Congenital Cognitive Impairment

Physicians and the public – but not the Federal Government – loosely refer to stable cognitive impairment since infancy or childhood as “mental retardation” or “developmental delay.” The preliminary DSM-5 equivalent is Intellectual Developmental Disorder. Its diagnosis requires significant impairment in adaptive function and its onset during the “developmental period.”

Physical manifestations of congenital cerebral injury, such as seizures and hemiparesis (“cerebral palsy,” see Chapter 13), frequently accompany Intellectual Developmental Disorder. In cases of genetic abnormalities, distinctive behavioral disturbances and anomalies of nonneurologic organs – the face, skin, ocular lenses, kidneys, and skeleton – often form syndromes.

Whatever the basic condition, children with Intellectual Developmental Disorder may, in later life, develop dementia. The most commonly cited example occurs when trisomy 21 (Down syndrome) individuals almost invariably develop an Alzheimer disease-like dementia by their fifth or sixth decades (see later).

Amnesia

Memory loss with otherwise preserved intellectual function constitutes amnesia. Individuals with amnesia typically cannot recall recently presented information (retrograde amnesia), newly presented information (anterograde amnesia), or both (global amnesia). Although amnesia may occur as an isolated deficit, it appears more often as one of two or more components of dementia. In fact, amnesia is a requirement for the diagnosis of dementia.

Neurologists usually attribute amnesia to transient or permanent dysfunction of the hippocampus (Greek, sea horse) and other portions of the limbic system, which are based in the temporal and frontal lobes (see Fig. 16-5). Dementia, in contrast, usually results from extensive cerebral cortex dysfunction (see later).

Transient amnesia is an important, relatively common disturbance that usually consists of a suddenly occurring period of amnesia lasting only several minutes to several hours. It has several potential medical and neurologic explanations (Box 7-1). One of them, electroconvulsive therapy (ECT), routinely induces both anterograde and retrograde amnesia, with retrograde amnesia, especially for autobiographic information, tending to persist longer than anterograde amnesia. ECT-induced amnesia is more likely to occur or to be more pronounced following treatment with high electrical dosage, with bilateral rather than unilateral electrode placement, with use of alternating current, and three-times rather than two-times weekly administration. Without a pretreatment assessment of a patient’s memory and other aspects of cognitive function, clinicians may have problems separating ECT-induced amnesia from memory difficulties reflecting underlying depression, medications, and, especially in the elderly, pre-existing cognitive impairment.

Various neuropsychologic and physical abnormalities usually accompany amnesia from neurologic conditions. For example, behavioral disturbances, depression, and headache are comorbid with posttraumatic amnesia. With severe traumatic brain injury (TBI, see Chapter 22), hemiparesis, ataxia, pseudobulbar palsy, or epilepsy accompanies posttraumatic amnesia. Similarly, in addition to its characteristic anterograde amnesia, the Wernicke–Korsakoff syndrome comprises ataxia and signs of a peripheral neuropathy (see later).

In another example, herpes simplex encephalitis causes amnesia accompanied by personality changes, complex partial seizures, and the Klüver–Bucy syndrome (see Chapters 12 and 16) because the virus typically enters the undersurface of the brain through the nasopharynx and attacks the frontal and temporal lobes. This condition occurs relatively frequently because herpes simplex is the most common cause of sporadically occurring (nonepidemic) viral encephalitis. (Human immunodeficiency virus [HIV] encephalitis, which does not cause this scenario, is epidemic.)

Conversely, apparent memory impairment may also appear as an aspect of several psychiatric disorders (see Chapter 11, dissociative amnesia). In general, individuals with amnesia from psychiatric illness or malingering (nonneurologic amnesia) lose memory for personal identity or emotionally laden events rather than recently acquired information. For example, a criminal deeply in debt may travel to another city and “forget” his debts, wife, and past associates, but he would retain his ability to recall people, events, and day-to-day transactions in his new life. Nonneurologic amnesia also characteristically produces inconsistent results on formal memory testing. In a simple example, a workman giving emphasis to the sequelae of a head injury may seem unable to recall three playing cards after 30 seconds, but half an hour after discussing neutral topics will recall three different cards after a 5-minute interval. Also, Amytal infusions may temporarily restore memories in individuals with nonneurologic amnesia, but not in those with brain damage.

