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Cognitive Impairment Access to a reliable informant familiar with the patient’s con- Increasing evidence also suggests that chronic vitamin D dition is critical in the evaluation of the cognitive disorder. The deficiency increases the odds of developing dementia. signs and symptoms of a cognitive disorder also may have an Therefore, measuring serum 25-hydroxyvitamin D levels can anatomic correlate that can be used to help guide the diagnosis be considered. When patient age, disease progression, or other and treatment. For example, a progressive loss of language associated symptoms raise the possibility of a more uncom- function localizes to a different anatomic location than does a mon type of dementia, additional diagnostic tests and early primary memory problem, which may be helpful in determin- referral to a specialist should be considered (Figure 16). ing the underlying cause of the impaired function. The age of Several more specialized testing modalities are available. the patient is another important consideration; for example, These tests should be reserved for patients with an uncertain both atypical presentations of typical dementia syndromes diagnosis (for example, to distinguish dementia from pseud- and nonneurodegenerative causes are more common in odementia), for an atypical progression of a previously estab- younger patients. lished diagnosis (such as an excessively slow course of For a slowly progressive dementia syndrome in an older Alzheimer disease), and for discriminating between two types patient, the American Academy of Neurology recommends of dementia with overlapping features (such as the detection that a minimum evaluation include the following elements: of Alzheimer disease-specific biomarkers). These tests, if required, are typically ordered by a dementia specialist. ¢ General neurologic examination, including a cognitive These specialized diagnostic tests fall into two categories: screening evaluation 1. Disease-specific tests: measurement of cerebrospinal e Evaluation for depression, sleep disorders, alcohol use, and fluid (CSF) levels of the tau protein and 42-residue form family history of dementia of amyloid-B peptide (AB,.) in patients with Alzheimer e Detailed medication review disease; amyloid-specific and tau-specific PET to detect amyloid plaques and neurofibrillary tangles in Alzheimer ¢ Serum chemistries, including plasma glucose level and he- disease; and dopamine transporter single-photon emission patic function CT in patients with cognitive impairment and symptoms of ¢ Complete blood count parkinsonism (see Movement Disorders chapter). ¢ Determination of vitamin B,, and thyroid-stimulating hor- 2. Disease-nonspecific tests: !8F-fluorodeoxyglucose (FDG)- mone levels PET to measure cerebral metabolism; neuropsychological e A rapid plasmin reagin test to evaluate for syphilis in high- testing to outline the pattern of cognitive impairment with risk populations greater sensitivity and specificity than that provided by e Basic neuroimaging (MRI or CT without contrast) brief cognitive screeners; MRI to detect and measure brain

Access to a reliable informant familiar with the patient’s con- Increasing evidence also suggests that chronic vitamin D dition is critical in the evaluation of the cognitive disorder. The deficiency increases the odds of developing dementia. signs and symptoms of a cognitive disorder also may have an Therefore, measuring serum 25-hydroxyvitamin D levels can anatomic correlate that can be used to help guide the diagnosis be considered. When patient age, disease progression, or other and treatment. For example, a progressive loss of language associated symptoms raise the possibility of a more uncom- function localizes to a different anatomic location than does a mon type of dementia, additional diagnostic tests and early primary memory problem, which may be helpful in determin- referral to a specialist should be considered (Figure 16). ing the underlying cause of the impaired function. The age of Several more specialized testing modalities are available. the patient is another important consideration; for example, These tests should be reserved for patients with an uncertain both atypical presentations of typical dementia syndromes diagnosis (for example, to distinguish dementia from pseud- and nonneurodegenerative causes are more common in odementia), for an atypical progression of a previously estab- younger patients. lished diagnosis (such as an excessively slow course of For a slowly progressive dementia syndrome in an older Alzheimer disease), and for discriminating between two types patient, the American Academy of Neurology recommends of dementia with overlapping features (such as the detection that a minimum evaluation include the following elements: of Alzheimer disease-specific biomarkers). These tests, if required, are typically ordered by a dementia specialist. ¢ General neurologic examination, including a cognitive These specialized diagnostic tests fall into two categories: screening evaluation 1. Disease-specific tests: measurement of cerebrospinal e Evaluation for depression, sleep disorders, alcohol use, and fluid (CSF) levels of the tau protein and 42-residue form family history of dementia of amyloid-B peptide (AB,.) in patients with Alzheimer e Detailed medication review disease; amyloid-specific and tau-specific PET to detect amyloid plaques and neurofibrillary tangles in Alzheimer ¢ Serum chemistries, including plasma glucose level and he- disease; and dopamine transporter single-photon emission patic function CT in patients with cognitive impairment and symptoms of ¢ Complete blood count parkinsonism (see Movement Disorders chapter). ¢ Determination of vitamin B,, and thyroid-stimulating hor- 2. Disease-nonspecific tests: !8F-fluorodeoxyglucose (FDG)- mone levels PET to measure cerebral metabolism; neuropsychological e A rapid plasmin reagin test to evaluate for syphilis in high- testing to outline the pattern of cognitive impairment with risk populations greater sensitivity and specificity than that provided by e Basic neuroimaging (MRI or CT without contrast) brief cognitive screeners; MRI to detect and measure brain For all patients

Access to a reliable informant familiar with the patient’s con- Increasing evidence also suggests that chronic vitamin D dition is critical in the evaluation of the cognitive disorder. The deficiency increases the odds of developing dementia. signs and symptoms of a cognitive disorder also may have an Therefore, measuring serum 25-hydroxyvitamin D levels can anatomic correlate that can be used to help guide the diagnosis be considered. When patient age, disease progression, or other and treatment. For example, a progressive loss of language associated symptoms raise the possibility of a more uncom- function localizes to a different anatomic location than does a mon type of dementia, additional diagnostic tests and early primary memory problem, which may be helpful in determin- referral to a specialist should be considered (Figure 16). ing the underlying cause of the impaired function. The age of Several more specialized testing modalities are available. the patient is another important consideration; for example, These tests should be reserved for patients with an uncertain both atypical presentations of typical dementia syndromes diagnosis (for example, to distinguish dementia from pseud- and nonneurodegenerative causes are more common in odementia), for an atypical progression of a previously estab- younger patients. lished diagnosis (such as an excessively slow course of For a slowly progressive dementia syndrome in an older Alzheimer disease), and for discriminating between two types patient, the American Academy of Neurology recommends of dementia with overlapping features (such as the detection that a minimum evaluation include the following elements: of Alzheimer disease-specific biomarkers). These tests, if required, are typically ordered by a dementia specialist. ¢ General neurologic examination, including a cognitive These specialized diagnostic tests fall into two categories: screening evaluation 1. Disease-specific tests: measurement of cerebrospinal e Evaluation for depression, sleep disorders, alcohol use, and fluid (CSF) levels of the tau protein and 42-residue form family history of dementia of amyloid-B peptide (AB,.) in patients with Alzheimer e Detailed medication review disease; amyloid-specific and tau-specific PET to detect amyloid plaques and neurofibrillary tangles in Alzheimer ¢ Serum chemistries, including plasma glucose level and he- disease; and dopamine transporter single-photon emission patic function CT in patients with cognitive impairment and symptoms of ¢ Complete blood count parkinsonism (see Movement Disorders chapter). ¢ Determination of vitamin B,, and thyroid-stimulating hor- 2. Disease-nonspecific tests: !8F-fluorodeoxyglucose (FDG)- mone levels PET to measure cerebral metabolism; neuropsychological e A rapid plasmin reagin test to evaluate for syphilis in high- testing to outline the pattern of cognitive impairment with risk populations greater sensitivity and specificity than that provided by e Basic neuroimaging (MRI or CT without contrast) brief cognitive screeners; MRI to detect and measure brain For all patients © General physical and neurologic examination * Detailed medication, alcohol, and recreational drug review e Evaluation for depression * Family history (for dementia)

© General physical and neurologic examination * Detailed medication, alcohol, and recreational drug review e Evaluation for depression * Family history (for dementia) ! 3-6 mo | —- Temporal onset and progression >6mo Vv ® Complete blood count © Complete blood count ¢ Metabolic profile ¢ Metabolic profile ¢ Liver chemistries e Serum By» ¢ Ammonia level ¢ Vitamin D e Serum B,» * Thyroid-stimulating hormone e Thyroid-stimulating hormone ¢ Syphilis testing (if high risk) ¢ Vitamin D ¢ Consider sleep evaluation ¢ Thiamine (poor nutrition, alcoholism) ¢ Brain MRI? © Toxin exposures ¢ Head CT if MRI contraindicated ¢ Infection evaluation (Lyme disease, syphilis, HIV) e Electroencephalography ¢ Consider autoimmune encephalitis evaluation ¢ Brain MRI ¢ Head CT if MRI contraindicated FIGURE 16. Diagnostic considerations in a patient with a dementia syndrome. By = vitamin By, level; HIV= human immunodeficiency virus. 40

