for seizures and epilepsy—published new diagnos- or equilibrium. tic guidelines. Amongst many changes, the new guidelines There are many different categories of focal seizures, discourage the use of the categories “complex” and “sim- depending on where in the brain they start and where they ple.” This stems from the finding that focal seizures, rather spread to. Here we focus on two types of focal s­ eizures: than merely being simple or complex, lie on a complexity simple and complex. Simple seizures are focal seizures continuum. Rather than rating a seizure in terms of the com- whose symptoms are primarily sensory or motor or plexity of its behavioral symptoms, the ILEA recommends both; they are sometimes called Jacksonian seizures after that focal seizures be classified in terms of the level of dis- the famous 19th-century neurologist Hughlings Jackson. ruption of consciousness during the seizure, ranging from Simple seizures involve only one sort of sensory or motor no disruption of consciousness (as is true for many simple symptom, and they are rarely accompanied by a loss of seizures) to disrupted consciousness (as is true for many consciousness. complex seizures) (see Zuberi & Brunklaus, 2018). In contrast, complex seizures often begin in the tem- GENERALIZED SEIZURES. Generalized seizures involve poral lobes and usually do not spread out of them. Accord- the entire brain. Some begin as focal discharges that gradu- ingly, those who experience them are often said to have ally spread through the entire brain. In other cases, the dis- temporal lobe epilepsy. About half of all cases of epilepsy incharges seem to begin almost simultaneously in all parts of adults are of the complex variety (see Bertram, 2014). Dur- the brain. Such sudden-onset generalized seizures may result ing a complex seizure, the patient engages in compulsive, from diffuse pathology or may begin focally in a structure, repetitive, simple behaviors commonly referred to as autom- such as the thalamus, that projects to many parts of the brain. atisms (e.g., doing and undoing a button) and in more com- Like focal seizures, generalized seizures occur in many plex behaviors that appear almost “normal.” The diversity forms. One is the tonic-clonic seizure. The primary symptoms of complex seizures is illustrated by the following two cases of a tonic-clonic seizure are loss of consciousness, loss of equi- (Lennox, 1960). librium, and a violent tonic-clonic convulsion (that is, a convul- sion involving both tonus and clonus). Tongue biting, urinary incontinence, and cyanosis (turning Figure 10.9 The bursting of an epileptic neuron, recorded by extracellular unit blue from a lack of oxygen during a recording. convulsion) are common manifesta- tions of tonic-clonic convulsions. The hypoxia (a shortage of oxygen sup- ply to a tissue, such as brain tissue) that accompanies a tonic-clonic sei- zure can itself cause brain damage. M10_PINE1933_11_GE_C10.indd 267 22/01/2021 11:15  268 Chapter 10 A second type of generalized seizure is the absence The initial symptoms of Parkinson’s disease are seizure. Absence seizures are not associated with convul- mild—perhaps no more than a slight stiffness or tremor of sions; their primary behavioral symptom is a loss of con- the fingers—but they inevitably increase in severity with sciousness associated with a cessation of ongoing behavior, advancing years. The most common symptoms of the full- a vacant look, and sometimes fluttering eyelids. The EEG of blown disorder are a tremor that is pronounced during an absence seizure is different from that of other seizures; it inactivity but not during voluntary movement or sleep, is a bilaterally symmetrical 3-per-second spike-and-wave muscular rigidity, difficulty initiating movement, slowness discharge (see Figure 10.10). Absence seizures are most of movement, and a masklike face. Certain ailments often common in children, and they frequently cease at puberty develop well before the motor symptoms of Parkinson’s (see Guilhoto, 2017). disease become apparent—up to a decade before in some Although there is no cure for epilepsy, the frequency and cases. These include sleep disturbances, loss of the sense severity of seizures can often be reduced by anticonvulsant of smell, and depression (see Bourzac, 2016; Charvin et al., medication (see Iyer & Marson, 2014; Rheims & Ryvlin, 2014). 