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A characteristic of animals and particularly of humans is their ability to alter behavior on the basis of experience. Learning is acquisition of the information that makes this possible and memory is the retention and storage of that information. The two are obviously closely related and are considered together in this chapter.
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From a physiologic point of view, memory is divided into explicit and implicit forms (Figure 15–2). Explicit or declarative memory is associated with consciousness, or at least awareness, and is dependent on the hippocampus and other parts of the medial temporal lobes of the brain for its retention. Clinical Box 15–2 describes how tracking a patient with brain damage has led to an awareness of the role of the temporal lobe in declarative memory. Implicit or nondeclarative memory does not involve awareness, and its retention does not usually involve processing in the hippocampus.
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CLINICAL BOX 15–1 Traumatic Brain Injury
Traumatic brain injury (TBI) is defined as a nondegenerative, noncongenital insult to the brain due to an excessive mechanical force or penetrating injury to the head. It can lead to a permanent or temporary impairment of cognitive, physical, emotional, and behavioral functions, and it can be associated with a diminished or altered state of consciousness. TBI is one of the leading causes of death or disability worldwide. According to the Centers for Disease Control and Prevention, each year at least 1.5 million individuals in the United States sustain a TBI. It is most common in children under age 4, in adolescents aged 15–19 years of age, and in adults over the age of 65. In all age groups, TBI occurs more often in males than in females (2:1). In about 75% of the cases, the TBI is considered mild and manifests as a concussion. Adults with severe TBI who are treated have a mortality rate of about 30%, but about 50% regain most if not all of their functions with therapy. The leading causes of TBI include falls, motor vehicle accidents, being struck by an object, and assaults. In some cases, areas remote from the actual injury also begin to malfunction, a process called diaschisis. TBI is often divided into primary and secondary stages. Primary injury is that caused by the mechanical force (eg, skull fracture and surface contusions) or acceleration–deceleration due to unrestricted movement of the head leading to shear, tensile, and compressive strains. These injuries can cause intracranial hematoma (epidural, subdural, or subarachnoid) and diffuse axonal injury. Secondary injury is often a delayed response and may be due to impaired cerebral blood flow that can eventually lead to cell death. A Glasgow Coma Scale is the most common system used to define the severity of TBI and evaluates motor responses, verbal responses, and eye opening to assess the levels of consciousness and neurologic functioning after an injury. Symptoms of mild TBI include headache, confusion, dizziness, blurred vision, ringing in the ears, a bad taste in the mouth, fatigue, disturbances in sleep, mood changes, and problems with memory, concentration, or thinking. Individuals with moderate or severe TBI show these symptoms as well as vomiting or nausea, convulsions or seizures, an inability to be roused, fixed and dilated pupils, slurred speech, limb weakness, loss of coordination, and increased confusion, restlessness, or agitation. In the most severe cases of TBI, the affected individual may go into a permanent vegetative state.
THERAPEUTIC HIGHLIGHTS The advancements in brain imaging technology have improved the ability of medical personnel to diagnose and evaluate the extent of brain damage. Since little can be done to reverse the brain damage, therapy is initially directed at stabilizing the patient and trying to prevent further (secondary) injury. Medications that can be administered include diuretics (to reduce pressure in the brain), anticonvulsant drugs during the first week post injury (to avoid additional brain damage resulting from a seizure), and coma-inducing drugs (to reduce oxygen demands). This is followed by rehabilitation that includes physical, occupational, and speech/language therapies. Recovery of brain function can be due to several factors: brain regions that were suppressed but not damaged can regain their function, axonal sprouting and redundancy allows other areas of the brain to take over the functions that were lost due to the injury, and behavioral substitution, by learning new strategies to compensate for the deficits.
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Explicit memory is for factual knowledge about people, places, and things. It is divided into semantic memory for facts (eg, words, rules, and language) and episodic memory for events. Explicit memories that are initially required for activities such as riding a bicycle can become implicit once the task is thoroughly learned.