Neuropsychologic Conditions

Confabulation is a neuropsychologic condition in which patients offer implausible explanations in a sincere, forthcoming, and typically jovial manner. Although individuals with confabulation disregard the truth, they do not intentionally deceive. Confabulation is a well-known aspect of Wernicke–Korsakoff syndrome, Anton syndrome (see cortical blindness, Chapter 12), and anosognosia (see Chapter 8). With these conditions referable to entirely different regions of the brain, confabulation lacks consistent anatomic correlations and physical features.

Discrete neuropsychologic disorders – aphasia, anosognosia, and apraxia – may occur alone, in various combinations, or as comorbidities of dementia (see Chapter 8). If one of them occurs with a comorbidity of dementia, it indicates that the dementia originates in “cortical” rather than “subcortical” dysfunction (see later). These disorders, unlike dementia, are attributable to discrete cerebral lesions. Sometimes only neuropsychologic testing can detect these disorders and tease them apart from dementia.

Memory and Other Neuropsychologic Functions

Compared to young adults, older well-functioning adults have impaired recall of newly learned lists, but given enough time, they will be able to retrieve the new material. Other age-related losses include shortened attention span, slowed learning, and decreased ability to perform complex tasks.

On the other hand, several cognitive processes normally withstand aging. For example, older people have little or no loss of vocabulary, language ability, reading comprehension, or fund of knowledge. They remain well spoken, well read, and knowledgeable. In addition, as determined by the Wechsler Adult Intelligence Scale – Revised (WAIS-R), older individuals’ general intelligence declines only slightly. Social deportment and beliefs in politics and religion continue – stable in the face of changing times.

Sleep

Among the elderly, times of falling asleep and awakening both phase-advance (occur earlier than usual), slow-wave sleep declines, and sleep fragments. In addition, restless legs syndrome and rapid eye movement (REM) behavioral disorder commonly disrupt their sleep (see Chapter 17). All these changes may occur whether or not the elderly have dementia.

Motor and Gait

As most older people recognize, they lose muscle mass and strength. Neurologists usually find that they lose deep tendon reflex activity in their ankles and vibration sensation in their legs. They also have impaired postural reflexes and loss of balance. A standard, simple test will show that most cannot stand on one foot with their eyes closed.

When combined with age-related skeletal changes, these motor and sensory impairments lead to the common walking pattern of older individuals, “senile gait.” This pattern is characterized by increased flexion of the trunk and limbs, diminished arm swing, and shorter steps. Many older individuals instinctively compensate by using a cane.

Age-related neurologic and skeletal changes predispose individuals to falls, which carry significant morbidity and mortality. Additional risk factors for falls include neurologic disorders, prior falls, visual impairment, cognitive impairment, and use of sedatives and antidepressants. Among antidepressants, selective serotonin reuptake inhibitors confer the same degree of risk as tricyclic antidepressants.

Special Senses

Age-related deterioration of sensory organs impairs hearing and vision (see Chapter 12). Older individuals typically have small, less reactive pupils and some retinal degeneration. They require greater light, more contrast, and sharper focusing to be able to read and drive. Their hearing tends to be poorer, especially for speech discrimination. Their senses of taste and smell also deteriorate.

Physicians or other professionals should regularly test vision and hearing in elderly patients because loss of these senses magnifies cognitive and physical impairments. As a practical matter, many elderly insist on driving, which requires almost full ability in all these skills. Deprivation of the special senses can cause or worsen depression, sleep impairment, and perceptual disturbances, including hallucinations.

EEG and Imaging Changes

As individuals age, the electroencephalogram (EEG) background alpha activity slows to the lower end of the normal 8–12-Hz alpha range. Computed tomography (CT) and magnetic resonance imaging (MRI) often reveal decreased volume of the frontal and parietal lobes, atrophy of the cerebral cortex, expansion of the Sylvian fissure, and concomitantly increased volume of the lateral and third ventricles (see Figs 20-2, 20-3, and 20-18). In addition, MRI reveals white-matter hyperintensities (“white dots”). Although striking, these abnormalities are usually innocuous and, by themselves, do not reflect the onset of Alzheimer disease.