2018; McGregor & Nelson, 2019; Potsuma & Berg, 2016). Unfortunately, these drugs often have adverse side effects Many Parkinson’s patients display only mild cognitive (e.g., memory impairment), and they don’t work for everyone deficits that don’t interfere with their daily life (see Aarsland (see Devinsky et al., 2013; Lowenstein, 2015). Other treatment et al., 2017; Perugini et al., 2018). In essence, these patients options include stimulation of the vagus nerve (see Dugan are thinking people trapped inside bodies they cannot con- & Devinsky, 2013; Vonck et al., 2014), transcranial magnetic trol. Do you remember the case of “The Lizard”—Roberto stimulation (see Chapter 5) (see Chen et al., 2016), and the Garcia d’Orta—from Chapter 4? ketogenic diet (a diet consisting of high levels of fat, moder- However, some Parkinson’s patients do experience ate levels of protein, and low levels of carbohydrates)—see more severe cognitive deficits. In general, there is a more Scharfman (2015). Brain surgery is sometimes used, but usu- rapid cognitive decline with age in Parkinson’s patients ally only in serious cases when other treatment options have than in the general population (see Aarsland et al., 2017; been exhausted (see Jetté, Sander, & Keezer, 2016). Yang, Tang, & Gou, 2016). Indeed, a majority of Parkinson’s patients will display symptoms of dementia if they live for Parkinson’s Disease more than 10 years after their initial diagnosis (see Aarsland et al., 2017; Fyfe, 2018). LO 10.9 Describe the symptoms of Parkinson’s disease Like epilepsy, Parkinson’s disease seems to have no and some treatments for this disorder. single cause; faulty DNA, brain infections, strokes, tumors, Parkinson’s disease is a movement disorder of middle TBI, and neurotoxins have all been implicated in specific and old age that affects 1–2 percent of the population over cases (see Przedborski, 2017). However, in the majority of the age of 65 (see Harris et al., 2020; Kalia & Lang, 2015). cases, there is no obvious cause, and no family history of the It is slightly more prevalent in males than in females (see disorder (see Przedborski, 2017). Although numerous genes Pringsheim et al., 2014). have been linked to Parkinson’s disease (see Singleton & Hardy, 2016; Verstraetan, Theuns, & Van Broeckhoven, 2015), most cases of Parkinson’s disease are likely the result Figure 10.10 The bilaterally symmetrical, 3-per-second of interactions between multiple genetic and environmental spike-and-wave EEG discharge associated with absence factors (see Przedborski, 2017). seizures. Parkinson’s disease is associated with widespread degeneration, but it is particularly severe in the substantia nigra—the midbrain nucleus whose neurons project via Left the nigrostriatal pathway to the striatum of the basal frontal ganglia (see Harris et al., 2020; McGregor & Nelson, 2019; Michel, Hirsh, & Hunot, 2016). Although dopamine Right is normally the major neurotransmitter released by most frontal neurons of the substantia nigra, there is little dopamine in Left the substantia nigra and striatum of long-term Parkinson’s temporal patients. Autopsy often reveals clumps of a protein called alpha-synuclein in the surviving dopaminergic neurons Right of the substantia nigra—these clumps are known as Lewy temporal bodies, after the German pathologist who first reported them in 1912 (see Lashuel et al., 2013). Alpha-synuclein 1 second is currently the focus of intense research because it is believed to play an important role in the development and M10_PINE1933_11_GE_C10.indd 268 22/01/2021 11:15  Brain Damage and Neuroplasticity 269 spread of pathology in the brains of Parkinson’s patients stimulation of the subthalamic nucleus, a nucleus that lies (see Harris et al., 2020; Mor et al., 2017; Roy, 2017; Visanji just beneath the thalamus and is richly connected to the et al., 2016; but see Surmeier, Obeso, & Halliday, 2017). basal ganglia (see Faggiani & Benazzouz, 2017; Limousin & As you saw in the case of d’Orta (see Chapter 4), the Foltynie, 2019; Stefani et al., 2017). High-frequency electrical symptoms of Parkinson’s disease can be alleviated by injec- stimulation is employed, and this blocks the function of tions of l-dopa—the chemical from which the body syn- the target structure, much as a lesion would (see Ashkan thesizes dopamine. However, l-dopa is not a permanent et al., 2017). Once the current is turned on, symptoms can be solution; it typically becomes less and less effective with alleviated within seconds; and when the stimulation is turned continued use, until its side effects (e.g., involuntary