Cognitive Impairment atrophy; and CSF analysis to detect inflammation, infec- TABLE 27. Clinical Features of Delirium tion, neuronal injury, and paraneoplastic antibodies. Fluctuations in mentation | Hypervigilance more than hypovigilance | e Many bedside cognitive evaluation tools have demon- Disorganized thoughts strated adequate sensitivity and specificity for detecting | Delusions cognitive impairment in population-based settings; no Hallucinations compelling data support the superiority of one test over Poorly sustained attention another. Altered circadian rhythm ¢ The minimum evaluation in slowly progressive demen- Tremors (with occasional myoclonus) tia syndrome in an older patient includes assessment Hyperreflexia for a reversible cause with a general neurologic exami- Motor restlessness more than stupor nation; evaluation for depression, sleep disorders, alco- hol use, and a family history of dementia; a detailed Amnesia

cognitive impairment in population-based settings; no Hallucinations compelling data support the superiority of one test over Poorly sustained attention another. Altered circadian rhythm ¢ The minimum evaluation in slowly progressive demen- Tremors (with occasional myoclonus) tia syndrome in an older patient includes assessment Hyperreflexia for a reversible cause with a general neurologic exami- Motor restlessness more than stupor nation; evaluation for depression, sleep disorders, alco- hol use, and a family history of dementia; a detailed Amnesia medication review; basic laboratory studies, including Increased sympathetic tone (particularly with alcohol withdrawal) | vitamin B,, and thyroid-stimulating hormone measure- ment; and basic neuroimaging (MRI or CT without Method is a useful tool with good sensitivity for diagnosing contrast). delirium. Delirium also has a multitude of causes (Table 28), HVC e Specialized tests for dementia—including cerebrospinal and almost any acute medical condition may provoke delirium fluid tests, dopamine transporter single-photon emis- in a susceptible patient. Evaluation for the underlying cause of sion CT and PET scans—should be reserved for uncer- delirium is mandatory but often difficult because the patient tain diagnoses or atypical presentations; they are usu- may not be able to direct the evaluation. Consideration should ally ordered in conjunction with dementia specialists. always be given to life-threatening causes of delirium, includ- ing vascular events and infection. Neuroimaging may be nec- essary, and in the appropriate setting, electroencephalography Delirium can be used to ensure that seizures are not the cause of the Although rarely considered in the same light as acute dysfunc- confusion. tion of other major organs, delirium is an acute alteration of brain function and should be approached with the same intent Treatment of alleviating the dysfunction as rapidly as possible. The clini- The primary treatment of delirium is identification and treat- cal consequences of delirium are substantial because delirium ment of the underlying cause. Use of sedating medications, is associated with greater hospital morbidity, more medical such as benzodiazepines and haloperidol, should be avoided complications, longer lengths of stay, and a higher rate of dis- because they may cause or worsen delirium. Current evi- charge to long-term care facilities. The frequency of delirium dence does not support routine use of haloperidol or second- depends on the setting and the patient population. Postsurgical generation antipsychotic agents to treat delirium in adult and ICU patients, particularly older populations, have the inpatients. Some evidence suggests that the melatonin recep- highest prevalence of delirium (see Pulmonary and Critical tor agonist ramelteon may be useful. The effectiveness of Care Medicine for ICU delirium). Risk increases with the acetylcholinesterase inhibitors remains uncertain. presence of baseline dementia, multiple medical problems, polypharmacy, and hypoxia. Prevention of delirium is likely more effective than treat- e The Confusion Assessment Method is a useful tool with

medication review; basic laboratory studies, including Increased sympathetic tone (particularly with alcohol withdrawal) | vitamin B,, and thyroid-stimulating hormone measure- ment; and basic neuroimaging (MRI or CT without Method is a useful tool with good sensitivity for diagnosing contrast). delirium. Delirium also has a multitude of causes (Table 28), HVC e Specialized tests for dementia—including cerebrospinal and almost any acute medical condition may provoke delirium fluid tests, dopamine transporter single-photon emis- in a susceptible patient. Evaluation for the underlying cause of sion CT and PET scans—should be reserved for uncer- delirium is mandatory but often difficult because the patient tain diagnoses or atypical presentations; they are usu- may not be able to direct the evaluation. Consideration should ally ordered in conjunction with dementia specialists. always be given to life-threatening causes of delirium, includ- ing vascular events and infection. Neuroimaging may be nec- essary, and in the appropriate setting, electroencephalography Delirium can be used to ensure that seizures are not the cause of the Although rarely considered in the same light as acute dysfunc- confusion. tion of other major organs, delirium is an acute alteration of brain function and should be approached with the same intent Treatment of alleviating the dysfunction as rapidly as possible. The clini- The primary treatment of delirium is identification and treat- cal consequences of delirium are substantial because delirium ment of the underlying cause. Use of sedating medications, is associated with greater hospital morbidity, more medical such as benzodiazepines and haloperidol, should be avoided complications, longer lengths of stay, and a higher rate of dis- because they may cause or worsen delirium. Current evi- charge to long-term care facilities. The frequency of delirium dence does not support routine use of haloperidol or second- depends on the setting and the patient population. Postsurgical generation antipsychotic agents to treat delirium in adult and ICU patients, particularly older populations, have the inpatients. Some evidence suggests that the melatonin recep- highest prevalence of delirium (see Pulmonary and Critical tor agonist ramelteon may be useful. The effectiveness of Care Medicine for ICU delirium). Risk increases with the acetylcholinesterase inhibitors remains uncertain. presence of baseline dementia, multiple medical problems, polypharmacy, and hypoxia. Prevention of delirium is likely more effective than treat- e The Confusion Assessment Method is a useful tool with ment of established delirium. In hospitalized patients, provid- good sensitivity for diagnosing delirium; management

medication review; basic laboratory studies, including Increased sympathetic tone (particularly with alcohol withdrawal) | vitamin B,, and thyroid-stimulating hormone measure- ment; and basic neuroimaging (MRI or CT without Method is a useful tool with good sensitivity for diagnosing contrast). delirium. Delirium also has a multitude of causes (Table 28), HVC e Specialized tests for dementia—including cerebrospinal and almost any acute medical condition may provoke delirium fluid tests, dopamine transporter single-photon emis- in a susceptible patient. Evaluation for the underlying cause of sion CT and PET scans—should be reserved for uncer- delirium is mandatory but often difficult because the patient tain diagnoses or atypical presentations; they are usu- may not be able to direct the evaluation. Consideration should ally ordered in conjunction with dementia specialists. always be given to life-threatening causes of delirium, includ- ing vascular events and infection. Neuroimaging may be nec- essary, and in the appropriate setting, electroencephalography Delirium can be used to ensure that seizures are not the cause of the Although rarely considered in the same light as acute dysfunc- confusion. tion of other major organs, delirium is an acute alteration of brain function and should be approached with the same intent Treatment of alleviating the dysfunction as rapidly as possible. The clini- The primary treatment of delirium is identification and treat- cal consequences of delirium are substantial because delirium ment of the underlying cause. Use of sedating medications, is associated with greater hospital morbidity, more medical such as benzodiazepines and haloperidol, should be avoided complications, longer lengths of stay, and a higher rate of dis- because they may cause or worsen delirium. Current evi- charge to long-term care facilities. The frequency of delirium dence does not support routine use of haloperidol or second- depends on the setting and the patient population. Postsurgical generation antipsychotic agents to treat delirium in adult and ICU patients, particularly older populations, have the inpatients. Some evidence suggests that the melatonin recep- highest prevalence of delirium (see Pulmonary and Critical tor agonist ramelteon may be useful. The effectiveness of Care Medicine for ICU delirium). Risk increases with the acetylcholinesterase inhibitors remains uncertain. presence of baseline dementia, multiple medical problems, polypharmacy, and hypoxia. Prevention of delirium is likely more effective than treat- e The Confusion Assessment Method is a useful tool with ment of established delirium. In hospitalized patients, provid- good sensitivity for diagnosing delirium; management ing patients with assistive visual and hearing devices, should emphasize identification and treatment of the