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Implicit memory is important for training reflexive motor or perceptual skills and is subdivided into four types. Priming is the facilitation of the recognition of words or objects by prior exposure to them and is dependent on the neocortex. An example of priming is the improved recall of a word when presented with the first few letters of it. Procedural memory includes skills and habits, which, once acquired, become unconscious and automatic. This type of memory is processed in the striatum. Associative learning relates to classical and operant conditioning in which one learns about the relationship between one stimulus and another. This type of memory is dependent on the amygdala for its emotional responses and the cerebellum for the motor responses. Nonassociative learning includes habituation and sensitization and is dependent on various reflex pathways.
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CLINICAL BOX 15–2 The Case of HM: Defining a Link between Brain Function & Memory
HM was a patient who suffered from bilateral temporal lobe seizures that began following a bicycle accident at age 9. His case has been studied by many scientists and has led to a greater understanding of the link between the temporal lobe and declarative memory. HM had partial seizures for many years, and then several tonic-clonic seizures by age 16. In 1953, at the age of 27, HM underwent bilateral surgical removal of the amygdala, large portions of the hippocampal formation, and portions of the association area of the temporal cortex. HM’s seizures were better controlled after surgery, but removal of the temporal lobes led to devastating memory deficits. He maintained long-term memory for events that occurred prior to surgery, but he suffered from anterograde amnesia. His short-term memory was intact, but he could not commit new events to long-term memory. He had normal procedural memory, and he could learn new puzzles and motor tasks. His case was the first to bring attention to the critical role of temporal lobes in formation of long-term declarative memories and to implicate this region in the conversion of short-term to long-term memories. Later work showed that the hippocampus is the primary structure within the temporal lobe involved in this conversion. Because HM retained memories from before surgery, his case also shows that the hippocampus is not involved in the storage of declarative memory. HM died in 2008 and only at that time was his identity released; his full name was Henry Gustav Molaison. An audio-recording by National Public Radio from the 1990s of HM talking to scientists was released in 2007 and is available at http://www.npr.org/templates/story/story.php?storyId=7584970.
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Explicit memory and many forms of implicit memory involve (1) short-term memory, which lasts seconds to hours, during which processing in the hippocampus and elsewhere lays down long-term changes in synaptic strength; and (2) long-term memory, which stores memories for years and sometimes for life. During short-term memory, the memory traces are subject to disruption by trauma and various drugs, whereas long-term memory traces are remarkably resistant to disruption. Working memory is a form of short-term memory that keeps information available, usually for very short periods, while the individual plans action based on it.
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NEURAL BASIS OF MEMORY
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The key to memory is alteration in the strength of selected synaptic connections. Second messenger systems contribute to the changes in neural circuitry required for learning and memory. Alterations in cellular membrane channels are often correlated to learning and memory. In all but the simplest of cases, the alteration involves the synthesis of proteins and the activation of genes. This occurs during the change from short-term working memory to long-term memory.
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In animals, acquisition of long-term learned responses is prevented if, within 5 min after each training session, the animals are anesthetized; given electroshock; subjected to hypothermia; or given drugs, antibodies, or oligonucleotides that block the synthesis of proteins. If these interventions are performed 4 h after the training sessions, there is no effect on acquisition. The human counterpart of this phenomenon is the loss of memory for the events immediately preceding a brain concussion or electroshock therapy (retrograde amnesia). This amnesia encompasses longer periods than it does in experimental animals (sometimes many days) but remote memories remain intact.
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SYNAPTIC PLASTICITY & LEARNING
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Short- and long-term changes in synaptic function can occur as a result of the history of discharge at a synapse; that is, synaptic conduction can be strengthened or weakened on the basis of past experience. These changes are of great interest because they represent forms of learning and memory. They can be presynaptic or postsynaptic in location.
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One form of plastic change is posttetanic potentiation, the production of enhanced postsynaptic potentials in response to stimulation. This enhancement lasts up to 60 s and occurs after a brief tetanizing train of stimuli in the presynaptic neuron. The tetanizing stimulation causes Ca2+ to accumulate in the presynaptic neuron to such a degree that the intracellular binding sites that keep cytoplasmic Ca2+ low are overwhelmed.
