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In everyone’s lifetime, at least one close friend or relative will develop a neurological disorder, even if we ourselves escape them. Disorder causes are understood in a general sense, and for most, rehabilitative treatment is emerging. In this section we review some common neurological disorders: traumatic brain injury, stroke, epilepsy, multiple sclerosis, and neurodegenerative disorders.

Traumatic brain injury (TBI), a wound to the brain that usually results from a blow to the head, is the most common form of brain damage in people under age 40. TBI commonly results from the head making impact with other objects—as can occur in automobile and industrial accidents and in sports injuries. TBI can also follow blows to the chest that result in a rapid increase in blood pressure, which can damage the brain indirectly. The incidence of TBI is about eight times that of breast cancer, AIDS, spinal cord injury, and multiple sclerosis combined.

The two most important factors in the incidence of head trauma are age and sex. Children and elderly people are more likely to injure their head in a fall than are others, and males between 15 and 30 incur brain injury especially in automobile and motorcycle accidents (Figure 16-5). A child’s chance of having significant traumatic brain injury before he or she is old enough to drive is 1 in 30.

Concussion is a critical concern for both professional and amateur athletes, especially those who play football, ice hockey, lacrosse, soccer, and no less for those on active military duty. Sports account for about 20 percent of TBIs, and the U.S. Army Institute of Surgical Research reports that traumatic brain injury affects more than 1 in 5 U.S. soldiers wounded in war.

A large-scale longitudinal study is under way in cooperation with football and ice hockey players who have a history of concussion and who have agreed to donate their brain for postmortem analysis. Preliminary examination of the brains of deceased professional football players who had a history of concussion and severe postconcussion symptoms, described in Clinical Focus 16-3, Concussion, reveal extensive, diffuse loss of cerebral tissue.

Symptoms and Outcome of Brain Trauma

TBI can cause direct damage to the brain. Trauma can disrupt the brain’s blood supply, induce bleeding (leading to increased intracranial pressure), cause swelling (leading to increased intracranial pressure), expose the brain to infection, and scar brain tissue (the scar being a focus for later epileptic seizures). The disruption in blood supply tends to be brief, but a parallel disruption of energy production by neuronal mitochondria, which can persist for weeks, is related to many postconcussion behavioral symptoms.

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Traumatic brain injury is commonly accompanied by a loss of consciousness that may be brief (minutes) or prolonged (coma). Duration of unconsciousness can serve as a measure of the severity of damage, because it correlates directly with mortality, intellectual impairment, and deficits in social skills. The longer coma lasts, the greater the possibility of serious impairment or death.

Two kinds of behavioral effects result from TBI: (1) impairment of specific functions mediated by the cortex at the coup (the site of impact) or contrecoup (opposite side) lesion, as illustrated in Figure 16-6, and (2) more generalized impairments from widespread trauma throughout the brain. Discrete impairment is most commonly associated with damage to the frontal and temporal lobes, the brain areas most susceptible to TBI. (See tissue samples in Focus 16-3.)

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More generalized impairment results from minute lesions and lacerations scattered throughout the brain. Movement of the hemispheres in relation to one another causes tearing characterized by a loss of complex cognitive functions, including mental speed, concentration, and overall cognitive efficiency.

TBI patients generally complain of poor concentration or lack of ability. They fail to do things as well as they could before the injury, even though their intelligence is unimpaired. In fact, in our experience, people with high skill levels seem to be the most affected by TBI, in large part because they are acutely aware of loss of a skill that prevents them from returning to their former competence level.

Traumatic brain injury that damages the frontal and temporal lobes also tends to significantly affect personality and social behavior. Few victims of traffic accidents who have sustained severe head injuries ever resume their studies or return to gainful employment. If they do reenter the work force, they do so at a lower level than before their accident.

One frustrating problem with traumatic brain injury is misdiagnosis: chronic effects of injuries often are unaccompanied by any obvious neurological signs or abnormalities in CT or MRI scans. Patients may therefore be referred for psychiatric or neuropsychological evaluation. MRI-based imaging techniques such as magnetic resonance spectroscopy (MRS), however, are useful for accurate TBI diagnosis (Reis et al., 2015).

