Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function

Structural alterations in arousal are divided according to the original location of the pathologic condition: supratentorial (above the tentorium cerebelli—membrane), infratentorial (subtentorial, below the tentorium cerebelli—membrane) (see Figs. 15.17 and 17.17), extracerebral (outside the brain tissue), and intracerebral (within the brain tissue). Causes include infection, vascular alterations, neoplasms, traumatic injury, congenital alterations, degenerative changes, polygenic traits, and metabolic disorders.

Supratentorial disorders (above the tentorium cerebelli) produce changes in arousal by either diffuse or localized dysfunction. Diffuse dysfunction may be caused by disease processes affecting the cerebral cortex or the underlying subcortical white matter (e.g., encephalitis). Disorders outside the brain but within the cranial vault (extracerebral) also can produce diffuse dysfunction, including neoplasms, closed-head trauma with subsequent bleeding (i.e., subdural hematoma or subarachnoid hemorrhage), and subdural empyema (accumulation of pus). Disorders within the brain substance (intracerebral)—bleeding, infarcts, emboli, and tumors—function primarily as masses. Such localized destructive processes directly impair function of the thalamic or hypothalamic activating systems or secondarily compress these structures in a process of expansion or herniation.

Infratentorial disorders (below the tentorium cerebelli) produce a decline in arousal by (1) direct destruction or compression of the RAS and its pathways (e.g., accumulations of blood or pus, neoplasms, and demyelinating disorders), or (2) the brainstem (midbrain, pons, and medulla) may be destroyed either by direct invasion or by indirect impairment of its blood supply. The most common cause of direct destruction is cerebrovascular disease. Demyelinating diseases, neoplasms, granulomas, abscesses, and head injury also may cause brainstem destruction by tissue compression. This compression may occur because of (1) direct pressure on the pons and midbrain, producing ischemia and edema of the neurons of the RAS; (2) upward herniation of the cerebellum through the tentorial notch, thus compressing the upper midbrain and diencephalon; or (3) downward herniation of the cerebellum through the foramen magnum, compressing and displacing the medulla oblongata.

Metabolic alterations in arousal produce a decline in arousal by alterations in delivery of energy substrates as occurs with hypoxia, electrolyte disturbances, hypoglycemia, or hyperglycemia. Examples of systemic diseases that eventually produce nervous system disorders include liver or renal failure that cause alterations in neuronal excitability because of failure to metabolize or eliminate drugs and toxins. Hypothyroidism and adrenal insufficiency may be associated with alterations in arousal (e.g., myxedema coma and adrenal crisis) and are medical emergencies (see Chapter 22).

Psychogenic alterations in arousal (unresponsiveness), although uncommon, may signal general psychiatric disorders (see Chapter 19). Despite apparent unconsciousness, the person is physiologically awake, and the neurologic examination reflects normal responses.

Five patterns of neurologic function are critical to the evaluation process: (1) level of consciousness, (2) pattern of breathing, (3) pupillary reaction, (4) oculomotor responses, and (5) motor responses. Patterns of clinical manifestations help determine the extent of brain dysfunction and serve as indices for identifying increasing or decreasing central nervous system (CNS) function. Distinctions are made between metabolic and structurally induced manifestations (Table 17.1). The types of manifestations suggest the mechanisms of the altered arousal state (Table 17.2).

Level of consciousness is the most critical clinical index of nervous system function, with changes indicating either improvement or deterioration of the individual's condition. A person who is alert and oriented to self, others, place, and time is functioning at the highest level of consciousness, which implies full use of all the person's cognitive capacities. From this normal alert state, levels of consciousness diminish in stages from confusion and disorientation (can occur simultaneously) to coma, each of which is clinically defined (Table 17.3). Guidelines are available to assist with the evaluation of prolonged disorders of consciousness.²

Patterns of breathing help evaluate the level of brain dysfunction and coma. Rate, rhythm, and pattern should be evaluated. Breathing patterns can be categorized as hemispheric or brainstem (Table 17.4 and Fig. 17.1).