Macroscopic and Microscopic Changes

With advancing age, brain weight decreases to about 85% of normal. Age-associated histologic changes include the accumulation of granulovacuolar degeneration, amyloid-containing senile plaques, and neurofibrillary tangles. These changes affect the frontal and temporal lobes more than the parietal lobe. In addition, advancing age leads to loss of neurons in many important deeply situated structures, including the locus ceruleus, suprachiasmatic nucleus, substantia nigra, and nucleus basalis of Meynert. In contrast, the mamillary bodies remain unaffected.

Classifications and Causes

The traditional classification of “dementia by etiology” overwhelms clinicians because of the seemingly innumerable illnesses. Instead, each of the following classifications based on salient clinical features, although overlapping, provides practical and easy-to-learn approaches:

Mental Status Testing

Screening Tests

Several screening tests are widely used, standardized, and have foreign-language versions. However, they also carry several inherent warnings. Unless these tests are carefully considered, they tend to overestimate cognitive impairment in several groups: the elderly, individuals with minimal education (8 years or less of school), and ethnic minorities. In addition, they may fail to detect cognitive impairment in a highly educated person. Screening tests cannot distinguish between dementia produced by Alzheimer disease, other dementia from other illnesses, or depression-induced cognitive dysfunction.

Mini-Mental State Examination (MMSE) (Fig. 7-1)

Physicians so regularly administer the MMSE that it has risen to the level of the standard screening test. Its results are reproducible and correlate with histologic changes in Alzheimer disease. In addition to detecting cognitive impairment, the MMSE has predictive value. For example, among well-educated individuals with borderline scores, as many as 10–25% may develop dementia in the next 2 years. The MMSE can also cast doubt on a diagnosis of Alzheimer disease as the cause of dementia under certain circumstances: (1) If scores on successive tests remain stable for 2 years, the diagnosis should be reconsidered because Alzheimer disease almost always causes a progressive decline. (2) If scores decline precipitously, illnesses that cause a rapidly progressive dementia become more likely diagnoses (see later).

FIGURE 7-1 Mini-Mental State Examination (MMSE). Points are assigned for correct answers. Scores of 20 points or less indicate dementia, delirium, schizophrenia, or affective disorders – alone or in combination. However, such low scores are not found in normal elderly people or in those with neuroses or personality disorders. MMSE scores fall in proportion to dementia-induced impairments in daily living as well as cognitive decline. For example, scores of 20 correlate with inability to keep appointments or use a telephone. Scores of 15 correlate with inability to dress or groom.

(Adapted from Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state:” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. © 1975, 1998 MiniMental LLC.)

Critics attack the MMSE. It is “too easy.” It permits mild cognitive impairment (MCI) and even early dementia to escape detection. Age, education, and language skills influence the score. The MMSE may also fail to test adequately for executive function and thereby miss cases of frontotemporal dementia. Also, because the MMSE depends so heavily on language function, it may be inadequate in measuring conditions, such as MS and toluene abuse, where the subcortical white matter receives the brunt of the damage.

Alzheimer Disease Assessment Scale (ADAS)

The ADAS consists of cognitive and noncognitive sections. Its cognitive section (ADAS-Cog) (Fig. 7-2) includes not only standard tests of language, comprehension, memory, and orientation, but also tests of visuospatial ability, such as drawing geometric figures, and physical tasks that reflect ideational praxis, such as folding a paper into an envelope. Patients obtain scores of 0–70 points in proportion to worsening performance.

FIGURE 7-2 The cognitive section of the Alzheimer Disease Assessment Scale (ADAS-Cog), the standard test for assessing pharmacologic intervention, has been designed to measure many important aspects of cognitive function that are apt to deteriorate in Alzheimer disease. The noncognitive section measures mood, attention, delusions, and motor activity, such as pacing and tremors. As dementia begins or worsens, patients’ responses change from no impairment (where the patient receives 0 points) to severe cognitive impairment (5 points). In other words, as dementia worsens, patients accumulate points. Total ADAS-Cog scores for patients with mild to moderate Alzheimer disease range from 15 to 25 and, as cognitive function declines, scores increase by 6–12 points yearly.