move- off, the therapeutic improvements dissipate very quickly (see ments) outweigh its benefits (see Charvin et al., 2018; De Lozano, Hutchison, & Kalia, 2017). Unfortunately, deep brain Deurwaerdere, Di Giovanni, & Millan, 2017). This is what stimulation can cause side effects such as cognitive, speech, happened to d’Orta. l-dopa therapy gave him a 3-year and gait problems (see Cossu & Pau, 2016; Moldovan et al., respite from his disease, but ultimately it became ineffec- 2015), and it does not slow the progression of Parkinson’s tive. His prescription was then changed to another dopa- disease (Limousin & Foltynie, 2019). mine agonist, and again his condition improved—but again the improvement was only temporary. Huntington’s Disease There is currently no drug that will permanently block LO 10.10 Describe the symptoms of Huntington’s the progressive development of Parkinson’s disease or per- disease and explain its genetic basis. manently reduce the severity of its symptoms (see Charvin et al., 2018), though there are ongoing attempts to develop Like Parkinson’s disease, Huntington’s disease is a pro- such drugs (see Elkouzi et al., 2019). Indeed, current evidence gressive motor disorder, but, unlike Parkinson’s disease, it suggests that by the time the motor symptoms of Parkinson’s is rare (1 in 7,500), it has a simple genetic basis, and it is disease become apparent, and a diagnosis is made, irreversible always associated with severe dementia. damage has already occurred (see Tison & Meissner, 2014). We The first clinical sign of Huntington’s disease is often will return to d’Orta’s roller-coaster case later in this chapter. increased fidgetiness. As the disorder develops, rapid, When medication is not effective in the treatment of complex, jerky movements of entire limbs (rather than Parkinson’s disease, deep brain stimulation is a treatment individual muscles) begin to predominate. Also prominent option. This entails applying low-intensity electrical are psychiatric symptoms and cognitive deficits (see Bachoud- stimulation continually to a particular area of the brain Lévi et al., 2019). Eventually, motor and cognitive deterioration through a stereotaxically implanted electrode (see Faggiani become so severe that sufferers are incapable of feeding & Benazzouz, 2017; Ligaard, Sannæs, & Pihlstrøm, 2019) themselves, controlling their bowels, or recognizing their (see Figure 10.11). The treatment of Parkinson’s disease friends and relatives. There is no cure; death typically occurs by this method usually involves chronic bilateral electrical about 20 years after the appearance of the first symptoms. Huntington’s disease is passed from generation to Figure 10.11 Deep brain stimulation for Parkinson’s generation by a single mutated dominant gene, called disease. huntingtin. The protein it codes for is known as the huntingtin protein. Because the gene is dominant, all individuals carrying the gene develop the disorder, as Implanted electrodes do about half their offspring (see Essa et al., 2019). The huntingtin gene has remained in the gene pool because, once Subthalamic nucleus inherited, the first symptoms of the disease do not appear until after the peak reproductive years (at about age 40). The mutated huntingtin protein seems to be “stickier” Connective wires than normal huntingtin protein—leading to the accumula- tion of clumps of the mutated huntingtin protein within cells (see Tyebji & Hannan, 2017). It is thought that these clumps are toxic to cells (see Caron, Dorsey, & Hayden, 2018). Early on in the disease, this accumulation becomes particularly pronounced in cells in the striatum, where the cells begin to die (see Mattis & Svendsen, 2018). The cell death in the striatum destroys the connections between the Pacemaker striatum and the cortex, and it is this disconnection which is believed to result in the early symptoms of Huntington’s dis- ease. As the disease progresses, cells throughout the brain M10_PINE1933_11_GE_C10.indd 269 22/01/2021 11:15  270 Chapter 10 begin to die from the clumps of mutated huntingtin-protein MS is often considered to be an autoimmune disorder—a (see Essa et al., 2019; Veldman & Yang, 2018). disorder in which the body’s immune system attacks part If one of your parents were to develop Huntington’s dis- of the body as if it were a foreign substance (see Dong & ease, the chance would be 50/50 that you too would develop Yong, 2019; Nave & Ehrenreich, 2017). In MS, the myelin it. If you