An illustration depicts the abnormal respiratory patterns associated with pathologic lesions at various levels of the brain. Tracings by chest-abdomen pneumograph, inspiration reads up. A; Cheyne-stokes respiration. B; Central neurogenic hyperventilation. C; Apneusis. D; Cluster breathing. E; Ataxic breathing.

With normal breathing, a neural center in the forebrain (cerebrum) produces a rhythmic breathing pattern. When consciousness decreases, lower brainstem centers regulate the breathing pattern by responding only to changes in PaCO₂ levels. This pattern is called posthyperventilation apnea (PHVA).

Cheyne-Stokes respiration is an abnormal rhythm of ventilation (periodic breathing) with alternating periods of hyperventilation and apnea (crescendo-decrescendo pattern). In the damaged brain, higher levels of PaCO₂ are required to stimulate ventilation, and increases in PaCO₂ lead to tachypnea. The PaCO₂ level then decreases to below normal and breathing stops (apnea) until the carbon dioxide reaccumulates and again stimulates tachypnea (see Fig. 17.1). In cases of opiate or sedative drug overdose, the respiratory center is depressed, and the rate of breathing gradually decreases until respiratory failure occurs.

Central neurogenic hyperventilation is a respiratory pattern of sustained hyperventilation caused by a lesion that stimulates the respiratory center in the central pons. Apneustic respirations have prolonged inspiratory phase and a short expiratory phase caused by injury to the pons or upper medulla. Cluster (Biots) respirations are characterized by periods or clusters of rapid respirations of near equal depth resulting from trauma or compression to the medulla near the pontine junction or from chronic opioid abuse. Ataxic respirations are variable respirations with irregular prolonged periods of apnea associated with damage to the medulla (see Fig. 17.1).

Pupillary changes indicate the presence and level of brainstem dysfunction because brainstem areas that control arousal are adjacent to areas that control the pupils (Fig. 17.2). For example, severe ischemia and hypoxia usually produce dilated, fixed pupils. Hypothermia may cause fixed pupils. Some drugs affect pupils and must be considered in evaluating individuals in comatose states. Large doses of atropine and scopolamine (drugs that block parasympathetic stimulation) fully dilate and fix pupils. Doses of sedatives (e.g., glutethimide) in sufficient amounts to produce coma cause the pupils to become mid-position or moderately dilated, unequal, and commonly fixed to light. Opiates (which stimulate the parasympathetic nervous system) cause pinpoint pupils.

A series of illustrations shows the appearance of pupils at different levels of consciousness with reference to the brain stem. The six appearances are as follows. • Metabolic imbalance or deep bilateral hemisphere lesion such as hydrocephalus or thalamic hemorrhage. The pupils are small, receptive, and regular. • Dysfunction of tectum (roof) of the midbrain; large, fixed hippus. • Pontine dysfunction; pinpoint. • Midbrain dysfunctional; midposition and fixed. • Dysfunction of third cranial nerve sluggish, dilated, and fixed. • Diencephalic dysfunction; small and reactive.

Oculomotor responses are resting, spontaneous, and reflexive eye movements. They change at various levels of brain dysfunction in comatose individuals (Table 17.5). Persons with metabolically induced coma, except in cases of barbiturate-hypnotic and phenytoin (Dilantin) poisoning, generally retain ocular reflexes, even when other signs of brainstem damage, such as central neurogenic hyperventilation, are present.

The presence of brisk oculocephalic reflexes and roving eye movements, as well as the failure to elicit nystagmus with instillation of cold or warm water into the external ear canal, indicates a decrease in consciousness (loss of cortical influence) but an intact brainstem (Figs. 17.3 and 17.4).