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Habituation is a simple form of learning in which a neutral stimulus is repeated many times. The first time it is applied it is novel and evokes a reaction (the orienting reflex or “what is it?” response). However, it evokes less and less electrical response as it is repeated. Eventually, the subject becomes habituated to the stimulus and ignores it. This is associated with decreased release of neurotransmitter from the presynaptic terminal because of decreased intracellular Ca2+. The decrease in intracellular Ca2+ is due to a gradual inactivation of Ca2+ channels. It can be short term, or it can be prolonged if exposure to the benign stimulus is repeated many times. Habituation is a classic example of nonassociative learning.
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Sensitization is in a sense the opposite of habituation. Sensitization is the prolonged occurrence of augmented postsynaptic responses after a stimulus to which one has become habituated is paired once or several times with a noxious stimulus. At least in the sea snail Aplysia, the noxious stimulus causes discharge of serotonergic neurons that end on the presynaptic endings of sensory neurons. Thus, sensitization is due to presynaptic facilitation. Sensitization may occur as a transient response, or if it is reinforced by additional pairings of the noxious stimulus and the initial stimulus, it can exhibit features of short-term or long-term memory. The short-term prolongation of sensitization is due to a Ca2+-mediated change in adenylyl cyclase that leads to a greater production of cAMP. The long-term potentiation (LTP) also involves protein synthesis and growth of the presynaptic and postsynaptic neurons and their connections.
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LTP is a rapidly developing persistent enhancement of the postsynaptic potential response to presynaptic stimulation after a brief period of rapidly repeated stimulation of the presynaptic neuron. It resembles posttetanic potentiation but is much more prolonged and can last for days. There are multiple mechanisms by which LTP can occur, some are dependent on changes in the N-methyl-D-aspartate (NMDA) receptor and some are independent of the NMDA receptor. LTP is initiated by an increase in intracellular Ca2+ in either the presynaptic or postsynaptic neuron.
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LTP occurs in many parts of the nervous system but has been studied in greatest detail in a synapse within the hippocampus, specifically the connection of a pyramidal cell in the CA3 region and a pyramidal cell in the CA1 region via the Schaffer collateral. This is an example of an NMDA receptor-dependent form of LTP involving an increase in Ca2+ in the postsynaptic neuron. Recall that NMDA receptors are permeable to Ca2+ as well as to Na+ and K+. The hypothetical basis of the Schaffer collateral LTP is summarized in Figure 15–3. At the resting membrane potential, glutamate release from a presynaptic neuron binds to both NMDA and non-NMDA receptors on the postsynaptic neuron. In the case of the Schaffer collateral the non-NMDA receptor of interest is the α-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA) receptor. Na+ and K– can flow only through the AMPA receptor because the presence of Mg2+ on the NMDA receptor blocks it. However, the membrane depolarization that occurs in response to high frequency tetanic stimulation of the presynaptic neuron is sufficient to expel the Mg2+ from the NMDA receptor, allowing the influx of Ca2+ into the postsynaptic neuron. This leads to activation of Ca2+/calmodulin kinase, protein kinase C, and tyrosine kinase which together induce LTP. The Ca2+/calmodulin kinase phosphorylates the AMPA receptors, increasing their conductance, and moves more of these receptors into the synaptic cell membrane from cytoplasmic storage sites. In addition, once LTP is induced, a chemical signal (possibly nitric oxide, NO) is released by the postsynaptic neuron and passes retrogradely to the presynaptic neuron, producing a long-term increase in the quantal release of glutamate.
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LTP identified in the mossy fibers of the hippocampus (connecting granule cells in the dentate cortex) is due to an increase in Ca2+ in the presynaptic rather than the postsynaptic neuron in response to tetanic stimulation and is independent of NMDA receptors. The influx of Ca2+ in the presynaptic neuron is thought to activate Ca2+/calmodulin-dependent adenylyl cyclase to increase cAMP.