MRS, a modification of MRI, can identify changes in specific markers of neuronal function. One such marker is N-acetylaspartate (NAA), the second most abundant amino acid in the human brain. Assessing the level of NAA expression provides a measure of neuronal integrity, and deviations from normal levels (up or down) can be taken as a marker of abnormal brain function. People with traumatic brain injury show a chronic decrease in NAA that correlates with the severity of the injury. Although not yet in wide clinical use, MRS is a promising tool, not only for identifying brain abnormalities but also for monitoring cellular response to therapeutic interventions.

Recovery from Traumatic Brain Injury

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Recovery from head trauma may continue for 2 to 3 years and longer, but most cognitive recovery occurs in the first 6 to 9 months. Recovery of memory functions appears to be slower than recovery of general intelligence, and the final level of memory performance is lower than for other cognitive functions. People with brainstem damage, as inferred from oculomotor disturbance, have a poorer cognitive outcome, and a poorer outcome is probably true of people with initial dysphasias or hemiparesis as well.

Although the prognosis for significant recovery of cognitive functions is good, optimism about the recovery of social skills or personality traits, areas that often show significant change, is less rosy. Findings from numerous studies support the conclusions that quality of life—in social interactions, perceived stress levels, and enjoyment of leisure—is significantly reduced after TBI and that this reduction is chronic. Attempts to develop tools to measure changes in psychosocial adjustment in brain-injured people are few, so we must rely largely on subjective descriptions and self-reports. Neither provides much information about the specific causes of these problems (Block et al., 2015).

Diagnosticians may be able to point to a specific immediate cause of stroke, an interruption of blood flow from either blockage of a vessel or bleeding from a vessel. This initial event, however, merely sets off a sequence of damage that progresses, even if the blood flow is restored. Stroke results in a lack of blood, called ischemia, followed by a cascade of cellular events that wreak the real damage. Changes at the cellular level can seriously compromise not only the injured part of the brain but other brain regions as well.

Effects of Stroke

Consider what happens after a stroke interrupts the blood supply to a cerebral artery. In the first seconds to minutes after ischemia, as illustrated in Figure 16-7, changes begin in the affected regions’ ionic balance, including changes in pH and in the properties of the cell membrane. These ionic changes result in several pathological events.

Treatments for Stroke

The ideal treatment is to restore blood flow in blocked vessels before the cascade of nasty events begins. One clot-busting drug is tissue plasminogen activator (t-PA), but t-PA must be administered within 3 to 5 hours to be effective. Currently, only a small percentage of stroke patients arrive at the hospital soon enough, in large part because stroke is not quickly identified, transportation is slow, or the stroke is not considered an emergency.

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Other drugs called neuroprotectants can be used to try to block the cascade of postinjury events, but to date we have no truly effective drugs. Clinical trials based on animal studies have generally failed, in part because understanding what the appropriate brain targets should be is limited.

When the course of the stroke leads to dead brain tissue, the only treatments that can be beneficial are those that facilitate plastic changes in the remaining brain. Examples are speech therapy and physical therapy. Revolutionary approaches to stroke rehabilitation use virtual reality, computer games, and robotic machines (Laver et al., 2015).

Still, some simple treatments are surprisingly effective. One is constraint-induced therapy, pioneered by Edward Taub in the 1990s (Kawakkel et al., 2015). Its logic confronts a problem in poststroke recovery related to learned nonuse. Stroke patients with motor deficits in a limb often compensate by overusing the intact limb, which in turn leads to increased loss of use in the impaired limb.

In constraint-induced therapy, the intact limb is held in a sling for several hours per day, forcing the patient to use the impaired limb. Nothing about the procedure is magical: virtually any treatment that forces patients to practice behaviors extensively is successful. An important component of these treatments, however, is a posttreatment contract in which the patients continue to practice after the formal therapy is over. If they fail to do so, the chances for learned nonuse and a return of symptoms are high.

Another common effect of stroke is loss of speech. Specific speech therapy programs can aid in the recovery of speech. Music and singing, mediated in part by the right hemisphere, can augment speech therapy after left hemisphere stroke.

Therapies using pharmacological interventions (e.g., noradrenergic, dopaminergic, cholinergic agonists) combined with behavioral therapies provide equivocal gains in stroke patients. The bulk of evidence suggests that patients with small gray matter strokes are most likely to show benefits from these treatments, whereas those with large strokes that include white matter show little benefit.

Finally, there have been many attempts to use either direct cortical stimulation or TMS in combination with behavioral therapy as a stroke treatment. The idea is to induce plasticity in regions adjacent to the dead tissue with the goal of enhancing the efficiency of the residual parts of the neuronal networks. These treatments have proved beneficial in patients with good residual motor control, but again, those with larger injuries show much less benefit, presumably because the residual neuronal network is insufficient.