were in such a situation, would you want to know sheath on axons is the focus of the faulty immune reaction. whether you would suffer the same fate? Medical geneticists Indeed, an animal model of MS, termed experimental autoim- have developed a test that can tell relatives of Huntington’s mune encephalomyelitis (see Deshmukh et al., 2013; Dong & patients whether they are carrying the gene. Some choose Yong, 2019), can be induced by injecting laboratory animals to take the test, and some do not. One advantage of the test with myelin and a preparation that stimulates the immune is that it permits the relatives of Huntington’s patients who system. However, it should be noted that in MS, damage have not inherited the gene to have children without the fear to neurons occurs even without demyelination (see Friese, of passing the disorder on to them. Another potential advan- Schattling, & Fugger, 2014). Indeed, the general consensus tage is that it may permit preventative therapies for carriers is that the progression of MS is driven by an interaction of the gene in the future (see Caron, Dorsey, & Hayden, 2018). between immune-system reactivity and neural degenera- There is currently no established treatment that slows tion (Faissner et al., 2019). the progression of Huntington’s disease. However, a clinical In MS, there is also a lack of remyelination of axons. trial in 2016 that used a novel medication generated some Remyelination refers to the generation of new myelin promising results (see Jankovic, 2017), and there are many sheaths on axons—a job taken care of by oligodendroglia other clinical trials for other candidate therapies in progress in the CNS (see Faissner et al., 2019; Franklin & Ffrench- (see Caron, Dorsey, & Hayden, 2018). Constant, 2017). In healthy individuals, remyelination of axons by oligodendroglia and the generation of new oligo- Multiple Sclerosis dendroglia are both ongoing processes that occur throughout one’s lifespan (see Jensen & Yong, 2016). In patients with MS, LO 10.11 Describe the symptoms of multiple sclerosis both processes appear to be disrupted. First, many newly born (MS) and its risk factors. oligodendroglia fail to develop into cells that are capable of Multiple sclerosis (MS) is a progressive disease that attacks remyelinating axons. Second, those oligodendroglia that are the myelin of axons in the CNS. It is particularly disturb- functional do not remyelinate affected brain areas (see Nave ing because the first symptoms typically appear in early & Ehrenreich, 2017). Accordingly, a major focus of current adulthood (Filippi et al., 2018). First, there are microscopic MS research is the development of treatments that encour- areas of degeneration on the myelin sheaths provided by age remyelination by oligodendroglia (see Filippi et al., 2018; oligodendroglia (see Chapter 3) (see Lucchinetti et al., 2011; Jensen & Yong, 2016; Kremer et al., 2016; Stangel et al., 2017). Filippi et al., 2018) but eventually damage to the myelin is Diagnosing MS is typically done with MRI (see so severe that the associated axons become dysfunctional Chapter 5) (see Matthews, 2019; Rotstein & Montalban, and degenerate (see Faissner et al., 2019; Filippi et al., 2018). 2019), and it focuses on identifying the time course of Ultimately, many areas of hard scar tissue develop in the development of white-matter lesions (see Geraldes et CNS (sclerosis means “hardening”). Figure 10.12 illustrates al., 2018; Tintore, Vidal-Jordana, & Sastre-Garriga, 2019). degeneration of the white matter of a patient with MS. However, MRI-based diagnosis is typically complex because the nature and severity of MS lesions depends on a variety of factors, including their number, size, and location Figure 10.12 Areas of sclerosis (see arrows) in the white (see Rotstein & Montalban, 2019; Sati et al., 2016). matter of a patient with multiple sclerosis (MS). In the majority of cases of MS, there are periods of remission (up to 2 years) during which the patient displays no symptoms; however, these are usually just oases in the progression of MS, which eventually becomes continuous and severe (see Larochelle et al., 2016). Common symptoms of advanced MS are visual disturbances, muscular weak- ness, numbness, tremor, and ataxia (loss of motor coordina- tion). In addition, cognitive deficits and emotional changes occur in some patients (see Filippi et al., 2018; Ransohoff, Hafler, & Lucchinetti, 2015; Rotstein & Montalban, 2019). Epidemiological studies