medication review; basic laboratory studies, including Increased sympathetic tone (particularly with alcohol withdrawal) | vitamin B,, and thyroid-stimulating hormone measure- ment; and basic neuroimaging (MRI or CT without Method is a useful tool with good sensitivity for diagnosing contrast). delirium. Delirium also has a multitude of causes (Table 28), HVC e Specialized tests for dementia—including cerebrospinal and almost any acute medical condition may provoke delirium fluid tests, dopamine transporter single-photon emis- in a susceptible patient. Evaluation for the underlying cause of sion CT and PET scans—should be reserved for uncer- delirium is mandatory but often difficult because the patient tain diagnoses or atypical presentations; they are usu- may not be able to direct the evaluation. Consideration should ally ordered in conjunction with dementia specialists. always be given to life-threatening causes of delirium, includ- ing vascular events and infection. Neuroimaging may be nec- essary, and in the appropriate setting, electroencephalography Delirium can be used to ensure that seizures are not the cause of the Although rarely considered in the same light as acute dysfunc- confusion. tion of other major organs, delirium is an acute alteration of brain function and should be approached with the same intent Treatment of alleviating the dysfunction as rapidly as possible. The clini- The primary treatment of delirium is identification and treat- cal consequences of delirium are substantial because delirium ment of the underlying cause. Use of sedating medications, is associated with greater hospital morbidity, more medical such as benzodiazepines and haloperidol, should be avoided complications, longer lengths of stay, and a higher rate of dis- because they may cause or worsen delirium. Current evi- charge to long-term care facilities. The frequency of delirium dence does not support routine use of haloperidol or second- depends on the setting and the patient population. Postsurgical generation antipsychotic agents to treat delirium in adult and ICU patients, particularly older populations, have the inpatients. Some evidence suggests that the melatonin recep- highest prevalence of delirium (see Pulmonary and Critical tor agonist ramelteon may be useful. The effectiveness of Care Medicine for ICU delirium). Risk increases with the acetylcholinesterase inhibitors remains uncertain. presence of baseline dementia, multiple medical problems, polypharmacy, and hypoxia. Prevention of delirium is likely more effective than treat- e The Confusion Assessment Method is a useful tool with ment of established delirium. In hospitalized patients, provid- good sensitivity for diagnosing delirium; management ing patients with assistive visual and hearing devices, should emphasize identification and treatment of the adequately controlling pain, limiting psychoactive medica- underlying causes.

ment of established delirium. In hospitalized patients, provid- good sensitivity for diagnosing delirium; management ing patients with assistive visual and hearing devices, should emphasize identification and treatment of the adequately controlling pain, limiting psychoactive medica- underlying causes. tions, providing frequent orientation, encouraging mobility, and enabling uninterrupted sleep on a normal sleep-wake cycle may help decrease the likelihood of developing delirium. Mild Cognitive Impairment Delirium presents with numerous and variable symptoms and The diagnosis of mild cognitive impairment (MCI) is com- signs (Table 27). The core of delirium is an alteration in the monly used to identify patients with clear symptoms of cogni- arousal system (that is, in the ascending reticular activating tive decline who do not meet criteria for dementia. The formal system of the midbrain, thalamus, and hypothalamus that criteria for MCI are a subjective report (from either the patient modulates sleep-wake transitions). Fluctuations in mental or a witness) of a decline in cognitive abilities with relative status, altered circadian rhythm, and poor attention are the preservation of day-to-day function and evidence of cognitive hallmarks of the clinical syndrome. The Confusion Assessment impairment on cognitive testing. 41

Cognitive Impairment TABLE 28. Causes of Delirium variability in the risk of progression, steps should be taken to confirm the underlying cause of the symptoms. The initial Drugs diagnostic approach should follow that outlined in Figure 16 Prescription medications (such as psychotropic medications, for those with cognitive impairment of greater than 3 months. opioids, sedative hypnotics, anticonvulsants, antiparkinsonian agents, glucocorticoids, Abnormalities on these studies, combined with a detailed immunosuppressants, antiarrhythmics, antihypertensive | family history screen, may help more accurately predict the agents, skeletal muscle relaxants, antibiotics) risk of progression. Nonprescription medications (such as NSAIDs, | antihistamines) | Treatment General anesthesia No medications are currently approved for the treatment of Alcohol or drug withdrawal (e.g., opioids, benzodiazepines) MCI, and no medications or dietary agents have been shown to | Central nervous system diseases Seizure, including nonconvulsive status epilepticus | prevent progression to dementia. The Lancet Commission 2020 supports addressing modifiable risk factors for dementia

TABLE 28. Causes of Delirium variability in the risk of progression, steps should be taken to confirm the underlying cause of the symptoms. The initial Drugs diagnostic approach should follow that outlined in Figure 16 Prescription medications (such as psychotropic medications, for those with cognitive impairment of greater than 3 months. opioids, sedative hypnotics, anticonvulsants, antiparkinsonian agents, glucocorticoids, Abnormalities on these studies, combined with a detailed immunosuppressants, antiarrhythmics, antihypertensive | family history screen, may help more accurately predict the agents, skeletal muscle relaxants, antibiotics) risk of progression. Nonprescription medications (such as NSAIDs, | antihistamines) | Treatment General anesthesia No medications are currently approved for the treatment of Alcohol or drug withdrawal (e.g., opioids, benzodiazepines) MCI, and no medications or dietary agents have been shown to | Central nervous system diseases Seizure, including nonconvulsive status epilepticus | prevent progression to dementia. The Lancet Commission 2020 supports addressing modifiable risk factors for dementia Acute ischemic infarction prevention, intervention, and care, including excessive alcohol

TABLE 28. Causes of Delirium variability in the risk of progression, steps should be taken to confirm the underlying cause of the symptoms. The initial Drugs diagnostic approach should follow that outlined in Figure 16 Prescription medications (such as psychotropic medications, for those with cognitive impairment of greater than 3 months. opioids, sedative hypnotics, anticonvulsants, antiparkinsonian agents, glucocorticoids, Abnormalities on these studies, combined with a detailed immunosuppressants, antiarrhythmics, antihypertensive | family history screen, may help more accurately predict the agents, skeletal muscle relaxants, antibiotics) risk of progression. Nonprescription medications (such as NSAIDs, | antihistamines) | Treatment General anesthesia No medications are currently approved for the treatment of Alcohol or drug withdrawal (e.g., opioids, benzodiazepines) MCI, and no medications or dietary agents have been shown to | Central nervous system diseases Seizure, including nonconvulsive status epilepticus | prevent progression to dementia. The Lancet Commission 2020 supports addressing modifiable risk factors for dementia Acute ischemic infarction prevention, intervention, and care, including excessive alcohol Intracranial hemorrhage use, head injury, air pollution, less education, hypertension, hearing loss, smoking, obesity, depression, physical inactivity, Head injury diabetes, and limited social contact. The American Academy of Metabolic disorders | Electrolyte disturbance | Neurology recommends that cognitively impairing medica- tions should be discontinued when possible and behavioral Hyperglycemia or hypoglycemia | symptoms treated. Clinicians should also recommend regular

Intracranial hemorrhage use, head injury, air pollution, less education, hypertension, hearing loss, smoking, obesity, depression, physical inactivity, Head injury diabetes, and limited social contact. The American Academy of Metabolic disorders | Electrolyte disturbance | Neurology recommends that cognitively impairing medica- tions should be discontinued when possible and behavioral Hyperglycemia or hypoglycemia | symptoms treated. Clinicians should also recommend regular Hypoxemia exercise and may recommend cognitive exercises, but there is insufficient evidence to support or refute the use of any indi- Hypercarbia vidual cognitive strategy. Use of vitamins B and E, polyunsatu- Organ failure (such as cardiac failure, kidney impairment, | liver failure) rated fatty acids, and multicomplex supplementation is not recommended. Endocrine (such as hypothyroidism, hyperthyroidism, | hyperparathyroidism, Cushing syndrome, adrenal insufficiency) Prevention Nutritional (such as malnourishment, vitamin Bj deficiency, With the growth of the aging population, the prevalence of thiamine deficiency, niacin deficiency) MCI and dementia is increasing. However, the incidence of Cardiovascular disease dementia is declining with the control of vascular risk fac- Myocardial infarction tors (diabetes mellitus, hypertension, hyperlipidemia). Hypertensive emergency Exercise is the most important modifiable lifestyle factor to

Hypoxemia exercise and may recommend cognitive exercises, but there is insufficient evidence to support or refute the use of any indi- Hypercarbia vidual cognitive strategy. Use of vitamins B and E, polyunsatu- Organ failure (such as cardiac failure, kidney impairment, | liver failure) rated fatty acids, and multicomplex supplementation is not recommended. Endocrine (such as hypothyroidism, hyperthyroidism, | hyperparathyroidism, Cushing syndrome, adrenal insufficiency) Prevention Nutritional (such as malnourishment, vitamin Bj deficiency, With the growth of the aging population, the prevalence of thiamine deficiency, niacin deficiency) MCI and dementia is increasing. However, the incidence of Cardiovascular disease dementia is declining with the control of vascular risk fac- Myocardial infarction tors (diabetes mellitus, hypertension, hyperlipidemia). Hypertensive emergency Exercise is the most important modifiable lifestyle factor to Dysrhythmias prevent the onset of MCI. Higher levels of education and midlife cognitive stimulation decrease the risk of MCI. The Infections? combination of the Mediterranean and DASH diet (called the Surgery MIND diet) is being studied by the National Institute of Aging Trauma as studies have suggested it plays a role in prevention of Environment | Alzheimer disease. Post-acute care setting

Dysrhythmias prevent the onset of MCI. Higher levels of education and midlife cognitive stimulation decrease the risk of MCI. The Infections? combination of the Mediterranean and DASH diet (called the Surgery MIND diet) is being studied by the National Institute of Aging Trauma as studies have suggested it plays a role in prevention of Environment | Alzheimer disease. Post-acute care setting ICU ¢ No medications are currently approved for the treat- HVC Other ment of mild cognitive impairment, and no medications Acute blood loss or dietary agents have been shown to prevent progres- Uncontrolled pain sion to dementia once reversible causes have been Fecal impaction excluded.