Epilepsy is characterized by recurrent seizures, which register on an electroencephalogram (EEG) as highly synchronized neuronal firing indicated by a variety of abnormal waves. About 1 person in 20 has at least one seizure in his or her lifetime, usually associated with an infection, temperature, and hyperventilation during childhood (6 months to 5 years of age). Most children who experience a seizure do not develop epilepsy, which affects between 0.2 percent and 4.1 percent of the population. Developed nations record a lower prevalence and incidence of epilepsy compared with developing nations.

Classifying Seizures

Causes of epileptic seizures are categorized as genetic, structural/metabolic, or unknown. Genetic epilepsy results directly from a known genetic defect. Causes of structural/metabolic epilepsy include brain malformations and tumors, acquired disorders such as stroke and trauma, and infections. The unknown category encompasses causes yet to be identified. Table 16-4 summarizes the great variety of circumstances that appear to precipitate a seizure. The range of circumstances is striking, but seizures do have a consistent feature: they are most likely to occur when a person is sleeping.

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Seizures are classified by the way participating neural networks are distributed. Focal seizures arise from a synchronous, hyperactive local brain region. Thus, focal seizures may have motor, sensory, autonomic, and/or psychogenic features. Focal seizures are further classified as to whether awareness is retained or altered (dyscognitive seizure). Generalized seizures may start at a focal location, then spread rapidly and bilaterally to distributed networks in both hemispheres. In primary generalized epilepsy, seizures begin in more widespread neural networks. Seizure diagnosis is improved by the use of a wearable device that records them (Gubbi et al., 2015).

People having a seizure may cycle through the four stages charted in Figure 16-8: (1) normal EEG record before onset; (2) onset and tonic phase, in which the body stiffens; (3) clonic phase, in which the person makes rhythmic movements in time with the large, highly synchronized discharges; and (4) a period of depressed EEG activity after the seizure ends.

For the most part, seizures self-terminate. In some cases, termed status epilepticus, the seizure’s driving force does not abate, often due to a brain insult or to drug withdrawal. In this life-threatening condition, drug intervention with a fast-acting GABA agonist or glutamate antagonist is required to end the seizure. Death due to status epilepticus is much more common in adults than in children (26 percent vs. 3 percent, respectively), and survivors often live with significant brain damage. The recommended time limit before intervention is 5 minutes. Longer-lasting seizures are unlikely to self-terminate.

People with epilepsy die unexpectedly at a rate 24 times that of the general population. Sudden unexpected death in epilepsy (SUDEP) has no identifiable cause (such as status epilepticus, drowning, or falling). Most evidence suggests that SUDEP occurs during or more often after a seizure. Respiratory and cardiac failure may be common causes, but events leading up to SUDEP have yet to be characterized.

Treating Epilepsy

The first-line treatment for epilepsy is drugs to inhibit seizure development and propagation. Among the diverse range of mechanisms drugs employ to raise seizure thresholds are enhancing the action of the inhibitory neurotransmitter GABA and stabilizing the inactive state of sodium channels. Most people with epilepsy work with their physician to find a drug and dosage that cause few side effects. In 30 percent to 40 percent of people with epilepsy, however, antiseizure drugs fail to completely control the condition—intractable epilepsy. The most common treatment for intractable epilepsy in adults is surgical resection of epileptogenic tissue, which has a success rate of about 70 percent. Deep-brain stimulation may prove useful for intractable epilepsy: bilateral stimulation of the anterior thalamus has been successful in reducing seizure frequency. While DBS shows promise, more research is needed (Ostergard & Miller, 2014).

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In multiple sclerosis (MS), the myelin that encases axons is damaged and neuronal functions are disrupted. MS is characterized by myelin loss in both motor and sensory tracts and nerves. The oligodendroglia that form the myelin sheath, and in some cases the axons, are destroyed. Brain imaging with MRI, as shown in Figure 16-9, identifies areas of sclerosis in the brain as well as in the spinal cord.

Remission followed by relapse is a striking feature of MS: in many cases, early symptoms initially are followed by improvement. The course varies, running from a few years to as long as 50 years. Paraplegia, the classic feature of MS, may eventually confine the affected person to bed.