have revealed several puzzling features of MS (see Filippi et al., 2018). Epidemiology is the study of the various factors such as diet, geographic loca- tion, and age that influence the distribution of a disease in M10_PINE1933_11_GE_C10.indd 270 22/01/2021 11:15  Brain Damage and Neuroplasticity 271 the general population. Genetic factors seem to play less of but it is an indicator that the symptoms of Alzheimer’s dis- a causal role in MS than they do in other neurological disor- ease are progressing. The combined presence of mild cogni- ders: The concordance rate is only 35 percent in monozygotic tive impairment and certain biological changes can lead to a twins, compared with 6 percent in dizygotic twins. Also, fairly reliable diagnosis during this stage (see Dolgin, 2018). the incidence of multiple sclerosis is substantially higher in During the final stage of Alzheimer’s, the dementia stage, there females than in males (see Friese, Schattling, & Fugger, 2014; is initially a progressive decline in memory, deficits in atten- Ransohoff, Hafler, & Lucchinetti, 2015), and in Caucasians tion, and personality changes; this is eventually followed by than in other groups (Filippi et al., 2018). Also, the incidence marked confusion, irritability, anxiety, and deterioration of is higher in people who have lived in cold climates, particu- speech. Eventually the patient deteriorates to the point that larly during their childhoods (Filippi et al., 2018). even simple responses such as swallowing and bladder con- Several established risk factors exist for MS. The most trol are difficult. Alzheimer’s disease is a terminal illness. well-established ones include vitamin D deficiency, expo- The three defining neuropathological characteristics sure to the Epstein-Barr virus (the most common cause of of the disease are neurofibrillary tangles, amyloid plaques, mononucleosis), and cigarette smoking (see Filippi et al., and neuron loss. Neurofibrillary tangles are threadlike tangles 2018; Hauser, Chan, & Oksenberg, 2013). of tau protein in the neural cytoplasm. Tau protein normally In the 1990s, immunomodulatory drugs were approved for plays a role in maintaining the overall structure of neurons the treatment of MS, and a large number of them are now (see Villemagne & Okamura, 2016; Wang & Mandelkow, available for MS treatment (see Chun et al., 2019). Although 2016). Amyloid plaques are clumps of scar tissue composed these drugs are still widely prescribed for MS, their benefits of degenerating neurons and aggregates of another protein are only marginal, and they help only some MS patients (see called beta-amyloid which is present in healthy brains in Faissner et al., 2019; Marino & Cosentino, 2016). Still, this only small amounts. The presence of amyloid plaques modest success has stimulated the current search for more in the brain of a patient who died of Alzheimer’s disease is effective drug treatments, such as those that encourage remy- illustrated in Figure 10.13. elination (see Stangel et al., 2017; Filippi et al., 2018). Although neurofibrillary tangles, amyloid plaques, and neuron loss tend to occur throughout the brains of Alzheimer’s Disease LO 10.12 Describe the symptoms of Alzheimer’s Figure 10.13 Amyloid plaques (stained blue) in the brain disease and evaluate the amyloid hypothesis. of a deceased patient who had Alzheimer’s disease. Alzheimer’s disease is the most common cause of dementia in the elderly; it currently affects about 50 million people worldwide (see Drew & Ashour, 2018; Götz, Bodea, & Goedert, 2018). It sometimes appears in individuals as young as 40, but the likelihood of its development becomes greater with advancing years. About 10 percent of people over the age of 65 suffer from the disease (see Mielke, Vemuri, & Rocca, 2014). Journal Prompt 10.2 Total dementia often creates less suffering than partial dementia for the individual with the dementia. Why do you think that is the case? Alzheimer’s disease is considered to progress through three stages (see Chiesa et al., 2017; Hickman, Faustin, & Wisniewski, 2016). The first stage, the preclinical stage, involves pathological changes in the brain without any behavioral or cognitive symptoms (see Brier et al., 2016; Dolgin, 2018; Polanco et al., 2019; Villemagne et al., 2018). The second stage of Alzheimer’s disease, known as the pro- dromal stage, involves mild cognitive impairment. The cog- nitive impairment observed during this stage is not nearly as severe as that