Three sets of illustrations demonstrate the test for oculocephalic reflect response. Each set shows a pair of hands positioned on the sides of a person’s face with the thumbs pulling upward on the eyebrows. In each set, the illustration on the left shows the head turned to the right, the illustration in the middle shows the head facing forward, and the illustration on the right shows the head turned toward the left. Top panel, A. The positions of the pupils are as follows. On the left, the pupils look to the left together. In the middle, the pupils look straight ahead together. On the right, the pupils look to the right together. Middle panel, B. The positions of the pupils are as follows. On the left, the pupils are converged toward the nose. In the middle, the pupils look straight ahead together. On the right, the right pupil looks to the right, while the pupil on the left look straight ahead. Bottom panel, C. The positions of the pupils are as follows. On the left, in the middle, and on the right, the pupils look absently straight ahead.

Three illustrations, A, B, and C, demonstrate the test of oculovestibular reflex. Each illustration shows a person's head in supine position, a hand pressing down on the head, and a syringe pressed into the right ear. Left panel, A. The pupils look together on the right, toward the syringe. Middle panel, B. The right pupil looks straight ahead, while the left pupil looks to the right. Right panel, C. Both pupils look straight ahead together.

Destructive or compressive injury to the brainstem causes specific abnormalities of the oculocephalic and oculovestibular reflexes. For example, a skewed deviation, in which one eye diverges downward and the other looks upward, indicates brainstem dysfunction. Destructive or compressive disease processes that involve an oculomotor nucleus or nerve cause the involved eye to deviate outward, producing a resting dysconjugate lateral position of the eyes (each eye diverges laterally). Unilateral abducens paralysis (paralysis of cranial nerve VI) results in an upward deviation of the ipsilateral eye. With bilateral abducens paralysis, the eyes come together (converge). Reflexive eye movements may be suppressed by drugs, most commonly phenytoin, tricyclics, and barbiturates. Occasionally alcohol, phenothiazines, and diazepam may alter reflex eye movements.

Motor signs indicating loss of cortical inhibition are commonly associated with decreased consciousness and include primitive reflexes and rigidity (paratonia). Primitive reflexes include grasping, reflex sucking (tapping on lips stimulates sucking), snout reflex (tapping of closed lips at midlines causes pursing of lips), and palmomental reflex (stroking palm causes twitch of chin muscle), all of which are normal in the newborn but disappear in infancy (Fig. 17.5). Abnormal flexor and extensor responses in the upper and lower extremities are defined in Table 17.6 and illustrated in Fig. 17.6.

Four pairs of illustrations, A, B, C, and D, demonstrate pathologic reflexes. Top-left panel, A. The illustration on the left, 1, shows two hands. The index and the middle fingers of one hand are placed on the open palm of the other hand. The illustration on the right, 2, shows the palm closed around the two fingers on the other hand. Top-right panel, B. The illustration on the left, 1, shows an index finger pressing above the upper lip. The illustration on the right, 2, shows the lips turned toward the finger, sucking. Bottom-left panel, C. The illustration on the left, 1, shows a hand holding a key and stroking near the thumb of an open palm. The illustration on the right, 2, shows the twitching chin of a person. Bottom-right panel, D. The illustration shows the right lateral profile of the lower jaw of a person. The lips are pursed around a pencil-like object.

Three illustrations of a person in supine position demonstrate the decorticate and decerebrate responses. Top panel, A. The illustration shows the person’s arms flexed with the hands together on the chest. The feet are pointed forward. Middle panel, B. The illustration shows the person’s arms on their sides, the hands flexed outward, and the feet pointing forward. Bottom panel, C. The illustration shows one arm of the person on the side, the other arm flexed with the wrist on the chest, and the feet pointing forward.

Vomiting, yawning, and hiccups are complex reflex-like motor responses that are integrated by neural mechanisms in the lower brainstem. These responses may be produced by compression or diseases involving tissues of the medulla oblongata (e.g., infection, neoplasm, infarct, or other more benign stimuli to the vagal nerve). Most CNS disorders produce nausea and vomiting. Vomiting without nausea indicates direct involvement of the central neural mechanism (or pyloric obstruction). Vomiting often accompanies CNS injuries that (1) involve the vestibular nuclei or its immediate projections, particularly when double vision (diplopia) also is present; (2) impinge directly on the floor of the fourth ventricle; or (3) produce brainstem compression secondary to increased intracranial pressure (IICP).