Worldwide, about 1 million people have MS; women outnumber men about two to one. Multiple sclerosis is most prevalent in northern Europe and northern North America, rare in Japan and in more southerly or tropical countries. Depending on region, incidence of MS ranges from 2 to 150 per 100,000 people, making it one of the most common structural nervous system diseases.

The cause or causes of MS are unknown. Proposed causes include bacterial infection, a virus, environmental factors including pesticides, an immune response of the central nervous system, misfolded proteins, and lack of vitamin D. Often, multiple cases occur in a single family. Many genes have been associated with MS, but no clear evidence indicates as yet that MS is inherited or transmitted from one person to another.

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Research has focused on the immune system’s relation to MS and the possibility that MS is an autoimmune disease. The ability to discriminate between a foreign pathogen in the body and the body itself is central to immune system functioning. If this discrimination fails, the immune system makes antibodies to a person’s own body, in this case, to myelin.

As various organisms’ genomes have been sequenced, it has become apparent that all have many genes in common. Thus the proteins found in different organisms are surprisingly similar. And here is the problem for the human immune system: a foreign microbe may contain proteins that are nearly identical to the body’s own proteins. If microbe and human have a common gene sequence, the immune system can mistakenly attack itself, a process known as horror autotoxicus.

Many microbial protein sequences are homologous with structures found in myelin, which leads to an attack against the microbe and a person’s own myelin. Research showing the important role of the immune system in MS has intensified work on developing new treatments (Kornek, 2015). One strategy is to build up immune system tolerance by injecting DNA-encoding myelin antigens and DNA-encoding specific molecules in the cascade of steps that leads to oligodendroglial cell death.

That MS is more common in extreme northern and southern latitudes has raised the possibility that inadequate direct sunlight, which is necessary for the body to synthesize vitamin D, factors into precipitating the condition (Sundström & Salzer, 2015). Lack of understanding whether an acute or a longstanding deficiency is relevant complicates identifying a possible relationship. Possibly a vitamin D deficiency interacts with other factors to increase susceptibility to MS. For example, a number of genes are involved in the transport and absorption of vitamin D and variants of these genes are related to low levels of vitamin D.

Some research has suggested that MS might originate from insufficient blood drainage from the brain, which can be improved by cleaning or expanding veins from the brain, including the jugular, to improve drainage. The treatment has been called liberation therapy for its potential relief from a condition of chronic cerebrospinal venous insufficiency (CCSVI). Internet discussion worldwide has led to Web sites advertising treatment using vascular surgery for patients with MS. Numerous studies are examining a plethora of questions related to CCSVI. Primary among them: Is venous flow restricted in people with MS? Optimism about an outcome has far outpaced the science, which questions the treatment (Tsivgoulis et al., 2015).

Human societies have never before undergone the age-related demographic shifts now developing in North America and Europe. Since 1900, the percentage of older people has increased steadily. In 1900, about 4 percent of the population had attained 65 years of age. By 2030, about 20 percent will be older than 65—about 50 million people in the United States alone.

Dementias affect 1 percent to 6 percent of the population older than age 65 and 10 percent to 20 percent of those older than age 80. For every person diagnosed with dementia, it is estimated that several others endure undiagnosed cognitive impairments that affect their quality of life. Currently, more than 6 million people in the United States have a dementia diagnosis, a number projected to rise to about 15 million by 2050. By then, 1 million new U.S. cases per year will be emerging. Extending these projections across the rest of the developed world portends staggering social and economic costs (Khachaturian & Khachaturian, 2015). The World Health Organization estimates that by 2050, the incidence of dementia will balloon to 135.5 million people worldwide.

Types of Dementia

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Dementia is an acquired and persistent syndrome of intellectual impairment. Its two essential features are (1) loss of memory and other cognitive deficits and (2) impairment in social and occupational functioning. Dementia is not a singular disorder, but there is no clear agreement on how to split up subtypes. Daniel Kaufer and Steven DeKosky (1999) divide dementias into the broad categories of degenerative and nondegenerative (Table 16-5).

Nondegenerative dementias, a heterogeneous group of disorders with diverse causes, including diseases of the vascular or endocrine systems, inflammation, nutritional deficiency, and toxins, are summarized on the right in Table 16-5. The most prevalent cause is vascular. The most significant risk factors for nondegenerative dementias are chronic hypertension, obesity, sedentary lifestyle, smoking, and diabetes. All are as well risk factors for cardiovascular disease. Degenerative dementias, listed on the left in the table, presumably have a degree of genetic transmission.