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Long-term depression (LTD) was first noted in the hippocampus but was subsequently shown to be present throughout the brain in the same fibers as LTP. LTD is the opposite of LTP. It resembles LTP in many ways, but it is characterized by a decrease in synaptic strength. It is produced by slower stimulation of presynaptic neurons and is associated with a smaller rise in intracellular Ca2+ than occurs in LTP. In the cerebellum, its occurrence appears to require the phosphorylation of the GluR2 subunit of the AMPA receptors. It may be involved in the mechanism by which learning occurs in the cerebellum.
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INTERCORTICAL TRANSFER OF MEMORY
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If a cat or monkey is conditioned to respond to a visual stimulus with one eye covered and then tested with the blindfold transferred to the other eye, it performs the conditioned response. This is true even if the optic chiasm has been cut, making the visual input from each eye go only to the ipsilateral cortex. If, in addition to the optic chiasm, the anterior and posterior commissures and the corpus callosum are sectioned (“split-brain animal”), no memory transfer occurs. Experiments in which the corpus callosum was partially sectioned indicate that the memory transfer occurs in the anterior portion of the corpus callosum. Similar results have been obtained in humans in whom the corpus callosum is congenitally absent or in whom it has been sectioned surgically in an effort to control epileptic seizures. This demonstrates that the neural coding necessary for “remembering with one eye what has been learned with the other” has been transferred to the opposite cortex via the commissures. Evidence suggests that similar transfer of information is acquired through other sensory pathways.
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It is now established that the traditional view that brain cells are not added after birth is wrong; new neurons form from stem cells throughout life in at least two areas: the olfactory bulb and the hippocampus. This is a process called neurogenesis. There is evidence implicating that experience-dependent growth of new granule cells in the dentate gyrus of the hippocampus may contribute to learning and memory. A reduction in the number of new neurons formed reduces at least one form of hippocampal memory production. However, a great deal more work is needed before the relation of new cells to memory processing can be considered established.
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ASSOCIATIVE LEARNING: CONDITIONED REFLEXES
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A classic example of associative learning is a conditioned reflex. A conditioned reflex is a reflex response to a stimulus that previously elicited little or no response, acquired by repeatedly pairing the stimulus with another stimulus that normally does produce the response. In Pavlov’s classic experiments, the salivation normally induced by placing meat in the mouth of a dog was studied. A bell was rung just before the meat was placed in the dog’s mouth, and this was repeated a number of times until the animal would salivate when the bell was rung even though no meat was placed in its mouth. In this experiment, the meat placed in the mouth was the unconditioned stimulus (US), the stimulus that normally produces a particular innate response. The conditioned stimulus (CS) was the bell ringing. After the CS and US had been paired a sufficient number of times, the CS produced the response originally evoked only by the US. The CS had to precede the US. An immense number of somatic, visceral, and other neural changes can be made to occur as conditioned reflex responses.
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Conditioning of visceral responses is often called biofeedback. The changes that can be produced include alterations in heart rate and blood pressure. Conditioned decreases in blood pressure have been advocated for the treatment of hypertension; however, the depressor response produced in this fashion is small.
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As noted above, working memory keeps incoming information available for a short time while deciding what to do with it. It is that form of memory which permits us, for example, to look up a telephone number, and then remember the number while we pick up the telephone and dial the number. It consists of what has been called a central executive located in the prefrontal cortex, and two “rehearsal systems:” a verbal system for retaining verbal memories and a parallel visuospatial system for retaining visual and spatial aspects of objects. The executive steers information into these rehearsal systems.
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HIPPOCAMPUS & MEDIAL TEMPORAL LOBE
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Working memory areas are connected to the hippocampus and the adjacent parahippocampal portions of the medial temporal cortex. Output from the hippocampus leaves via the subiculum and the entorhinal cortex and somehow binds together and strengthens circuits in many different neocortical areas, forming over time the stable remote memories that can now be triggered by many different cues.
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In humans, bilateral destruction of the ventral hippocampus, or Alzheimer disease and similar disease processes that destroy its CA1 neurons, can cause striking defects in short-term memory. Humans with such destruction have intact working memory and remote memory. Their implicit memory processes are generally intact. They perform adequately in terms of conscious memory as long as they concentrate on what they are doing. However, if they are distracted for even a very short period, all memory of what they were doing and what they proposed to do is lost. They are thus capable of new learning and retain old prelesion memories, but they cannot form new long-term memories.