(From Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364. Reprinted with permission from the American Journal of Psychiatry, Copyright 1984. American Psychiatric Association.)

Compared to the MMSE, the ADAS-Cog is more sensitive, reliable, and less influenced by educational level and language skills. However, it is more complex and subjective. Test-givers, who need not be physicians, must undergo special training. The testing usually requires 45–60 minutes. Alzheimer disease researchers, especially those involved in pharmaceutical trials, routinely use the ADAS-Cog to monitor the course of Alzheimer disease and measure the effect of medication.

Montreal Cognitive Assessment (MoCA) (Fig. 7-3)

The MoCA, which has greater sensitivity than the MMSE, readily detects mild impairment. It is useful when a patient’s only symptom is memory impairment or physicians suspect cognitive impairment in individuals who score 25 points or better on the MMSE. Neurologists also administer the MoCA to patients with any neurodegenerative illness – a category that includes Alzheimer, Parkinson, and dementia with Lewy bodies diseases, and frontotemporal dementia. In Parkinson disease, the MoCA compared to the MMSE is more sensitive in detecting early cognitive impairment (see Chapter 18).

FIGURE 7-3 The Montreal Cognitive Assessment (MoCA). This assessment includes eight cognitive domains. As with the MMSE, the total score reaches 30 and values lower than 26 indicate cognitive impairment. However, some authors found that a cut-off of 23 gave a sensitivity and specificity of at least 95%.

(Copyright Z. Nasreddine MD. Reproduced with permission. The test and instruction may be accessed at www.mocast.org.)

Further Testing

If the results of a screening test yield borderline or otherwise indefinite results, a battery of neuropsychologic tests may help clarify the diagnosis. These tests, which usually require at least 3 hours, assess the major realms of cognitive function, including language (which physicians should test first to assure the validity of the entire test), memory, calculations, judgment, perception, and construction. Neuropsychologic tests are not required for a diagnosis of dementia and are not part of a standard evaluation, but they can help in several situations:

• For very intelligent, well-educated, or highly functional individuals with symptoms compatible with dementia whose screening tests fail to show a cognitive impairment.

• For individuals whose ability to execute critical occupational or personal decisions, including legal competency, must be assured.

• For assessing individuals with confounding deficits, such as intellectual development disorder, learning disabilities, minimal education, deafness, or aphasia.

• In distinguishing dementia from depression, other psychiatric disturbances, and malingering.

• In distinguishing Alzheimer disease from frontotemporal dementia.

Alzheimer Disease

The preliminary DSM-5 defines Mild and Major subtypes of Neurocognitive Disorder due to Alzheimer’s Disease. Its Major subtype definition relies on the clinical picture and accepts additional evidence to support the diagnosis. The Mild subtype allows the diagnosis if genetic, imaging, or other physiologic tests support it.

Neurologists have recently come to recognize three stages of Alzheimer disease, which are not exactly analogous to those in the DSM-5:

Dementia

Alzheimer disease eventually produces dementia, but at different rates and in uneven trajectories for different patients. Cognitive reserve potentially explains some of the differences. In this explanation, education, occupation, and leisure-time activities insulate the brain. Well-educated individuals, for example, continue to maintain an intellectual perspective and employ alternate psychologic strategies that allow them to cope with decline in certain domains.

In the dementia stage, patients may remain superficially conversant, sociable, able to perform routine tasks, and physically intact. Nevertheless, the spouse or caregiver will report that they suffer from incapacitating memory impairment and inability to cope with new situations. Patients’ language impairment typically includes a decrease in spontaneous verbal output, an inability to find words (anomia), use of incorrect words (paraphasic errors), and a tendency to circumvent forgotten words – elements of aphasia (see Chapter 8).

Several other symptoms stem from deterioration in visuospatial abilities. This impairment explains why patients lose their way in familiar surroundings. It also explains constructional apraxia, the inability either to translate an idea into use of a physical object or to integrate visual and motor functions.

Neuropsychiatric Manifestations

As the Neuropsychiatric Inventory (NPI) has shown, the majority of Alzheimer disease patients demonstrate apathy or agitation. In addition, many demonstrate dysphoria and abnormal behavior. Delusions, which emerge in about 20–40% of patients, are usually relatively simple, but often incorporate paranoid ideation.