We now review two degenerative dementias, Parkinson and Alzheimer diseases. Both pathological processes are primarily intrinsic to the nervous system, and both tend to affect certain neural systems selectively.

Parkinson Disease

Parkinson disease is common. Estimates of its incidence vary up to 1.0 percent of the population, rise sharply in old age, and are certain to grow in coming decades. The disease seems related to degeneration of the substantia nigra and attendant loss of the neurotransmitter dopamine produced there and released in the striatum. The disease therefore offers insight into the roles played by the substantia nigra and dopamine in movement control.

That Parkinson symptoms vary enormously illustrates the complexity inherent in understanding a neurological disorder. A well-defined set of cells degenerates, yet the symptoms are not the same in every patient. Many symptoms strikingly resemble changes in motor activity that occurs as a consequence of aging. Thus Parkinson disease offers indirect insight into more general problems of neural changes in aging.

Symptoms begin insidiously, often with a tremor in one hand and slight stiffness in distal parts of the limbs. Movements may become slower, the face becoming masklike with loss of eye blinking and poverty of emotional expression. Thereafter the body may stoop and the gait become a shuffle, with arms hanging motionless at the sides. Speech may slow and become monotonous, and difficulty swallowing may cause drooling.

Although the disease is progressive, the rate at which symptoms worsen varies; only rarely is progression so rapid that a person becomes disabled within 5 years. Usually 10 to 20 years elapse before symptoms cause incapacity. A distinctive aspect of Parkinson disease is its on-again–off-again quality: symptoms may appear suddenly and just as suddenly disappear.

Partial remission may also occur in response to interesting or stimulating situations. Neurologist Oliver Sacks (1998) recounted an incident in which a stationary Parkinson patient leaped from his wheelchair at the seaside and rushed into the breakers to save a drowning man, only to fall back into his chair immediately afterward and become inactive again. Remission of some symptoms in activating situations is common but usually not as dramatic as this case. Simply listening to familiar music can help an otherwise inactive patient get up and dance, for example. Or a patient who has difficulty walking may ride a bicycle or skate effortlessly. Such activities can be used as physical therapy, and physical therapy is important because it may slow disease progression.

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The four major symptoms of Parkinson disease are tremor, rigidity, loss of spontaneous movement (hypokinesia), and postural disturbances. Each symptom may manifest in different body parts in different combinations. Because some symptoms entail the appearance of abnormal behaviors (positive symptoms) and others the loss of normal behaviors (negative symptoms), we consider both major categories.

POSITIVE SYMPTOMS Because positive symptoms are common in Parkinson disease, they are thought to be inhibited, or held in check, in unaffected people but released from inhibition in the process of the disease. Following are the three most common:

NEGATIVE SYMPTOMS After detailed analysis of negative symptoms, Jean Prudin Martin (1967) divided patients severely affected with Parkinson disease into five groups:

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COGNITIVE SYMPTOMS Although Parkinson disease is usually viewed as a motor disorder, changes in cognition occur as well. Psychological symptoms in Parkinson patients are as variable as the motor symptoms. Nonetheless, a significant percentage of patients show cognitive symptoms that mirror their motor symptoms.

Oliver Sacks (1998) reported impoverishment of feeling, libido, motive, and attention: people may sit for hours, apparently lacking the will to begin or continue any activity. Thinking seems generally to be slowed and is easily confused with dementia because patients do not appear to be processing the content of conversations. In fact, they may be simply processing very slowly.

CAUSES OF PARKINSONISM The ultimate cause of Parkinson disease—loss of cells in the substantia nigra—may result from disease, such as encephalitis or syphilis, from drugs such as MPTP, or from unknown causes. Idiopathic causes—those related to the individual—may include environmental pollutants, insecticides, and herbicides. Demographic studies of patient admissions in the cities of Vancouver, Canada, and Helsinki, Finland, show an increased incidence of patients contracting the disease at ages younger than 40. This finding has prompted the suggestion that water and air might contain environmental toxins that work in a fashion similar to MPTP (1-methyl-4-phenylpyridinium), a contaminant that has been found in synthetic heroin and causes Parkinson disease.

TREATING PARKINSON DISEASE The cure for Parkinson disease is either to stop degeneration in the substantia nigra or to replace it. Neither goal is achievable at present. Thus, current treatment is pharmacological and directed toward support and comfort.