ICU ¢ No medications are currently approved for the treat- HVC Other ment of mild cognitive impairment, and no medications Acute blood loss or dietary agents have been shown to prevent progres- Uncontrolled pain sion to dementia once reversible causes have been Fecal impaction excluded. Urinary retention e Exercise is the most important modifiable lifestyle fac- tor to prevent the onset of mild cognitive impairment *Such as urinary tract infections, respiratory infections, cellulitis, meningitis or encephalitis, and sepsis. (MCI); midlife cognitive stimulation decreases the risk of MCI. The annual risk of MCI progressing to dementia ranges from 5% to 15%, but a significant percentage of patients have normal findings on subsequent examinations. Reversible Dementias causes of MCI include medication adverse effects, sleep apnea, Dementia syndromes can be divided into those without early depression, and other medical conditions. Because of wide motor signs and those with early motor signs. 42

Cognitive Impairment Dementias without Early Motor Signs The typical presentation of Alzheimer disease is that of an Alzheimer Disease insidious worsening of memory, language, and visuospatial The most common memory-predominant dementia is Alzheimer abilities. Manifestations include forgetfulness (misplacing disease, which is also the most common cause of dementia. Age objects, missing appointments, frequently repeating questions is the greatest risk factor; after age 65 years, the prevalence dou- or statements, missing bill payments), word-finding difficul- bles every 5 years. A second major risk factor is the presence of ties, hesitation in speech, and navigational problems (diffi-

The most common memory-predominant dementia is Alzheimer abilities. Manifestations include forgetfulness (misplacing disease, which is also the most common cause of dementia. Age objects, missing appointments, frequently repeating questions is the greatest risk factor; after age 65 years, the prevalence dou- or statements, missing bill payments), word-finding difficul- bles every 5 years. A second major risk factor is the presence of ties, hesitation in speech, and navigational problems (diffi- one or two copies of the apolipoprotein-E ¢4 (APOE ¢4) allele, culty with directions while driving, even to familiar places, or which increases susceptibility. Of note, the APOE ¢4 allele is not a disorientation in unfamiliar places). These symptoms are causative gene and thus testing for it is not recommended in often followed by problems with executive function (organiza- diagnostic evaluation. Additional risk factors include a family his- tional abilities and multitasking), problems with calculations tory of dementia, female sex, history of stroke, and (to a lesser (managing finances), and behavioral and mood symptoms extent) head injury and cardiovascular disease. (apathy, depression, anxiety, irritability, and agitation). As the The exact pathophysiology of Alzheimer disease is disease progresses, behavioral symptoms, including delusions, unclear. The principal pathologic findings, however, include become more common. In contrast to dementia with Lewy brain volume loss, extracellular fibrillar amyloid beta (AB) bodies, however, hallucinations are rare. Motor symptoms and plaques, and intracellular neurofibrillary tau tangles. Notably, gait problems also do not typically occur until well into the the development of AB pathologic features begins as early as 15 moderate stages of the disease when daily function is signifi- to 20 years before symptom onset; these features are diffusely cantly impaired. Early hallucinations and motor problems distributed in the brain, whereas neurofibrillary tangles suggest the presence of a disorder other than Alzheimer dis- appear in the areas of greatest atrophy. ease (Table 29).

one or two copies of the apolipoprotein-E ¢4 (APOE ¢4) allele, culty with directions while driving, even to familiar places, or which increases susceptibility. Of note, the APOE ¢4 allele is not a disorientation in unfamiliar places). These symptoms are causative gene and thus testing for it is not recommended in often followed by problems with executive function (organiza- diagnostic evaluation. Additional risk factors include a family his- tional abilities and multitasking), problems with calculations tory of dementia, female sex, history of stroke, and (to a lesser (managing finances), and behavioral and mood symptoms extent) head injury and cardiovascular disease. (apathy, depression, anxiety, irritability, and agitation). As the The exact pathophysiology of Alzheimer disease is disease progresses, behavioral symptoms, including delusions, unclear. The principal pathologic findings, however, include become more common. In contrast to dementia with Lewy brain volume loss, extracellular fibrillar amyloid beta (AB) bodies, however, hallucinations are rare. Motor symptoms and plaques, and intracellular neurofibrillary tau tangles. Notably, gait problems also do not typically occur until well into the the development of AB pathologic features begins as early as 15 moderate stages of the disease when daily function is signifi- to 20 years before symptom onset; these features are diffusely cantly impaired. Early hallucinations and motor problems distributed in the brain, whereas neurofibrillary tangles suggest the presence of a disorder other than Alzheimer dis- appear in the areas of greatest atrophy. ease (Table 29). TABLE 29. Features That Distinguish Alzheimer Disease from Other Dementias | Dementia Type Clinical Features Alzheimer disease Impaired memory or forgetfulness as prominent early symptom Minimal motor symptoms until disease reaches moderate severity (that is, at the point of significant impairment of activities of daily living) Rare visual hallucinations

| Dementia Type Clinical Features Alzheimer disease Impaired memory or forgetfulness as prominent early symptom Minimal motor symptoms until disease reaches moderate severity (that is, at the point of significant impairment of activities of daily living) Rare visual hallucinations Delusions not common at early stages of disease (that is, at the point of relatively preserved activities of daily living) Frontotemporal dementia Poor insight into impairment or denial of impairment, especially when cognitive impairment is mild New-onset obsessive-compulsive behaviors | Criminal behaviors Gluttonous eating behaviors or adoption of bizarre food restrictions or fads Motor neuron disease (such as muscle wasting) | | Dementia with Lewy bodies Severe autonomic symptoms (such as orthostatic hypotension, constipation, and erectile dysfunction) | Sleep disorders (such as rapid eye movement sleep behavior disorder and daytime hypersomnia) | Severe fluctuations in mental status or seizure-like activity Early visual hallucinations | Syncopal events or unexplained episodes of severe alteration in mentation Repeated falls Severe sensitivity to medications that act on the central nervous system _ Normal pressure hydrocephalus Pronounced gait disorder and repeated falls, especially early in the disease course (at mild dementia | stage) Minimal cognitive impairment, compared with much greater gait disorder and non-memory- predominant pattern Pronounced bladder incontinence proximate to onset of gait changes | | Vascular cognitive impairment Pronounced gait disorder and repeated falls, especially early in the disease course (at mild dementia stage) Emotional incontinence (explosive crying, laughter)

Pronounced bladder incontinence proximate to onset of gait changes | | Vascular cognitive impairment Pronounced gait disorder and repeated falls, especially early in the disease course (at mild dementia stage) Emotional incontinence (explosive crying, laughter) | Pronounced apathy Severe cognitive slowing 43

Cognitive Impairment In younger-onset Alzheimer disease, nonmemory symp- the MRI is normal and the diagnosis is in question or a non- toms are more frequently the predominant pattern and include Alzheimer disease process is being considered, functional language-predominant, executive function-predominant brain scanning (FDG-PET) can be used to look for the (impaired organizational abilities, disorganized thoughts, poor Alzheimer disease pattern of decreased brain function in the attention span), and visual/perceptive-predominant (impaired bilateral parietal and temporal regions. depth perception, navigational problems, problems with In situations involving an uncertain diagnosis or a coordination) forms. Memory impairment can be initially younger patient, Alzheimer disease-specific biomarkers also minimal. can be sought. A CSF test for Alzheimer disease biomarkers is FDA approved but not frequently covered by insurers. In the Evaluation presence of dementia, a pattern of decreased ABy. and MRI of the brain supports the diagnosis of Alzheimer disease increased tau and phosphorylated tau levels is highly specific when it shows evidence of decreased volume of the hip- for Alzheimer disease; conversely, a normal AB, level has a pocampi (Figure 17) out of proportion to rest of the brain. high negative-predictive probability for Alzheimer disease. When seen in MCI, decreased hippocampal volume predicts a Three AB plaque PET scans are FDA approved for detecting higher likelihood of progression to Alzheimer dementia. When these findings but are not covered by insurers. Recent evidence suggests that these scans change management by dementia specialists in approximately 60% of patients, which can affect the role of amyloid scanning in the evaluation of dementia and Alzheimer disease outside of clinical trials. The first Tau neu- rofibrillary tangle PET scan was FDA approved in May 2020 and its utility has yet to be established.