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The hippocampus is closely associated with the overlying parahippocampal cortex in the medial frontal lobe. Memory processes have now been studied not only with fMRI but with measurement of evoked potentials (event-related potentials; ERPs) in epileptic patients with implanted electrodes. When subjects recall words, activity in their left frontal lobe and their left parahippocampal cortex increases. In contrast, when they recall pictures or scenes, activity takes place in their right frontal lobe and the parahippocampal cortex on both sides.
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The connections of the hippocampus to the diencephalon are also involved in memory. Some people with alcoholism-related brain damage develop impairment of recent memory, and the memory loss correlates well with the presence of pathologic changes in the mamillary bodies, which have extensive efferent connections to the hippocampus via the fornix. The mamillary bodies project to the anterior thalamus via the mamillothalamic tract, and in monkeys, lesions of the thalamus cause loss of recent memory. From the thalamus, the fibers concerned with memory project to the prefrontal cortex and from there to the basal forebrain. From the nucleus basalis of Meynert in the basal forebrain, a diffuse cholinergic projection goes to all of the neocortex, the amygdala, and the hippocampus. Severe loss of these fibers occurs in Alzheimer disease.
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The amygdala is closely associated with the hippocampus and is concerned with encoding and recalling emotionally charged memories. During retrieval of fearful memories, the theta rhythms of the amygdala and the hippocampus become synchronized. In healthy subjects, events associated with strong emotions are remembered better than events without an emotional charge, but in patients with bilateral lesions of the amygdala, this difference is absent.
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Confabulation is an interesting though poorly understood condition that sometimes occurs in individuals with lesions of the ventromedial prefrontal cortex. These individuals perform poorly on memory tests, but they spontaneously describe events that never occurred. This has been called “honest lying.”
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While the encoding process for short-term explicit memory involves the hippocampus, long-term memories are stored in various parts of the neocortex. Apparently, the various parts of the memories (visual, olfactory, auditory, etc) are located in the cortical regions concerned with these functions. These pieces are tied together by long-term changes in the strength of transmission at relevant synaptic junctions so that all the components are brought to consciousness when the memory is recalled.
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Once long-term memories have been established, they can be recalled or accessed by a large number of different associations. For example, the memory of a vivid scene can be evoked not only by a similar scene but also by a sound or smell associated with the scene and by words such as “scene,” “vivid,” and “view.” Thus, each stored memory must have multiple routes or keys. Furthermore, many memories have an emotional component or “color,” that is, in simplest terms, memories can be pleasant or unpleasant.
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STRANGENESS & FAMILIARITY
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It is interesting that stimulation of some parts of the temporal lobes in humans causes a change in interpretation of one’s surroundings. For example, when the stimulus is applied, the subject may feel strange in a familiar place or may feel that what is happening now has happened before. The occurrence of a sense of familiarity or a sense of strangeness in appropriate situations probably helps the healthy individual adjust to the environment. In strange surroundings, one is alert and on guard, whereas in familiar surroundings, vigilance is relaxed. An inappropriate feeling of familiarity with new events or in new surroundings is known clinically as the déjà vu phenomenon, from the French words meaning “already seen.” The phenomenon occurs from time to time in healthy individuals, but it also may occur as an aura (a sensation immediately preceding a seizure) in patients with temporal lobe epilepsy.
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ALZHEIMER DISEASE & SENILE DEMENTIA
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Alzheimer disease is the most common age-related neurodegenerative disorder. Memory decline initially manifests as a loss of episodic memory, which impedes recollection of recent events. Loss of short-term memory is followed by general loss of cognitive and other brain functions, agitation, depression, the need for constant care, and, eventually, death. Clinical Box 15–3 describes the etiology and therapeutic strategies for the treatment of Alzheimer disease.