seen in full-blown Alzheimer’s disease, Dr. Cecil H. Fox/Science Source M10_PINE1933_11_GE_C10.indd 271 22/01/2021 11:15  272 Chapter 10 Alzheimer’s patients, they are more prevalent in some areas Yamazaki et al., 2019). Notably, the presence of a particular than in others. For example, neurofibrillary tangles are par- allele of the APOE gene, APOE4, has been shown to increase ticularly prevalent in medial temporal lobe structures such susceptibility to the late-onset form of Alzheimer’s disease as the entorhinal cortex, amygdala, and hippocampus—all struc- by approximately 50 percent (see Sala Frigerio & tures involved in various aspects of memory. Figure 10.14 De Strooper, 2016; Karch, Cruchaga, & Goate, 2014; Yu, Tan, summarizes the various neuropathological changes seen in & Hardy, 2014). The exact cellular functions of APOE are Alzheimer’s disease. not yet known (see Spinney, 2014). However, in Alzheimer’s Early attempts to identify the genes involved in disease, it appears that APOE binds to beta-amyloid, and Alzheimer’s disease focused on a rare, early-onset form of that such binding reduces beta-amyloid clearance from the the disorder that runs in a few families. Mutations to four brain, and it increases beta-amyloid clumping (see Ulrich et al., different genes have been shown to contribute to the early- 2017)—leading to the development of amyloid plaques. onset, familial form; however, these four gene mutations There is currently no cure for Alzheimer’s disease. One seem to contribute little (only about 1 percent) to the more factor complicating the search for a treatment or cure for common, late-onset form (see Kanekiyo, Xu, & Bu, 2014; Alzheimer’s disease is that it is not entirely clear which Ulrich et al., 2017). symptom is primary (see O’Brien & Wong, 2011; Spires- Subsequent research on the late-onset form of Jones & Hyman, 2014). The amyloid hypothesis is currently Alzheimer’s disease has implicated other genes (see Tanzi, the dominant view (see Castellani, Plascencia-Villa, & Perry, 2012). Attention has focused on one particular gene, the gene 2019). It proposes that amyloid plaques are the primary on chromosome 19 that codes for the protein apolipoprotein symptom of the disorder; that is, the plaques cause all the E (APOE) (see Belloy, M. E., Napolioni, V., & Greicius, 2019; other symptoms (see Liu et al., 2019; Selkoe & Hardy, 2016). Figure 10.14 A summary of the neuropathological changes that accompany Alzheimer’s disease. Amyloid plaque Gross Neuroanatomical Changes: In the later stages of Alzheimer’s, the brain is noticeably shrunken due to Neurofibrillary significant neuron loss. tangle Microscopic Changes: 1. Neurofibrillary tangles are threadlike tangles of BRAIN OF tau protein in the neural PATIENT WITH TYPICAL cytoplasm. ALZHEIMER’S BRAIN 2. Amyloid plaques are clumps of scar tissue composed of degenerat- ing neurons and aggre- gates of another protein called beta-amyloid. 3. Neuron loss. Hippocampus Neocortex Base on Drew, L. (2018). M10_PINE1933_11_GE_C10.indd 272 22/01/2021 11:15  Brain Damage and Neuroplasticity 273 The main support for the amyloid hypothesis has the development of effective treatments (see Hampel et al., come from the genetic analysis of families with early-onset 2018; Lee et al., 2019). Alzheimer’s disease (see Herrup, 2015). All four different Attention has also focused on Down syndrome as a gene mutations that cause early-onset Alzheimer’s disease potential provider of insights into the neural mechanisms influence the synthesis of beta-amyloid. Additional support of Alzheimer’s disease. This link stems from the fact that, for the amyloid hypothesis comes from the finding that the by age 40, almost all individuals with Down syndrome have production of neurofibrillary tangles is downstream from developed numerous amyloid plaques and neurofibrillary alterations to beta-amyloid (Amar et al., 2017). One of the tangles, the core symptoms of Alzheimer’s disease (see main arguments against the amyloid hypothesis is the Lott & Head, 2019; Marshall, 2014); and that, by age 60, fact that many people without observable dementia carry two-thirds of individuals with Down syndrome will have significant loads of amyloid plaques. These individuals are developed dementia (see Wiseman et al., 2015). It turns known as high-plaque normals (see Herrup, 2015; Spires- out that people with Down syndrome have three copies Jones & Hyman, 2014). However, these high-plaque normals of chromosome 21, instead