Psychological factors influence Parkinsonism’s major symptoms: outcome is affected by how well a person copes. Patients should seek behaviorally oriented treatment early—counseling on the meaning of symptoms, the nature of the disease, and the potential for most patients to lead long, productive lives. Physical therapy consists of simple measures, such as heat and massage, to alleviate painful muscle cramps as well as training and exercise to cope with debilitating movement changes. Used therapeutically, music and exercise can improve other aspects of behavior, including balance and walking, and may actually slow the course of the disease.

The prime objective of pharmacological treatment is increasing the activity in whatever dopamine synapses remain. l-Dopa, a precursor of dopamine, is converted into dopamine in the brain and enhances effective dopamine transmission, as do drugs such as amantadine, amphetamine, monoamine oxidase inhibitors, and tricyclic antidepressants. Anticholinergic drugs, such as atropine, scopolamine, benztropine (Cogentin), and trihexyphenidyl (Artane), block the brain cholinergic systems that seem to show heightened activity in the absence of adequate dopamine activity. As the disease progresses, drug therapies become less effective, and the incidence of side effects increases. Some drug treatments that directly stimulate dopamine receptors have been reported to result in increased sexuality and an increased incidence of compulsive gambling.

Two surgical treatments described in Section 16-2 are based on the idea that increased activity of globus pallidus neurons inhibits motor function. A lesion of the internal part of the globus pallidus (GPi) can reduce rigidity and tremor. Hyperactivity of GPi neurons can also be reduced neurosurgically by electrically stimulating the neurons via deep brain stimulation (see Figure 16-4). A stimulating electrode is permanently implanted in the GPi or an adjacent area, the subthalamic nucleus. Patients carry a small electric stimulator that they can turn on to induce DBS and so reduce rigidity and tremor. These two treatments may be used sequentially: when DBS becomes less effective as the disease progresses, a GPi lesion may be induced.

A promising prospective Parkinson treatment involves increasing the population of dopamine-producing cells. The simplest way is to transplant embryonic dopamine cells into the basal ganglia. In the 1980s and 1990s, this treatment reported varying degrees of success marked by poorly conducted studies with inadequate preassessment and postassessment procedures. A newer treatment course proposes either transplanting stem cells that could then be induced to take a dopaminergic phenotype or stimulating endogenous stem cells to migrate to the basal ganglia. The advantage is that these stem cells need not be derived from embryonic tissue but can come from a variety of sources, including the person’s own body.

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All these treatments are experimental (Politis & Lindvall, 2012). Before cell replacement will become a useful therapy, many questions must be resolved, including which cell source is best, where in the brain to put grafts, and how new cells can be integrated into existing brain circuits. Stem cells are not a quick fix for Parkinson disease, but the pioneering work on this disease will be instrumental in applying such technology to other diseases.

Anatomical Correlates of Alzheimer Disease

Given the increasing population of elderly people and thus of Alzheimer disease, which accounts for about 65 percent of all dementias, research is directed toward potential causes. Personal lifestyle, environmental toxins, high levels of trace elements such as aluminum in the blood, an autoimmune response, a slow-acting virus, reduced blood flow to the cerebral hemispheres, and genetic predisposition are targets of ongoing research.

Incidence of Alzheimer disease is high in some families, making genetic causes pertinent to understanding disease progression. Risk factors include the presence of the Apoe4 gene, below-average IQ score, poor education, and TBI. Presumably, better educated and/or more intelligent people and those who carry the Apoe2 gene are better able to compensate for cell death in degenerative dementia.

A decade ago, the only way to identify and study Alzheimer disease was postmortem pathology examination. This approach was less than ideal because determining which brain changes came early in the disease and which resulted from those early changes was impossible. Nonetheless, it became clear that widespread changes take place in neocortex and allocortex and that associated changes take place in many neurotransmitter systems. Most of the brainstem, cerebellum, and spinal cord are relatively spared from Alzheimer’s major ravages.

The principal neuroanatomical change in Alzheimer disease is the emergence of amyloid plaques (clumps of protein from dead neurons and astrocytes), chiefly in allocortex and neocortex. Increased plaque concentration in the cortex has been correlated with the magnitude of cognitive deterioration. Plaques are generally considered nonspecific phenomena in that they can be found in non-Alzheimer patients and in dementias caused by other known events.