In younger-onset Alzheimer disease, nonmemory symp- the MRI is normal and the diagnosis is in question or a non- toms are more frequently the predominant pattern and include Alzheimer disease process is being considered, functional language-predominant, executive function-predominant brain scanning (FDG-PET) can be used to look for the (impaired organizational abilities, disorganized thoughts, poor Alzheimer disease pattern of decreased brain function in the attention span), and visual/perceptive-predominant (impaired bilateral parietal and temporal regions. depth perception, navigational problems, problems with In situations involving an uncertain diagnosis or a coordination) forms. Memory impairment can be initially younger patient, Alzheimer disease-specific biomarkers also minimal. can be sought. A CSF test for Alzheimer disease biomarkers is FDA approved but not frequently covered by insurers. In the Evaluation presence of dementia, a pattern of decreased ABy. and MRI of the brain supports the diagnosis of Alzheimer disease increased tau and phosphorylated tau levels is highly specific when it shows evidence of decreased volume of the hip- for Alzheimer disease; conversely, a normal AB, level has a pocampi (Figure 17) out of proportion to rest of the brain. high negative-predictive probability for Alzheimer disease. When seen in MCI, decreased hippocampal volume predicts a Three AB plaque PET scans are FDA approved for detecting higher likelihood of progression to Alzheimer dementia. When these findings but are not covered by insurers. Recent evidence suggests that these scans change management by dementia specialists in approximately 60% of patients, which can affect the role of amyloid scanning in the evaluation of dementia and Alzheimer disease outside of clinical trials. The first Tau neu- rofibrillary tangle PET scan was FDA approved in May 2020 and its utility has yet to be established. Treatment The nonpharmacologic management of Alzheimer disease includes aggressively treating possible factors contributing to disease progression, such as sleep disorders (including obstructive sleep apnea) and cardiovascular disease; risk fac- tors for cardiovascular disease also should be addressed. Adhering to an exercise program should be encouraged. Dietary recommendations for slowing cognitive decline in Alzheimer disease or MCI remain uncertain. Given the links between cardiovascular disease risk factors and Alzheimer disease, it is generally recommended that affected patients fol- low a “heart-healthy” diet (a diet rich in whole grains, fruits, and vegetables and low in simple carbohydrates, polyunsatu- rated or trans-fatty acids, nitrates, and alcohol). The use of nutraceuticals (supplements enriched with nutrient precur- sors of many substrates for healthy brain function) has shown benefit in some, but not all, trials and remains controversial. No conclusive data have showna link between statin use and development of Alzheimer disease, and meta-analyses of ran- domized controlled trials have shown no clear benefit or harm to cognition from statins. However, given case reports of cogni- tive decline after statin therapy, the FDA has issued a warning about possible worsening cognition after initiation of some statins. Clinicians should consider discontinuing statin ther- apy if there is a clear temporal link between starting this therapy and significant cognitive decline. The acetylcholinesterase inhibitors donepezil, rivastig- mine, and galantamine are approved for treating mild to mod-

Treatment The nonpharmacologic management of Alzheimer disease includes aggressively treating possible factors contributing to disease progression, such as sleep disorders (including obstructive sleep apnea) and cardiovascular disease; risk fac- tors for cardiovascular disease also should be addressed. Adhering to an exercise program should be encouraged. Dietary recommendations for slowing cognitive decline in Alzheimer disease or MCI remain uncertain. Given the links between cardiovascular disease risk factors and Alzheimer disease, it is generally recommended that affected patients fol- low a “heart-healthy” diet (a diet rich in whole grains, fruits, and vegetables and low in simple carbohydrates, polyunsatu- rated or trans-fatty acids, nitrates, and alcohol). The use of nutraceuticals (supplements enriched with nutrient precur- sors of many substrates for healthy brain function) has shown benefit in some, but not all, trials and remains controversial. No conclusive data have showna link between statin use and development of Alzheimer disease, and meta-analyses of ran- domized controlled trials have shown no clear benefit or harm to cognition from statins. However, given case reports of cogni- tive decline after statin therapy, the FDA has issued a warning about possible worsening cognition after initiation of some statins. Clinicians should consider discontinuing statin ther- apy if there is a clear temporal link between starting this therapy and significant cognitive decline. The acetylcholinesterase inhibitors donepezil, rivastig- mine, and galantamine are approved for treating mild to mod- erate dementia in patients with Alzheimer disease and have demonstrated modest benefits in cognitive performance.

Treatment The nonpharmacologic management of Alzheimer disease includes aggressively treating possible factors contributing to disease progression, such as sleep disorders (including obstructive sleep apnea) and cardiovascular disease; risk fac- tors for cardiovascular disease also should be addressed. Adhering to an exercise program should be encouraged. Dietary recommendations for slowing cognitive decline in Alzheimer disease or MCI remain uncertain. Given the links between cardiovascular disease risk factors and Alzheimer disease, it is generally recommended that affected patients fol- low a “heart-healthy” diet (a diet rich in whole grains, fruits, and vegetables and low in simple carbohydrates, polyunsatu- rated or trans-fatty acids, nitrates, and alcohol). The use of nutraceuticals (supplements enriched with nutrient precur- sors of many substrates for healthy brain function) has shown benefit in some, but not all, trials and remains controversial. No conclusive data have showna link between statin use and development of Alzheimer disease, and meta-analyses of ran- domized controlled trials have shown no clear benefit or harm to cognition from statins. However, given case reports of cogni- tive decline after statin therapy, the FDA has issued a warning about possible worsening cognition after initiation of some statins. Clinicians should consider discontinuing statin ther- apy if there is a clear temporal link between starting this therapy and significant cognitive decline. The acetylcholinesterase inhibitors donepezil, rivastig- mine, and galantamine are approved for treating mild to mod- erate dementia in patients with Alzheimer disease and have demonstrated modest benefits in cognitive performance. FIGURE 17. op, MRI showing bilateral hippocampal atrophy, which is a typical Donepezil and rivastigmine also have been approved for mod- feature of Alzheimer disease. Bottom, Normal hippocampi. erate to severe stage dementia in Alzheimer disease. Although

erate dementia in patients with Alzheimer disease and have demonstrated modest benefits in cognitive performance. FIGURE 17. op, MRI showing bilateral hippocampal atrophy, which is a typical Donepezil and rivastigmine also have been approved for mod- feature of Alzheimer disease. Bottom, Normal hippocampi. erate to severe stage dementia in Alzheimer disease. Although 44