Occurring about half as frequently as delusions, hallucinations are usually visual, but sometimes auditory or even olfactory. Whatever their form, hallucinations portend behavioral disturbances, rapidly progressive dementia, an unequivocally abnormal EEG, and a poor prognosis. However, their presence carries several important clinical caveats. An underlying toxic-metabolic disturbance, such as pneumonia, rather than progression of dementia, is often the cause of hallucinations. In another caveat, visual hallucinations early in the course of dementia, particularly if the patient has a parkinsonian gait, suggest a different illness – DLB (see later).

Disruptive behavior – wandering, verbal outbursts, physical agitation, and restlessness – occurs in almost 50% of Alzheimer disease patients and increases in frequency as cognition and function deteriorate. It prompts institutionalization and the problematic use of antipsychotics. Despite its dangerous aspects and association with deterioration, disruptive behavior does not increase the mortality rate.

Wandering constitutes a particularly troublesome, although not unique, manifestation of Alzheimer disease. It may originate in any combination of numerous disturbances, including memory impairment, visuospatial perceptual difficulties, delusions and hallucinations, akathisia (see Chapter 18), and mundane activities, such as looking for food.

Alzheimer patients also lose their normal circadian sleep–wake pattern to a greater degree than cognitively intact elderly people (see Chapter 17). Their sleep becomes fragmented throughout the day and night. The disruption of their sleep parallels the severity of their dementia.

Alzheimer patients’ motor vehicle accident rate is greater than comparably aged individuals, and it increases with the duration of their illness. Clues to unsafe driving include missing exits, under- or over-turning, inability to parallel park, and delayed braking. Accidents are more apt to occur on local streets than on the highway. (Yet, 16–24-year-old men have an even higher rate of motor vehicle accidents than Alzheimer patients!) Several states require that physicians report patients with medical impairments, presumably including Alzheimer disease, that interfere with safe driving. Another potentially dangerous activity of Alzheimer disease patients is that about 60% of them vote.

Physical Signs

Patients with Alzheimer disease characteristically have no physical impairment, except for one small but intriguing finding – anosmia (see Chapter 4). Even before the onset of dementia, Alzheimer disease patients require high concentrations of a volatile substance to detect and identify it. Neurologists also find anosmia in patients with Parkinson disease and dementia with Lewy bodies disease, but not in those with VCI or depression. Patients with TBI with or without dementia also have anosmia because they have had shearing of the olfactory nerve fibers at the cribriform plate (see Chapter 22).

Until Alzheimer disease advances to unequivocal dementia, patients usually remain ambulatory and able to feed themselves. The common sight of an Alzheimer disease patient walking steadily but aimlessly through a neighborhood characterizes the disparity between intellectual and motor deficits. When patients reach advanced stages of the illness, physicians can elicit frontal release signs (Fig. 7-4), increased jaw jerk reflex (see Fig. 4-13), and Babinski signs. Unlike patients with VCI, those with Alzheimer disease do not have lateralized signs. They eventually become mute, fail to respond to verbal requests, remain confined to bed, and assume a decorticate (fetal) posture. They frequently slip into a persistent vegetative state (see Chapter 11).

FIGURE 7-4 The snout and grasp reflexes – frontal lobe release reflexes – are frequently present in individuals with severe dementia. A, Physicians elicit the snout reflex by tapping the patient’s upper lip with a finger or a percussion hammer. This reflex causes the patient’s lips to purse and lower facial muscles to pout. B, Physicians elicit the grasp reflex by stroking the patient’s palm crosswise or the fingers lengthwise. The reflex causes the patient to grasp the physicians’ fingers and fail to release despite requests.

Pathology

Compared to age-matched controls, brains of Alzheimer disease patients are even more atrophic. The cerebral atrophy in Alzheimer disease, although generalized, primarily affects the cortical association areas, such as the parietal–temporal junction, and the limbic system. It particularly strikes the hippocampus and prominently involves the locus ceruleus and olfactory nerve. The atrophy spares the cerebral regions governing motor, sensory, and visual functions, thus explaining the absence of paresis, sensory loss, and blindness in Alzheimer disease.