Complications of alterations in arousal fall into two categories: extent of disability (morbidity) and mortality. The outcomes depend on the cause and extent of brain damage and the duration of coma. Some individuals may recover consciousness and an original level of function, some may have permanent disability, and some may never regain consciousness and experience neurologic death. Two forms of neurologic death—brain death and cerebral death—result from severe pathologic conditions and are associated with irreversible coma. Other possible outcomes are a vegetative state (VS), a minimally conscious state (MCS), or locked-in syndrome. The extent of disability has four subcategories: recovery of consciousness, residual cognitive function, psychologic function, and vocational function. Technological advances in imaging, including functional magnetic resonance imaging (MRI) and positron emission tomography (PET), have provided new opportunities for assessing cognition and detecting consciousness for individuals in a prolonged coma.3

Brain death (total brain death) occurs when brain damage is so extensive that it can never recover (irreversible) and cannot maintain the body's internal homeostasis. State laws define brain death as irreversible cessation of function of the entire brain, including the brainstem and cerebellum. On postmortem examination, the brain is autolyzing (self-digesting) or already autolyzed. Brain death has occurred when there is no evidence of brain function for an extended period.⁴ The abnormality of brain function must result from structural or known metabolic disease and must not be caused by a depressant drug, alcohol poisoning, or hypothermia. An isoelectric, or flat, electroencephalogram (EEG) (electrocerebral silence) for 6 to 12 hours in a person who is not hypothermic and has not ingested depressant drugs indicates brain death. The clinical criteria used to determine brain death are noted in Box 17.1. A task force for determination of brain death in children recommended the same criteria as for adults but with a longer observation period.^5,6

Cerebral death or irreversible coma is death of the cerebral hemispheres exclusive of the brainstem and cerebellum. Brain damage is permanent, and the individual is unable to ever respond behaviorally in any significant way to the environment. The brainstem may continue to maintain internal homeostasis (i.e., body temperature, cardiovascular functions, respirations, and metabolic functions). The survivor of cerebral death may remain in a coma or emerge into a persistent VS or a MCS. In coma, the eyes are usually closed with no eye opening. The person does not follow commands, speak, or have voluntary movement (Table 17.7).

A persistent VS, or unresponsive wakefulness syndrome, is complete unawareness of the self or surrounding environment and complete loss of cognitive function. The individual does not speak any comprehensible words or follow commands.⁷ Sleep-wake cycles are present, eyes open spontaneously, and blood pressure and breathing are maintained without support. Brainstem reflexes (pupillary, oculocephalic, chewing, swallowing) are intact but cerebral function is lost. There may be random hand, extremity, or head movements. There is bowel and bladder incontinence. Recovery is unlikely if the state persists for 12 months.

In a MCS, individuals may follow simple commands; manipulate objects; gesture or give yes/no responses; have intelligible speech; and have movements, such as blinking or smiling, that occur in a meaningful relationship to the eliciting stimulus and are not attributable to reflexive activity.⁸

With locked-in syndrome (ventral pontine syndrome), there is complete paralysis of voluntary muscles apart from vertical gaze and upper eyelid movement. Content of thought and level of arousal are intact, but the efferent pathways are disrupted (injury at the base of the pons with the reticular formation intact, often caused by basilar artery occlusion).⁹ The individual cannot communicate either through speech or through body movement but is fully conscious with intact cognitive function. The upper cranial nerves (I to IV) often are preserved so that the person possesses vertical eye movement and blinking as a means of communication.