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CLINICAL BOX 15–3 Alzheimer Disease
Alzheimer disease was originally characterized in middle-aged people, and similar deterioration in elderly individuals is technically senile dementia of the Alzheimer type, though it is frequently just called Alzheimer disease. Both genetic and environmental factors are thought to contribute to the etiology of the disease (Table 15-1). Most cases are sporadic, but a familial form of the disease (accounting for about 5% of the cases) is seen in an early-onset form of the disease. In these cases, the disease is caused by mutations in genes for the amyloid precursor protein on chromosome 21, presenilin 1 on chromosome 14, or presenilin 2 on chromosome 1. It is transmitted in an autosomal dominant mode, so offspring in the same generation have a 50/50 chance of developing familial Alzheimer disease if one of their parents is affected. Each mutation leads to an overproduction of the β-amyloid protein found in neuritic plaques. Senile dementia can be caused by vascular disease and other disorders, but Alzheimer disease is the most common cause, accounting for 50–60% of the cases. The most common risk factor for developing Alzheimer disease is age. This neurodegenerative disease is present in 8–17% of the population over the age of 65, with the incidence increasing steadily with age (nearly doubling every 5 years after reaching the age of 60). In those who are 95 years of age and older, the incidence is 40–50%. It is estimated that by the year 2050, up to 16 million people age 65 and older in the United States will have Alzheimer disease. Although the prevalence of the disease appears to be higher in women, this may be due to their longer life span as the incidence rates are similar for men and women. Alzheimer disease plus the other forms of senile dementia are a major medical problem.
THERAPEUTIC HIGHLIGHTS Research is aimed at identifying strategies to prevent the occurrence, delay the onset, slow the progression, or alleviate the symptoms of Alzheimer disease. The use of acetylcholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine, or tacrine) in early stages of the disease increases the availability of acetylcholine in the synaptic cleft. This class of drugs has shown some promise in ameliorating global cognitive dysfunction, but not learning and memory impairments in these patients. These drugs also delay the worsening of symptoms for up to 12 months in about 50% of the cases studied. Memantine (an NMDA receptor antagonist) prevents glutamate-induced excitotoxicity in the brain and is used to treat moderate to severe Alzheimer disease. It has been shown to delay but not prevent worsening of symptoms (eg, loss of memory and confusion) in some patients. Antidepressants (eg, paroxetine, imipramine) have been useful for treating depression in individuals with Alzheimer disease. Drugs used to block the production of β-amyloid proteins are under development. Also attempts are underway to develop vaccines that would allow the body’s immune system to produce antibodies to attack these proteins.
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The cytopathologic hallmarks of Alzheimer disease are intracellular neurofibrillary tangles, made up in part of hyperphosphorylated forms of the tau protein that normally binds to microtubules, and extracellular amyloid plaques, which have a core of β-amyloid peptides surrounded by altered nerve fibers and reactive glial cells (Figure 15–4). The β-amyloid peptides are products of a normal protein, amyloid precursor protein (APP), a transmembrane protein that projects into the extracellular fluid from all nerve cells. This protein is hydrolyzed at three different sites by α-secretase, β-secretase, and γ-secretase, respectively. When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced. However, when it is hydrolyzed by β-secretase and γ-secretase, polypeptides with 40–42 amino acids are produced; the actual length varies because of variation in the site at which γ-secretase cuts the protein chain. These polypeptides are toxic, the most toxic being Aβσ1–42. The polypeptides form extracellular aggregates, which can stick to AMPA receptors and Ca2+ ion channels, increasing Ca2+ influx. The polypeptides also initiate an inflammatory response, with production of intracellular tangles. The damaged cells eventually die, leading to a third characterization of the brain pathology in individuals with this neurodegenerative disease – atrophy associated with narrowing of the gyri, widening of the sulci, enlargement of the ventricles, and reduction in brain weight.
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An interesting finding that may well have broad physiologic implications is the observation—now confirmed in a rigorous prospective study—that frequent effortful mental activities, such as doing difficult crossword puzzles and playing board games, slow the onset of cognitive dementia due to Alzheimer disease and vascular disease. The explanation for this “use it or lose it” phenomenon is as yet unknown, but it certainly suggests that the hippocampus and its connections have plasticity like other parts of the brain and skeletal and cardiac muscles.