Cerebral atrophy naturally leads to compensatory dilation of the lateral and third ventricles. Of these, the temporal horns of the lateral ventricles expand the most. Nevertheless, in Alzheimer disease and most other illnesses that cause dementia, the anterior horns of the lateral ventricles maintain their concave (bowed inward) shape because of the indentation on their lateral border by the head of the preserved caudate nucleus (see Figs 20-2 and 20-18). The exception is Huntington disease, where atrophy of the head of the caudate nucleus permits the ventricle to expand laterally and assume a convex (bowed outward) shape (see Fig. 20-5).

On a histologic level, “plaques and tangles” remain the most conspicuous feature of Alzheimer disease. Although also present in normal aging and several other illnesses, in Alzheimer disease the plaques and tangles are more plentiful. Moreover, they do not distribute themselves randomly, but congregate, like the atrophy, in the cortex association areas, limbic system, and hippocampus.

The plaques, technically neuritic plaques, which are a form of senile plaques, consist of an amyloid core surrounded by abnormal axons and dendrites (neurites) that looks like a burned-out campfire. Up to 50% of the amyloid core contains an insoluble, 42-amino-acid peptide, amyloid beta-peptide (Aβ) (see later). Accumulation of Aβ is necessary, but alone is insufficient for the development of Alzheimer disease.

The tangles, neurofibrillary tangles, are also necessary but insufficient. They follow a somewhat different geographic distribution than plaques. They cluster within hippocampus neurons. The tangles appear as paired, periodic helical filaments within neurons and disrupt the normal cytoskeletal architecture. They consist mostly of hyperphosphorylated forms of tau protein, which is a microtubule binding protein that undergoes conformational changes. In other words, an abnormal intraneuronal protein – tau – aggregates in Alzheimer disease and contributes to the death of critical neurons. Although the concentration of plaques correlates with dementia, the correlation between neurofibrillary tangles and dementia is stronger. On the other hand, neurofibrillary tangles occur in other conditions, including progressive supranuclear palsy (PSP), frontotemporal dementia, and TBI.

Another histologic feature of Alzheimer disease is the loss of neurons in the frontal and temporal lobes. Neuron loss in the nucleus basalis of Meynert (also known as the substantia innominata), which is a group of large neurons located near the septal region beneath the globus pallidus (see Fig. 21-4), constitutes the most distinctive change. Their loss depletes cerebral acetylcholine (ACh: see later). Of all these histologic features, loss of neuron synapses correlates most closely with dementia.

Histologic examination of the majority of Alzheimer disease brains also reveals coexistent vascular disease. The reverse is also true: The brains of many VCI patients also show the histologic signs of Alzheimer disease. In other words, many cases of dementia have combinations of both pathologies.

Amyloid Deposits

Returning to the formation of Aβ, enzymes encoded on chromosome 21 cleave amyloid precursor protein (APP) to precipitate Aβ in the plaques (Fig. 7-5). Aβ differs from amyloid deposited in viscera as part of various systemic illnesses, such as multiple myeloma and amyloidosis. In Alzheimer disease, Aβ accumulates early and permanently in the cerebral cortex and vital subcortical regions.

FIGURE 7-5 The amyloid precursor protein (APP) consists of 770 amino acids. Three secretase enzymes (α-, β-, and γ-) cleave it into polypeptide fragments. In one pathway, α-secretase cleaves APP to form the polypeptide αAPP. Then γ-secretase cleaves αAPP into soluble, nontoxic polypeptides. In the other pathway, β-secretase cleaves APP into a different polypeptide, βAPP. Then γ-secretase cleaves βAPP to form the insoluble, toxic, 42-amino-acid polypeptide, Aβ.

Several lines of evidence have given rise to the amyloid cascade hypothesis or simply the amyloid hypothesis as the critical mechanism in Alzheimer disease. This hypothesis proposes that the enzymatic degradation of APP results in accumulation of Aβ, which causes inflammatory and oxidative cerebral damage. Evidence for this theory includes several powerful observations:

• All known genetic mutations associated with Alzheimer disease increase Aβ production (chromosomes 1, 14, 21) or Aβ aggregation (chromosome 19).

• The most powerful established genetic risk factor, which involves apolipoprotein-E (Apo-E), promotes Aβ deposition.