Cognitive Impairment there is no immediate improvement in daily functioning, this the diagnosis early in the disease is discordance between nor- class of medications has been shown to stabilize progression of mal or near-normal performance on objective cognitive testing symptoms and functional loss. These three drugs have differ- and a significant degree of functional impairment. Because ences in pharmacodynamics and pharmacokinetics but these behaviors often manifest as obsessive-compulsive ten- appear equally efficacious. Because of their possible adverse dencies, impulsivity, apathy, and impaired judgment, patients effects on cardiac conduction, acetylcholinesterase inhibitors with this disorder are often misdiagnosed as having bipolar should be used with caution or avoided in patients with brady- disorder, obsessive-compulsive disorder, and depression. cardia or other conduction abnormalities. The most common Other common symptoms are lack of empathy, disinhibition, adverse effects are gastrointestinal issues, which result in dis- excessive spending, and excessive eating, particularly of high- continuation of the medication in nearly 20% of patients. calorie foods. These behaviors occasionally result in legal trou- Additional adverse effects include syncope, agitation, noctur- bles. Those with behavioral-variant FTD often have poor nal cramps, and vivid dreams. The N-methyl-p-aspartate insight into their disease. receptor antagonist memantine is approved for moderate to Diagnostic criteria have been proposed, with the diagno- severe dementia in patients with Alzheimer disease associated sis of behavioral-variant FTD being established when three of with significant functional impairment and is not associated the following six criteria are met: early behavioral disinhibi- with adverse cardiovascular effects. It has no established ben- tion, early apathy or inertia, early loss of sympathy or empathy, efit in mild dementia and must be added to an acetylcholinest- perseverative or compulsive behaviors, hyperorality and die- erase inhibitor for effect in moderate- to severe-stage dementia. tary changes, and neuropsychological deficits in executive Antibodies targeting AB plaques represent another potential function with memory and visuospatial sparing. means of treatment and are the subject of current study. Antibodies targeting soluble tau are also being studied in Evaluation human clinical trials. Because cognitive testing results can be normal early in the disease course, Alzheimer disease screening tools are not help- ful for evaluating FTD. When this diagnosis is suspected, e An MRI of the brain supports the diagnosis of Alzheimer detailed cognitive testing by a neuropsychologist is indicated. disease when it shows evidence of decreased volume of Because structural lesions of the frontal lobes can result in the hippocampi. a syndrome similar to behavioral-variant FTD, neuroimaging

there is no immediate improvement in daily functioning, this the diagnosis early in the disease is discordance between nor- class of medications has been shown to stabilize progression of mal or near-normal performance on objective cognitive testing symptoms and functional loss. These three drugs have differ- and a significant degree of functional impairment. Because ences in pharmacodynamics and pharmacokinetics but these behaviors often manifest as obsessive-compulsive ten- appear equally efficacious. Because of their possible adverse dencies, impulsivity, apathy, and impaired judgment, patients effects on cardiac conduction, acetylcholinesterase inhibitors with this disorder are often misdiagnosed as having bipolar should be used with caution or avoided in patients with brady- disorder, obsessive-compulsive disorder, and depression. cardia or other conduction abnormalities. The most common Other common symptoms are lack of empathy, disinhibition, adverse effects are gastrointestinal issues, which result in dis- excessive spending, and excessive eating, particularly of high- continuation of the medication in nearly 20% of patients. calorie foods. These behaviors occasionally result in legal trou- Additional adverse effects include syncope, agitation, noctur- bles. Those with behavioral-variant FTD often have poor nal cramps, and vivid dreams. The N-methyl-p-aspartate insight into their disease. receptor antagonist memantine is approved for moderate to Diagnostic criteria have been proposed, with the diagno- severe dementia in patients with Alzheimer disease associated sis of behavioral-variant FTD being established when three of with significant functional impairment and is not associated the following six criteria are met: early behavioral disinhibi- with adverse cardiovascular effects. It has no established ben- tion, early apathy or inertia, early loss of sympathy or empathy, efit in mild dementia and must be added to an acetylcholinest- perseverative or compulsive behaviors, hyperorality and die- erase inhibitor for effect in moderate- to severe-stage dementia. tary changes, and neuropsychological deficits in executive Antibodies targeting AB plaques represent another potential function with memory and visuospatial sparing. means of treatment and are the subject of current study. Antibodies targeting soluble tau are also being studied in Evaluation human clinical trials. Because cognitive testing results can be normal early in the disease course, Alzheimer disease screening tools are not help- ful for evaluating FTD. When this diagnosis is suspected, e An MRI of the brain supports the diagnosis of Alzheimer detailed cognitive testing by a neuropsychologist is indicated. disease when it shows evidence of decreased volume of Because structural lesions of the frontal lobes can result in the hippocampi. a syndrome similar to behavioral-variant FTD, neuroimaging e Acetylcholinesterase inhibitors have demonstrated with MRI or CT is mandatory. Additionally, many patients with modest benefits in cognitive performance in patients behavioral-variant FTD have frontotemporal lobe atrophy vis-

there is no immediate improvement in daily functioning, this the diagnosis early in the disease is discordance between nor- class of medications has been shown to stabilize progression of mal or near-normal performance on objective cognitive testing symptoms and functional loss. These three drugs have differ- and a significant degree of functional impairment. Because ences in pharmacodynamics and pharmacokinetics but these behaviors often manifest as obsessive-compulsive ten- appear equally efficacious. Because of their possible adverse dencies, impulsivity, apathy, and impaired judgment, patients effects on cardiac conduction, acetylcholinesterase inhibitors with this disorder are often misdiagnosed as having bipolar should be used with caution or avoided in patients with brady- disorder, obsessive-compulsive disorder, and depression. cardia or other conduction abnormalities. The most common Other common symptoms are lack of empathy, disinhibition, adverse effects are gastrointestinal issues, which result in dis- excessive spending, and excessive eating, particularly of high- continuation of the medication in nearly 20% of patients. calorie foods. These behaviors occasionally result in legal trou- Additional adverse effects include syncope, agitation, noctur- bles. Those with behavioral-variant FTD often have poor nal cramps, and vivid dreams. The N-methyl-p-aspartate insight into their disease. receptor antagonist memantine is approved for moderate to Diagnostic criteria have been proposed, with the diagno- severe dementia in patients with Alzheimer disease associated sis of behavioral-variant FTD being established when three of with significant functional impairment and is not associated the following six criteria are met: early behavioral disinhibi- with adverse cardiovascular effects. It has no established ben- tion, early apathy or inertia, early loss of sympathy or empathy, efit in mild dementia and must be added to an acetylcholinest- perseverative or compulsive behaviors, hyperorality and die- erase inhibitor for effect in moderate- to severe-stage dementia. tary changes, and neuropsychological deficits in executive Antibodies targeting AB plaques represent another potential function with memory and visuospatial sparing. means of treatment and are the subject of current study. Antibodies targeting soluble tau are also being studied in Evaluation human clinical trials. Because cognitive testing results can be normal early in the disease course, Alzheimer disease screening tools are not help- ful for evaluating FTD. When this diagnosis is suspected, e An MRI of the brain supports the diagnosis of Alzheimer detailed cognitive testing by a neuropsychologist is indicated. disease when it shows evidence of decreased volume of Because structural lesions of the frontal lobes can result in the hippocampi. a syndrome similar to behavioral-variant FTD, neuroimaging e Acetylcholinesterase inhibitors have demonstrated with MRI or CT is mandatory. Additionally, many patients with modest benefits in cognitive performance in patients behavioral-variant FTD have frontotemporal lobe atrophy vis- with mild to moderate Alzheimer disease without clear ible on imaging (Figure 18). If the MRI is normal, a functional improvements in daily functioning; memantine is brain scan (FDG-PET) may showa pattern of prominent fron- approved for moderate to severe dementia in patients tal lobe abnormalities.

with mild to moderate Alzheimer disease without clear ible on imaging (Figure 18). If the MRI is normal, a functional improvements in daily functioning; memantine is brain scan (FDG-PET) may showa pattern of prominent fron- approved for moderate to severe dementia in patients tal lobe abnormalities. with Alzheimer disease associated with significant A CSF evaluation also can be helpful in distinguishing functional impairment. FTD from Alzheimer disease because the AB level is typically depressed in Alzheimer disease but normal in FTD. Frontotemporal Dementia Finally, because of the association with amyotrophic lat- The frontotemporal dementias (FTDs), which comprise lan- eral sclerosis, all patients with a diagnosis of behavioral-vari- guage-variant and behavioral-variant types, are the second ant FTD should be monitored closely for muscle weakness, most common cause (after Alzheimer disease) of neurodegen- cramping, or fasciculations. erative dementia in patients younger than 65 years. The lan- guage-variant FTDs consist of two forms of primary progressive Treatment aphasia and are discussed separately in Language-Predominant There are currently no approved therapies to treat behavioral- Dementias. In behavioral-variant FTD, there is a slight male variant FTD, and clinical trials testing the effectiveness of predominance and shorter disease duration than in Alzheimer acetylcholinesterase inhibitors and memantine have shown disease. As many as 20% to 40% of patients with behavioral- no benefit. Studies have shown SSRIs to be helpful for com- variant FTD have familial inheritance. Amyotrophic lateral pulsive behaviors, if present, in patients with FTD. Treatment sclerosis occurs in as many as 15% of patients with behavioral- is symptomatic and can involve collaboration with a variant FTD and generally portends a much more rapid pro- psychiatrist.

variant FTD have familial inheritance. Amyotrophic lateral pulsive behaviors, if present, in patients with FTD. Treatment sclerosis occurs in as many as 15% of patients with behavioral- is symptomatic and can involve collaboration with a variant FTD and generally portends a much more rapid pro- psychiatrist. gression than other forms of FTD. The pathology underlying FTD involves phosphorylated tau, transactive-response DNA- e A clue to the diagnosis of behavioral-variant frontotem- binding protein 43 inclusions, or-in a small number of poral dementia early in the disease course is discord- patients—fused in sarcoma protein. ance between normal or near-normal performance on The most prominent feature of behavioral-variant FTD is objective cognitive testing and a significant degree of an alteration in personality and behavior that typically devel- functional impairment. ops years before the onset of cognitive impairment. A clue to 45

Cognitive Impairment FIGURE 18. Axial (/eft) and sagittal (right) brain MRI findings showing changes associated with frontotemporal dementia, including severe bilateral frontal cortical atrophy (arrows).