Another anatomical correlate of Alzheimer disease is neurofibrillary tangles (accumulations of microtubules from dead cells) found in both neocortex and allocortex, where the posterior half of the hippocampus is affected more severely than the anterior half. Neurofibrillary tangles have been described mainly in human tissue and have also been observed in patients with Down syndrome and Parkinson disease and other dementias.

Finally, neocortical changes that correlate with Alzheimer disease are not uniform. As Figure 16-10 shows plainly, the cortex atrophies and can lose as much as one-third of its volume as the disease progresses. But cellular analyses at the microscopic level reveal that some areas, including the primary sensory and motor cortices, especially the visual and sensorimotor cortex, are relatively spared. The frontal lobes are less affected than is the posterior cortex.

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Areas of most extensive change are the neocortical association areas and the allocortex. The entorhinal cortex is affected earliest and most severely. Entorhinal cortex is the major information relay from the neocortex traveling to the hippocampus and related structures, then back to the neocortex. Entorhinal damage is associated with memory loss, an early and enduring symptom of Alzheimer disease, and is most likely caused by degenerative changes that take place in this area.

Many studies describe cell loss in the cortices of Alzheimer patients, but this finding is disputed. There seems to be a substantial reduction in large neurons, but these cells may shrink rather than disappear. The more widespread cause of cortical atrophy appears to be a loss of dendritic arborization (Figure 16-11).

In addition to cell loss and shrinkage, changes take place in the remaining cells’ neurotransmitters. In the 1970s, researchers believed that a treatment paralleling l-dopa treatment of Parkinson disease could be found for Alzheimer disease. The prime candidate neurotransmitter was acetylcholine, and one treatment developed for Alzheimer disease is medication that increases acetylcholine levels in the forebrain. An example, available both orally and as a skin patch, is Exelon, the brand name for rivastigmine, a cholinergic agonist that appears to provide temporary relief from disease progression. Unfortunately, Alzheimer has proved far more complex, because transmitters other than ACh clearly are changed as well. Noradrenaline, dopamine, and serotonin are reduced, as are the NMDA and AMPA receptors for glutamate.

Neither Parkinson nor Alzheimer disease is related to a single brain structure or region, although dopamine in the case of the former and acetylcholine in the case of the latter seem more affected. Other similarities in their pathology suggest some common neurodegenerative processes. Donald Calne (Calne & Mizuno, 2004) noted that when scientists traveled to Guam at the end of World War II to investigate a reportedly widespread dementia described as similar to Alzheimer disease, they did indeed report a high incidence of Alzheimer. Many years later, Calne and his colleagues, also experts in Parkinson disease, examined the same general group of people and found that they had Parkinson disease. Calne noted that, if you look for Alzheimer symptoms in these people, you find them and miss the Parkinson symptoms. And vice versa.

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The best-studied similarity between the two diseases is the Lewy body (Figure 16-12), a fibrous ring that forms within neuronal cytoplasm and is thought to correspond to abnormal neurofilament metabolism. Until recently, the Lewy body was most often found in the region of the midbrain substantia nigra and believed to be a hallmark of Parkinson disease, as amyloid plaques were viewed as a marker of Alzheimer disease. In fact, Lewy bodies appear in several neurodegenerative disorders, including Alzheimer disease. There are even reports of people with Alzheimerlike dementias who have no plaques and tangles but do have extensive Lewy bodies in the cortex.

Alzheimer and Parkinson symptoms may be similar because both diseases have similar origins. Indeed, the idea that several diseases marked by brain degeneration—including Huntington disease, MS, and ALS—may have a similar origin is central to prion theory, advanced in 1982 by Stanley B. Prusiner, who received the Noble Prize for his work in 1997. Its name derived from the terms protein and infection, a prion is an abnormally folded protein that causes progressive neurodegeneration.

Prions were identified during investigation of various degenerative brain diseases in humans and other animals. Creutzfeldt-Jakob disease, a rare human degenerative disease that progresses rapidly, gained public prominence in the 1990s. People were contracting a similar condition after eating beef from cattle that had displayed symptoms of bovine spongiform encephalopathy (BSE), a degenerative brain condition accompanied by muscle wasting. BSE in turn is similar to a condition in sheep called scrapies (the animals scrape or scratch themselves) that also features wasting of brain and body. Chronic wasting disease is a similar condition found in deer and elk.