• Aβ is toxic in vitro probably because it binds to cerebral ACh receptors and poisons cerebral mitochondria.

• Accumulation of Aβ is a requirement for the development of Alzheimer disease.

• At least in some nonhuman studies, antibodies to Aβ reduce clinical and pathologic aspects of Alzheimer disease.

Biochemical Abnormalities

Under normal circumstances, neurons in the basal nucleus of Meynert synthesize ACh. Using the enzyme choline acetyltransferase (ChAT), these neurons convert acetylcoenzyme-A (acetyl-CoA) and choline to ACh:

Normally, neurons emanating from the basal nucleus of Meynert project upward to almost the entire cerebral cortex and the limbic system to provide cholinergic (i.e., ACh) innervation. A loss of neurons in the basal nucleus of Meynert characterizes Alzheimer disease. It leads to a marked reduction in ChAT activity, then cerebral cortex ACh concentrations, and finally cerebral cholinergic activity. As with the distribution of the macroscopic and microscopic changes in Alzheimer disease, ACh activity is particularly reduced in the cortical association areas and limbic system.

Alzheimer disease is also associated with reduced concentrations of other established or putative neurotransmitters: somatostatin, substance P, norepinephrine, vasopressin, and several other polypeptides. However, compared to the ACh loss, their concentrations are not decreased profoundly or consistently, and do not correlate with dementia.

The cholinergic hypothesis, drawn from these biochemical observations, postulates that reduced cholinergic activity causes the dementia of Alzheimer disease. In addition to the histologic and biochemical data, supporting evidence includes the finding that, even in normal individuals, blocking cerebral ACh receptors causes profound memory impairments. For example, an injection of scopolamine, which has central anticholinergic activity, induces a several-minute episode of Alzheimer-like cognitive impairment that can be reversed with physostigmine (Fig. 7-6). The cholinergic hypothesis led to the introduction of donepezil (Aricept) and other cholinesterase inhibitors in an attempt at preserving ACh activity by inactivating its metabolic enzyme, cholinesterase (see Fig. 7-6 and later).

FIGURE 7-6 Top, The enzyme choline acetyltransferase (ChAT) catalyzes the reaction of choline and acetyl-coenzyme A (ACoA) to form acetylcholine (ACh) in neurons of the central (CNS), peripheral (PNS), and autonomic nervous system. When released from its presynaptic neurons, ACh interacts with postsynaptic ACh receptors. Middle, However, various substances block ACh from interacting with its receptors. For example, scopolamine, which readily crosses the blood–brain barrier, blocks ACh–receptor interaction in the CNS. Likewise, atropine blocks ACh receptors, but predominantly those in the autonomic nervous system. (Unless its concentration is great, atropine does not cross the blood–brain barrier.) Bottom, Cholinesterase metabolizes ACh. Thus, enzyme degradation rather than reuptake terminates ACh activity. (In contrast, reuptake terminates most dopamine and serotonin activity.) Anticholinesterases or cholinesterase inhibitors block cholinesterase and preserve ACh concentrations. The most widely known application of this strategy is using donepezil (Aricept) and other cholinesterase inhibitors to preserve ACh activity in Alzheimer disease. Similarly, physostigmine, a powerful anticholinesterase medicine that can cross the blood–brain barrier, purportedly briefly corrects ACh deficits in tardive dyskinesia as well as Alzheimer disease (see Chapter 18). Physostigmine might also counteract excessive anticholinergic activity in tricyclic antidepressant overdose or reverse the effects of scopolamine or atropine. Using cholinesterase inhibitors is also applicable to PNS disorders. For example, edrophonium (Tensilon) and pyridostigmine (Mestinon) are anticholinesterases that restore neuromuscular junction ACh activity in myasthenia gravis (see Fig. 6-2). In the opposite situation, insecticides contain powerful anticholinesterases that create excessive ACh activity at neuromuscular junctions, which paralyzes insects by overstimulating muscle contractions.

Although the ChAT deficiency in Alzheimer disease is striking, it is not unique. Pronounced, widespread ChAT deficiencies are also present in the cortex of brains in trisomy 21, Parkinson disease, and DLB, but not in those of Huntington disease.