Cognitive Impairment FIGURE 18. Axial (/eft) and sagittal (right) brain MRI findings showing changes associated with frontotemporal dementia, including severe bilateral frontal cortical atrophy (arrows). Language-Predominant Dementias KEY POINT The primary progressive aphasias (PPAs) are a group of neuro- ¢ Because most cognitive tests are language based, patients degenerative dementia syndromes in which a progressive with a primary progressive aphasia often perform worse impairment in language is the principal cognitive deficit and than expected given their level of day-to-day function- cause of functional impairment for at least the first 2 years. ing, in contrast to what is seen in behavioral-variant PPAs can be subdivided into three types: nonfluent agram- frontotemporal dementia. matic variant, semantic variant, and logopenic variant. Although language decline is common in many dementia Traumatic Encephalopathy Syndrome syndromes, in PPA it is the symptom noted first, and language Traumatic encephalopathy syndrome (TES) is the progressive is often the only cognitive domain affected for years before neurodegenerative syndrome associated with repetitive head the development of additional cognitive deterioration. trauma. Chronic traumatic encephalopathy (CTE) is techni- Pathologically, the PPAs are related to FTD and Alzheimer dis- ease but typically occur at a younger age. cally a pathologic diagnosis. Retrospective studies were used in

Language-Predominant Dementias KEY POINT The primary progressive aphasias (PPAs) are a group of neuro- ¢ Because most cognitive tests are language based, patients degenerative dementia syndromes in which a progressive with a primary progressive aphasia often perform worse impairment in language is the principal cognitive deficit and than expected given their level of day-to-day function- cause of functional impairment for at least the first 2 years. ing, in contrast to what is seen in behavioral-variant PPAs can be subdivided into three types: nonfluent agram- frontotemporal dementia. matic variant, semantic variant, and logopenic variant. Although language decline is common in many dementia Traumatic Encephalopathy Syndrome syndromes, in PPA it is the symptom noted first, and language Traumatic encephalopathy syndrome (TES) is the progressive is often the only cognitive domain affected for years before neurodegenerative syndrome associated with repetitive head the development of additional cognitive deterioration. trauma. Chronic traumatic encephalopathy (CTE) is techni- Pathologically, the PPAs are related to FTD and Alzheimer dis- ease but typically occur at a younger age. cally a pathologic diagnosis. Retrospective studies were used in Evaluation The language components of the cognitive screening evalua- tion are disproportionately affected in language-predominant dementias. Because most cognitive tests are language based, patients with PPA often perform worse than expected given their level of day-to-day functioning (the opposite of what is seen in behavioral-variant FTD). Structural imaging can be very helpful; attention should be paid to asymmetric involvement of the left temporal lobe, which is atrophied in the semantic variant of PPA (Figure 19). Functional brain imaging (FDG-PET) can identify a pattern of asymmetric lobar abnormality in patients with inconclusive

Evaluation The language components of the cognitive screening evalua- tion are disproportionately affected in language-predominant dementias. Because most cognitive tests are language based, patients with PPA often perform worse than expected given their level of day-to-day functioning (the opposite of what is seen in behavioral-variant FTD). Structural imaging can be very helpful; attention should be paid to asymmetric involvement of the left temporal lobe, which is atrophied in the semantic variant of PPA (Figure 19). Functional brain imaging (FDG-PET) can identify a pattern of asymmetric lobar abnormality in patients with inconclusive brain MRIs. Treatment There are no pharmacologic therapies specifically approved for PPA. All affected patients should be assessed by a speech therapist. If language comprehension is an issue, assistive lan- FIGURE 19. Brain MRI of a 64-year-old woman showing severe left temporal guage devices can be helpful. lobe atrophy (arrow), consistent with semantic variant primary progressive aphasia. 46

Cognitive Impairment order to develop the criteria laid out in TES. Prospective stud- TABLE 30. Diagnostic Features of Dementia with Lewy ies are underway to correlate the clinical diagnosis of TES with Bodies the pathology found in CTE. | Features Specific Symptoms The frontal and temporal lobes are most susceptible to | : Central feature Dementia , damage from head trauma, and symptoms often reflect dam- Core features Parkinsonism, fluctuations in attention, age to these areas. TES may develop over many years, which | rapid eye movement sleep behavior | makes the diagnosis challenging, particularly when it occurs disorder, and recurrent visual | in patients in their sixties and seventies when the prevalence | hallucinations of other dementias also increases. | Supportive Severe neuroleptic sensitivity, transient | The proposed clinical diagnostic criteria for TES require features episodes of loss of consciousness, | significant daytime somnolence, severe persistence of symptoms for longer than 2 years, no other neu- delusions (especially early in dementia rologic disorder more likely to account for all of the clinical course), apathy, repeated falls, and | features, history of repetitive head trauma exposure, progres- orthostatic hypotension |

of other dementias also increases. | Supportive Severe neuroleptic sensitivity, transient | The proposed clinical diagnostic criteria for TES require features episodes of loss of consciousness, | significant daytime somnolence, severe persistence of symptoms for longer than 2 years, no other neu- delusions (especially early in dementia rologic disorder more likely to account for all of the clinical course), apathy, repeated falls, and | features, history of repetitive head trauma exposure, progres- orthostatic hypotension | sive course, delayed symptom onset, and subjective report of | Indicative Polysomnographic confirmation of REM | biomarkers sleep without atonia cognitive dysfunction confirmed by objective decline on for- mal neuropsychological testing. Supportive features include Reduced dopamine transporter uptake in | | basal ganglia evident on SPECT or PET | emotional dysregulation, behavior change, and motor distur- | scans s bance with Parkinsonian features. REM = rapid eye movement; SPECT = single photon emission CT. — Evaluation Yearly neuropsychological testing is recommended in patients DLB is the second most common neurodegenerative

sive course, delayed symptom onset, and subjective report of | Indicative Polysomnographic confirmation of REM | biomarkers sleep without atonia cognitive dysfunction confirmed by objective decline on for- mal neuropsychological testing. Supportive features include Reduced dopamine transporter uptake in | | basal ganglia evident on SPECT or PET | emotional dysregulation, behavior change, and motor distur- | scans s bance with Parkinsonian features. REM = rapid eye movement; SPECT = single photon emission CT. — Evaluation Yearly neuropsychological testing is recommended in patients DLB is the second most common neurodegenerative with TES to document objective cognitive decline over time. dementia after Alzheimer disease. «-Synuclein deposits, or Brain atrophy is typically global as seen on structural brain Lewy bodies, are the chief pathologic feature of DLB and com- imaging, which can help differentiate TES from FTD (which is monly coexist with pathologic features of Alzheimer disease. associated with frontal lobe atrophy). The prevalence of DLB significantly increases with age, and this dementia often progresses more rapidly than Alzheimer Treatment disease. The clinical diagnosis rests on the key features of No clinical trials comparing various treatments have been dementia, parkinsonian motor features (particularly gait

associated with frontal lobe atrophy). The prevalence of DLB significantly increases with age, and this dementia often progresses more rapidly than Alzheimer Treatment disease. The clinical diagnosis rests on the key features of No clinical trials comparing various treatments have been dementia, parkinsonian motor features (particularly gait performed in TES or CTE. Cholinergic deficits have been problems and slowness of movements), visual hallucinations, identified pathologically, which suggests that acetylcho- rapid eye movement (REM) sleep behavior disorder, and fre- linesterase inhibitors might be useful. As in behavioral- quent fluctuations in attention (Table 30). The latter may variant FTD, treatment is often symptom directed and manifest as acute confusional episodes in which the patient is includes antidepressants, mood stabilizers, and (occasion- less responsive than usual or as intermittent days with exces- ally) stimulants for severe apathy. Close monitoring for sive daytime sleepiness.