Akinetic mutism (AM) is a rare neurobehavioral state characterized by a severe loss of motivation to move or inability to voluntarily initiate goal-directed motor responses (akinetic), including speech (mutism), gestures, and facial expression. Generally, these individuals are alert, orient to external stimuli, and can follow the examiner with their eyes but do not initiate other voluntary activity or movement. This is not attributable to decreased wakefulness, motor weakness, or paralysis but rather a lack of “willfulness” to do so. The neuropathology is different when compared with the VS and locked-in syndrome and involves damage to frontal-subcortical structures involved in the translation of a motivational stimulus to a behavioral response. It may occur with cerebrovascular disease, obstructive hydrocephalus, or be associated with tumors. Combined deficits of vigilance, detection, and working memory accompanied by other deficits of the cognitive systems are common.¹⁰

Very generally, the primary pathophysiologic mechanisms that operate in disorders of awareness are (1) direct destruction because of ischemia and hypoxia or indirect destruction because of compression and (2) the effects of toxins, inflammation, and chemicals, or metabolic derangement, including processes related to dementia. The pathophysiologic processes are summarized in Fig. 17.11.

Three flowcharts show cognitive network deficits. Top panel, midbrain tectum (coordination of eye and body movement) (selected attention -move component). The pathways in the flowchart are as follows. 1. Toxin or chemical. Leads to 8. 2. Direct destruction. Leads to 6. 3. Edema. Leads to 7. 4. Herniation. Leads to 7. 5. Metabolic derangement. Leads to 8. 6. Ischemia. Leads to 8. 7. Compression. 8. Disorder in move component. Leads to 10. 9. Failure of inhibitory component of spatial orientation. Leads to 11. 10. Loss of voluntary vertical eye movement. Leads to 12. 11. Orient when should not. 12. Decreased visual search and scanning. Leads to 13. 13. Slowness to orient to events. Middle panel, thalamus (selected attention-engage component). The pathways in the flowchart are as follows. 1. Toxin or chemical. Leads to 8. 2. Direct destruction. Leads to 6. 3. Edema. Leads to 7. 4. Herniation. Leads to 7. 5. Metabolic derangement. Leads to 8. 6. Ischemia. Leads to 8. 7. Compression. 8. Disorder in engage component. Leads to 9 and 10. 9. Failure to spotlight or amplify the currently attended to information. 10. Failure to filter out irrelevant distractions. Bottom panel, hippocampal and related temporal areas (declarative domain-independent memory). The pathways in the flowchart are as follows. 1. Toxin or chemical. Leads to 10. 2. Bacterial invasion. Leads to 5. 3. Viral infiltration. Leads to 5. 4. Nutritional deficiency. Leads to 8. 5. irect destruction. Leads to 9. 6. Compression. Leads to 9. 7. Withdrawal state. Leads to 10. 8. Metabolic derangement. Leads to 10. 9. Ischemia. Leads to 10. 10. Decreased memory transfer (anterograde amnesia). Leads to 11. 11. Impaired recent memory (learning). Two flowcharts show cognitive network deficits. Top panel, cortical association areas (selective attention, disengage components, declarative domain-specific memory). The pathways in the flowchart are as follows. 1. Direct destruction. Leads to 5. 2. Compression. Leads to 5. 3. Metabolic derangement. Leads to 7. 4. Drug effect. Leads to 3. 5. Ischemia. Leads to 6 and 7. 6. Decreased parietal lobe function. Leads to 8. 7. Decreased cortical association area function. Leads to 9. 8. Disorder disengagement mechanism. Leads to 10 and 11. 9. Impaired remote memory formation and retrieval (retrograde amnesia). 10. Delay in reaction time. 11. Sensory inattentiveness. Bottom panel, frontal areas (vigilance, detection, working memory). The pathways in the flowchart are as follows. 1. Direct destruction. Leads to 7. 2. Compression. Leads to 7. 3. Withdrawal state. Leads to 8. 4. Metabolic derangement. Leads to 8, 11, and 12. 5. Sedative drugs. Leads to 4. 6. Other drug effects. Leads to 4. 7. Ischemia. Leads to 10, 11, and 12. 8. Disinhibition of prefrontal areas. Leads to 10. 9. Preestablished preferences. Leads to 13. 10. Decreased vigilance. Leads to 15. 11. Decreased detection. Leads to 17 and 18. 12. Decreased working memory. Leads to 21, 22, and 23. 13. Impaired cue utilization. Leads to 14. 14. Self-monitoring deficit. Leads to 24. 15. Decreased search and scanning. Leads to 16. 16. Accidents and safety issues. 17. Motivation deficit. Lead to 18 and 19. 18. Lack of initiative. 19. Apathy. 20. Lack of emotional tone. 21. Goal selection or goal development deficit. Leads to 25. 22. Planning deficit. Leads to 26 and 30. 23. Programming deficit. Leads to 27, 28, and 29. 24. Overestimation of self-performance. 25. Indecisiveness. 26. Failure to act in accord with stated goal. Leads to 31. 27. Inability to initiate activity. 28. Inability to maintain activity. Leads to 32, 33, and 34. 29. Inability to discontinue activity. Leads to 34. 30. Inability to use feedback. Leads to 35 and 36. 31. Impulsiveness. 32. Sequencing problems. 33. Discontinuity of motor movement. 34. Motor preservation. 35. Loose-stay errors. 36. Inability to shift response.