The infectious nature of such conditions was observed in the Fore tribe of Papua New Guinea in the 1950s. A large number of Fore were dying of a muscle-wasting condition called kuru (meaning to shake in Fore). The Fore contracted kuru by practicing ritual cannibalism: they ate the brains of dead relatives, which the Fore believed preserves their spirits. In an experiment to investigate the condition, body parts from kuru victims were fed to a chimp that contracted the disease.

The infectious agent in these conditions is a prion. Prion proteins are found in healthy cell membranes and may play a role in attaching one cell to another. Prion proteins also bind to metallic ions, for example, copper. The proteins typically fold in a normal configuration but can also misfold (Figure 16-13). The altered configuration causes disease.

A misfolded prion protein will attach to a healthy prion protein and cause it to misfold. Misfolded prions tend to clump together, forming protein aggregates that eventually result in cell death. Misfolded prions can also infect neighboring brain and body cells, resulting in general brain degeneration and muscle wasting. An infectious prion can pass from one individual to another, and even from one species to another, but only if the normal prion proteins in the two individuals are similar. Investigations show that among several alleles of the gene that produces normal prion proteins, some are more susceptible to misfolding than are others. Individuals with alleles that are not susceptible to misfolding, as are those Fore tribespeople who did not contract kuru, are resistant to prion disease.

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In Parkinson disease, the misfolded protein is proposed to be alpha synuclein. Its accumulation, largely in substantia nigra cells, is a Lewy body (Olanow & Brundin, 2013). In Alzheimer disease, the accumulating protein forms amyloid plaques and mainly affects cortical cells (Kumar et al., 2015). Misfolded proteins in oligodendroglia may be responsible for the cell demyelination characteristic of MS and ALS (Shi et al., 2015).

The prion theory opens new avenues for investigating degenerative disease treatments, including drugs that remove prions, block prion misfolding, or alter prion forms prone to misfolding (Asante et al., 2015). Selective cattle breeding for prion alleles that do not produce misfolding prevents BSE. Inserting a misfolding-resistant human prion allele into mice renders them resistant to prion disease. Any treatment developed for humans could potentially treat BSE in cattle, scrapie in sheep, and wasting disease in deer and elk. Preventing prion misfolding could even arrest, in part, degenerative consequences of traumatic brain injury and concussion.

Most people who grow old do not become demented, but virtually everyone acquires age-related cognitive loss, even while living an active, healthy, productive life. Aging is associated with declines in perceptual functions, especially vision, hearing, and olfaction, and declining motor, cognitive, and executive (planning) functions as well. Older people tend to learn at a slower pace and typically do not attain the same mastery of new skills as do younger adults.

Noninvasive imaging studies reveal that aging is correlated with decreased white matter volume, probably related to myelin loss. This condition is reparable. There is little evidence of neuronal loss in typical aging, although a reduction in neurogenesis in the hippocampus does occur. Compared with younger people, older people tend to activate larger regions of their attentional and executive networks (parietal and prefrontal cortex) when they perform complex cognitive and executive tasks. This increased activation correlates with reduced performance on tests of working memory as well as tests of attentional and executive tasks.

Two lines of evidence suggest that that age-related declines in function can be slowed. The first is aerobic exercise to enhance general health and improve the brain’s plasticity via increased neurogenesis, gliogenesis, and trophic factor support. The second treatment is brain exercise employing training strategies that enhance neural plasticity and reverse learned nonuse. Most of us know the frustration of losing a skill—whether it’s trigonometry or tennis—after getting out of practice. Skill loss does not reflect dementia but simply a use-it-or-lose-it effect. Training programs designed to stimulate plasticity in the appropriate cerebral circuitry include motor, auditory, or visual system–based cognitive and/or attentional training. Brain training is designed to stimulate plasticity rather than to rehabilitate specific losses.

William Milberg and his colleagues (e.g., Kuo et al., 2005; Leritz et al., 2011) have explored the idea that aging changes in the brain take place in the context of the entire body’s aging. For example, dementia may reflect a chronic cerebrovascular disorder, marginal high blood pressure. Marginal elevations in blood pressure can lead to cerebral microbleeds, especially in white matter. The cumulative effect of years or even decades of tiny bleeds would lead eventually to increasingly disturbed cognition. The condition may first appear as a mild cognitive impairment (MCI) that slowly progresses, with cumulative microbleeds, toward dementia.

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Understanding and Treating Neurological Disorders

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Question 5

Answers appear in the Self Test section of the book.