variant FTD, treatment is often symptom directed and manifest as acute confusional episodes in which the patient is includes antidepressants, mood stabilizers, and (occasion- less responsive than usual or as intermittent days with exces- ally) stimulants for severe apathy. Close monitoring for sive daytime sleepiness. suicidality also should be part of treatment strategy for Distinguishing DLB from Alzheimer disease on the basis patients with TES. of cognition alone can be difficult, but other symptoms can help differentiate the two. Delusions and hallucinations are common and frequently occur at the mild stages of DLB. ¢ The cognitive pattern typical of traumatic encephalopa- Additionally, significant sleep problems, especially daytime thy syndrome is often one of cognitive slowing and dis- sleepiness, can be a debilitating feature of DLB, and REM organized thought processing, with less involvement of sleep behavior disorder is much more common in DLB than memory and visuospatial function early in the disease Alzheimer disease. course; as the disease progresses, symptoms of mild Making the diagnosis of DLB as early as possible is parkinsonism can occur. important because the behavioral problems associated with this condition frequently result in the use of antip- Dementias with Early Motor Signs sychotic agents. Many patients with DLB are extremely Dementia with Lewy Bodies and Parkinson sensitive to neuroleptic medications, particularly first- Disease Dementia generation agents, and are at high risk for developing a Because Parkinson disease is a progressive neurodegenerative severe worsening of symptoms resembling neuroleptic disorder, cognitive symptoms frequently develop at some malignant syndrome. point in the disease course. When dementia occurs well after the motor symptoms, it is considered Parkinson disease Evaluation dementia. When dementia and motor symptoms develop Clinical history and neurologic examination findings are criti- within 1 to 2 years of each other, it is classified as dementia cal for the diagnosis of DLB. Indicative biomarkers also have with Lewy bodies (DLB). been developed to support the diagnosis when sufficient

suicidality also should be part of treatment strategy for Distinguishing DLB from Alzheimer disease on the basis patients with TES. of cognition alone can be difficult, but other symptoms can help differentiate the two. Delusions and hallucinations are common and frequently occur at the mild stages of DLB. ¢ The cognitive pattern typical of traumatic encephalopa- Additionally, significant sleep problems, especially daytime thy syndrome is often one of cognitive slowing and dis- sleepiness, can be a debilitating feature of DLB, and REM organized thought processing, with less involvement of sleep behavior disorder is much more common in DLB than memory and visuospatial function early in the disease Alzheimer disease. course; as the disease progresses, symptoms of mild Making the diagnosis of DLB as early as possible is parkinsonism can occur. important because the behavioral problems associated with this condition frequently result in the use of antip- Dementias with Early Motor Signs sychotic agents. Many patients with DLB are extremely Dementia with Lewy Bodies and Parkinson sensitive to neuroleptic medications, particularly first- Disease Dementia generation agents, and are at high risk for developing a Because Parkinson disease is a progressive neurodegenerative severe worsening of symptoms resembling neuroleptic disorder, cognitive symptoms frequently develop at some malignant syndrome. point in the disease course. When dementia occurs well after the motor symptoms, it is considered Parkinson disease Evaluation dementia. When dementia and motor symptoms develop Clinical history and neurologic examination findings are criti- within 1 to 2 years of each other, it is classified as dementia cal for the diagnosis of DLB. Indicative biomarkers also have with Lewy bodies (DLB). been developed to support the diagnosis when sufficient 47

Cognitive Impairment clinical history is lacking. Reduced dopamine transporter Normal Pressure Hydrocephalus uptake in the basal ganglia on a single photon emission CT or Normal pressure hydrocephalus (NPH) is characterized by the PET scan is supportive of a parkinsonian disorder, as is REM triad of gait changes, urinary incontinence, and cognitive sleep behavior disorder seen on polysomnography. impairment. Gait impairment, the most prominent feature, is characterized by shuffling short step length and often prob- Treatment lems with starting ambulation (hesitation). The feet can Although not formally approved for DLB, acetylcholinester- appear as though they are stuck to the ground, which is ase inhibitors can be effective in treating the cognitive described as a “magnetic” gait. symptoms of the disorder, according to expert opinion. Rivastigmine has been approved for treating Parkinson dis- Evaluation ease dementia but not DLB; there is no evidence that Gait changes can occur for multiple reasons and in several memantine is beneficial. The treatment of behavioral symp- neurodegenerative diseases, so recognition of the gait pat- toms is often necessary, but first-generation antipsychotic tern specific for NPH is crucial. Similarly, alternative causes agents are strongly contraindicated. REM sleep behavior for urinary incontinence should be excluded. Of note, the disorder typically improves with high-dose melatonin sup- typical pattern of urinary incontinence in NPH is a lack of plementation (5-12 mg) at bedtime. In those not responding awareness of a full bladder, which leads to problems reach- to melatonin supplementation, clonazepam is considered ing the bathroom in time; this can be categorized as urge or the drug of choice. functional incontinence. Cognitive testing typically reveals a pattern of slowing and executive cognitive impairment; KEY POINTS some patients may require formal neuropsychological e The clinical diagnosis of dementia with Lewy bodies testing. rests on the key features of dementia, parkinsonian A brain MRI or CT scan should be obtained because motor features (particularly gait problems and slow- NPH cannot be diagnosed without evidence of ventriculo- ness of movements), visual hallucinations, REM megaly (enlarged cerebral ventricles) (Figure 20). Lumbar sleep behavior disorder, and frequent fluctuations in puncture with high-volume (30 mL) CSF removal and attention. determination of opening pressure also is required. A timed e Many patients with dementia with Lewy bodies are gait evaluation should be performed just before CSF extremely sensitive to neuroleptic medications, particu- removal and within 30 minutes after removal. Objective larly first-generation agents, and are at high risk for improvement in quality and speed of gait after CSF removal developing a severe worsening of symptoms resembling is an accurate predictor of NPH improvement with neuroleptic malignant syndrome. shunting.

clinical history is lacking. Reduced dopamine transporter Normal Pressure Hydrocephalus uptake in the basal ganglia on a single photon emission CT or Normal pressure hydrocephalus (NPH) is characterized by the PET scan is supportive of a parkinsonian disorder, as is REM triad of gait changes, urinary incontinence, and cognitive sleep behavior disorder seen on polysomnography. impairment. Gait impairment, the most prominent feature, is characterized by shuffling short step length and often prob- Treatment lems with starting ambulation (hesitation). The feet can Although not formally approved for DLB, acetylcholinester- appear as though they are stuck to the ground, which is ase inhibitors can be effective in treating the cognitive described as a “magnetic” gait. symptoms of the disorder, according to expert opinion. Rivastigmine has been approved for treating Parkinson dis- Evaluation ease dementia but not DLB; there is no evidence that Gait changes can occur for multiple reasons and in several memantine is beneficial. The treatment of behavioral symp- neurodegenerative diseases, so recognition of the gait pat- toms is often necessary, but first-generation antipsychotic tern specific for NPH is crucial. Similarly, alternative causes agents are strongly contraindicated. REM sleep behavior for urinary incontinence should be excluded. Of note, the disorder typically improves with high-dose melatonin sup- typical pattern of urinary incontinence in NPH is a lack of plementation (5-12 mg) at bedtime. In those not responding awareness of a full bladder, which leads to problems reach- to melatonin supplementation, clonazepam is considered ing the bathroom in time; this can be categorized as urge or the drug of choice. functional incontinence. Cognitive testing typically reveals a pattern of slowing and executive cognitive impairment; KEY POINTS some patients may require formal neuropsychological e The clinical diagnosis of dementia with Lewy bodies testing. rests on the key features of dementia, parkinsonian A brain MRI or CT scan should be obtained because motor features (particularly gait problems and slow- NPH cannot be diagnosed without evidence of ventriculo- ness of movements), visual hallucinations, REM megaly (enlarged cerebral ventricles) (Figure 20). Lumbar sleep behavior disorder, and frequent fluctuations in puncture with high-volume (30 mL) CSF removal and attention. determination of opening pressure also is required. A timed e Many patients with dementia with Lewy bodies are gait evaluation should be performed just before CSF extremely sensitive to neuroleptic medications, particu- removal and within 30 minutes after removal. Objective larly first-generation agents, and are at high risk for improvement in quality and speed of gait after CSF removal developing a severe worsening of symptoms resembling is an accurate predictor of NPH improvement with neuroleptic malignant syndrome. shunting. FIGURE 20. Axial fluid-attenuated inversion recovery (FLAIR) (left) and coronal 11 with contrast (right) MRIs showing ventriculomegaly (arrows), little cortical atrophy, and mild periventricular FLAIR hyperintensities, all consistent with normal pressure hydrocephalus.

FIGURE 20. Axial fluid-attenuated inversion recovery (FLAIR) (left) and coronal 11 with contrast (right) MRIs showing ventriculomegaly (arrows), little cortical atrophy, and mild periventricular FLAIR hyperintensities, all consistent with normal pressure hydrocephalus. 48