Clinical manifestations of selective attention deficits, memory deficits, and executive attention function deficits are presented in Table 17.8.

Agnosia is produced by damage to the primary sensory area or in the interpretive areas of the cerebral cortex (parietal, temporo-occipital areas—Broca area and Wernicke area) (see Fig. 17.9). The symptoms of agnosia vary according to the location of the damage. The types of agnosia and the associated areas most involved with each are presented in Table 17.9. Although agnosia is commonly associated with cerebrovascular accidents, it may arise from any pathologic process that injures these specific areas of the brain (e.g., encephalitis, tumors, PD, trauma, or toxins).²³

Aphasia is typically an acquired impairment of comprehension or production of language with impaired written or verbal communication. The terms aphasia and dysphasia are often used interchangeably; the term aphasia is used here.24 Aphasia results from dysfunction in the left cerebral hemisphere (e.g., Broca area [inferior frontal gyrus] and Wernicke area [superior temporal gyrus]) and the subcortical and cortical connecting networks (see Fig. 15.8B and C). Aphasias are commonly associated with a cerebrovascular accident involving the middle cerebral artery or one of its many branches (see Fig. 15.21). Language disorders, however, may arise from a variety of injuries and diseases, including vascular, neoplastic, traumatic, degenerative, metabolic, or infectious causes. Most language disorders result from acute processes or a chronic residual deficit of the acute process.

Aphasias have been classified anatomically (e.g., Wernicke or Broca area aphasias) or functionally as disorders of fluency (quality and content of speech). Aphasia associated with the frontal lobe, also known as Broca or motor aphasia, involves loss of ability to produce spoken or written language with slow or difficult speech. The speech that is produced is dysfluent and agrammatic. Verbal comprehension is usually present. Aphasia is differentiated from dysarthria, in which words cannot be articulated clearly because of cranial nerve damage or muscle impairment. Aphasia that is known as Wernicke or sensory involves an inability to understand written or spoken language. Speech is fluent, flowing at a normal rate, but words and phrases have no meaning (fluent dysphasia). Language deficits can be comprehensive; motor language deficits can be accompanied by deficits in comprehension, and comprehension deficits can be accompanied by motor deficits in language. For this reason, it can be misleading to classify aphasia as being expressive or receptive.²⁵

Anomic aphasia is a sensory aphasia distinguished by difficulty finding words and naming a person or object. It is the most common symptom of cerebrovascular-related aphasia. Circumlocution, or describing an object as a way of trying to name something, is common in anomic aphasia. Auditory comprehension is present in conductive aphasia, but there is impaired verbatim repetition. Naming also can be impaired. The person recognizes the errors and tries to correct them. Speech is fluent, but words and sounds may be transposed. Damage is typically in the left hemisphere to networks that connect Broca and Wernicke areas. Anomic aphasias can also result from AD and other neurodegenerative diseases. Transcortical aphasias are rare and can be motor, sensory, or mixed. They involve areas of the brain that connect to the language centers. Anomic aphasia resulting from right hemisphere damage is rare as well.

Global aphasia is the most severe aphasia and involves both motor and sensory aphasia. The individual is non-fluent or mute; cannot read or write; and has impaired comprehension, naming, reading, and writing. Global aphasia is usually associated with a cerebrovascular accident involving the middle cerebral artery. Table 17.10 compares types of aphasia, and Table 17.11 illustrates some of the language disturbances. Pure aphasias are rare and are often mixed, making diagnosis difficult. Most types of aphasia improve with speech rehabilitation; however, if the cause is progressive disease (e.g., AD), improvement is not expected. Maintenance and quality of life are typically the treatment goals for progressive disease.

Delirium (also known as acute confusional states or acute organic brain syndromes) are disorders of awareness, may be transient (acute) or persistent (chronic), and have either a sudden or a gradual onset. Delirium can be considered as a type of ACS, but for this discussion, ACSs, acute organic brain syndrome, and delirium are synonymous. Hospitalized older individuals are at greatest risk for delirium.26,27

Dementia is an acquired deterioration and a progressive failure of many cerebral functions that includes impairment of intellectual processes with decreasing abilities in the areas of orientation, memory, language, judgment, and decision making. Because of declining intellectual ability, the individual may exhibit alterations in behavior, for example, agitation, wandering, and aggression.38

Dementias can be classified according to etiologic factors (e.g., genetics, trauma, tumors, vascular disorders, infections) and to associated clinical and laboratory signs. Dementing processes also have been grouped as cortical, subcortical, or both. Box 17.2 lists the potentially reversible and irreversible causes of dementia. AD is the most common cause followed by vascular dementia, then dementia with Lewy bodies (i.e., Parkinsonian dementia [see section on PD]), and FTD. Parkinsonian and Lewy body (intracellular inclusions with high concentrations and abnormal folding of alpha-synuclein and other proteins) dementia can be difficult to diagnose, and AD and vascular disease can appear concurrently. When different types of dementia occur concurrently, it is classified as a mixed dementia.³⁹ In people younger than 60 years, FTD rivals AD in terms of frequency.⁴⁰

Alzheimer disease

AD also known as Alzheimer type dementia (ATD) is the leading cause of severe cognitive and behavioral dysfunction in older adults. An estimated 6.2 million Americans have AD, and two-thirds of these individuals are women.44 However, the estimated number of Americans with dementia is thought to be much higher. Individuals with MCI are at a higher risk of developing AD. With better diagnostic tools, such as imaging and biomarkers, individuals with MCI related to AD will be included in the prevalence numbers. The greatest risk factors associated with AD are age and family history. Modifiable risk factors for dementia have been discussed previously (see previous section on Dementia). Fig. 17.12 summarizes the risk factors and pathogenesis of AD.

Two flowcharts show the proposed factors and pathogenesis of Alzheimer’s disease. The flowchart on the left shows data for early onset, 10 percent (familial A D). 1. Risk factors: Genes, presenilin 1, presenilin 2, A P P, A p o E 4. 2. Risk factors: Altered processing of A P P. 3. Risk factors: Alterations in intracellular calcium signaling. 4. Pathogenesis: Altered processing and over-production of beta-amyloid. 5. Pathogenesis: Extracellular beta-amyloid plaques. The flowchart on the right shows data for late onset, 90 percent (sporadic A D). 1. Risk factors: age greater than 65. A p E gene; menopause-less estrogen; hypertension, hyperlipidemia, atherosclerosis; obesity; insulin resistance; traumatic brain injury; sleep disturbance; high fat diet; infection; alterations in gut-brain microbial axis. 2. Pathogenesis: blood brain barrier dysfunction; dysfunctional mitochondria; activated microglia; oxidative stress; neuroinflammation. 3. Pathogenesis: altered breakdown and clearance of beta-amyloid and formation of extracellular beta amyloid plaques. 4. Hyperphosphorylation and tau protein. 5. Intracellular neurofibrillary tangles. Both types of onsets of the disease result in the following manifestations. • Loss of synaptic plasticity and neural transmission. • Cholinergic dysfunction. • Loss of neuronal repair and remodeling. • Neurodegeneration. • Dementia. • Death.