Alzheimer’s disease

In 2011, the National Institute on Aging and the Alzheimer’s Association Workgroup revised the diagnostic criteria for AD. The revision identified three distinct stages of AD: preclinical AD (no clinical application; diagnosed using cerebral spinal fluid and neuroimaging as biomarkers and intended to guide research); mild cognitive impairment attributed to AD without functional deficits; and dementia due to AD with cognitive impairment severe enough to cause deficits in activities of daily living.[16]

Alzheimer’s dementia is the most common form of dementia in the elderly, accounting for 60%– 80% of all cases.[2] It is estimated that approximately 5 million adults over the age of 65 are currently living with AD in the United States.[2, 17] The cost of caring for one patient with AD is $47,000 per year, primarily as a result of hospitalization, long-term care, and hospice.[2] The economic burden of this disease is surpassed only by the tremendous social and emotional burden on patients, families, and caregivers.

Epidemiological research has identified the following risk factors for AD: age, presence of the apolipoprotein E epsilon 4 (APO E4) genotype, family history, Down syndrome, and head trauma. Cardiovascular risk factors, including diabetes, hypertension, and lipid abnormalities, have also been associated with AD.[8–10] It appears that “what is good for the heart is good for the brain.”

Higher education has been found to be a protective risk factor for AD. Experts believe that individual differences in how tasks are processed may allow for a degree of “cognitive reserve” from brain pathology. Participation in both leisure and physical activity may also be protective for development of AD.[2]

Brain pathology consistent with AD includes the presence of extracellular amyloid-β protein-42 (Aβ₄₂) deposition, intracellular neurofibrillary tangles (NFTs), and dystrophic neuritis.[19, 20] AD is characterized by accumulation of an abnormal form of the protein tau inside neurons, leading to neuronal loss, especially among neurons that release the neurotransmitter acetylcholine.[19, 21]

The etiology of neuronal damage in the brains in AD patients is believed to be related to misfolded proteins that trigger oxidative and inflammatory damage to the neurons. The pathophysiology of AD likely traces back to a family of amyloid precursor proteins that are cleaved by specific secretases. When amyloid precursor protein is cleaved by a γ-secretase on one end and a β-secretase on the other end, a highly amyloidogenic Abeta42 protein is released. This protein appears to aggregate in diffuse plaques, which evolve into dense neuritic plaques.[22] Abeta oligomers, therefore, are probable mediators of neurotoxicity.[23] Once the neuritic plaque has formed, secondary cascades of inflammation, excitotoxicity, and apoptosis may trigger additional damage.[19]

The formation of NFTs and their role in the pathophysiology of AD remains controversial. NFTs consist of a hyperphosphorylated form of the microtubule-associated protein, tau. Severity of cognitive decline correlates with NFT burden more so than with amyloid deposition, suggesting that a mutant tau protein, rather than the NFT, may be the primary neurotoxic mediator.[24, 25] Cleavage of tau, a critical step in NFT formation, appears to be triggered by accumulation of Abeta42 protein through activation of caspases. Interestingly, brain changes may accumulate for more than 20 years before clinical symptoms are observed, leading experts to recognize that there may be a “continuum” of AD in which individuals are initially able to function without impairment but may progress as neuronal damage escalates.[2]

Clinically, AD is characterized by an insidious onset, and early detection is often the result of informant concerns. Early symptoms include loss of short-term memory, repeating statements, and apathy or depression. Later symptoms include difficulty with communication, confusion, poor judgment, and behavior changes. More advanced symptoms include difficulty speaking, swallowing, and walking. In late stages of AD, patients frequently become dependent on others for activities of daily living (ADLs), such as bathing and toileting.

AD is marked by a gradually progressive course and a shortened life expectancy. The sixth leading cause of death in the United Sates and the fifth leading of all-cause mortality in individuals aged 65 and older is AD. Median survival time from time of diagnosis is four to eight years.[2] Mortality predictors include dementia severity at time of diagnosis, abnormal neurological findings, and the presence of comorbidities, such as heart disease and diabetes.[26] Pneumonia is the most common terminal event in patients with progressive dementia.

Vascular dementia and vascular cognitive impairment

Cerebrovascular disease (CVD) is a heterogeneous group of disorders characterized by brain infarct, cerebral hemorrhage, white matter lesions, atherosclerosis, cerebral amyloid angiopathy, and genetic disorders.[27, 31, 32] Cerebrovascular disease is implicated in and contributes to various subtypes of dementia.[29] Due to a lack of consensus on the diagnostic criteria for vascular dementia (VaD), identification of VaD has been challenging for clinicians, and estimates of prevalence are harder to identify.[27, 29, 30] The American Heart Association (AHA) and American Stroke Association (ASA) recently proposed the terminology vascular cognitive impairment (VCI) to include syndromes of cognitive impairment with evidence of either clinical or subclinical vascular brain injury, spanning a spectrum from least severe to most severe.[27]

Vascular dementia (or VCI) is currently believed to be the second most common etiology for dementia, with risk doubling every 5.3 years after the age of 65.[27, 31, 33] Prevalence increases with both age and male gender.[27] Risk factors are similar to those for CVD and include hypertension, diabetes mellitus, smoking, hyperlipidemia, and atrial fibrillation.[27, 31, 33]

Diffuse hypoxia, disruption of the blood brain barrier, inflammation, and oxidative stress alter the neuronal networks involved in cognition, behavior, memory, and execution.[13, 27] Studies have shown that both AD and vascular lesions often coexist in approximately 25%–80% of subjects with dementia, confirming an overlap in these syndromes.[13] Increasingly experts agree that “mixed” dementia with AD plus VCI is far more common than previously recognized.[13]

Despite suffering from a lack of uniform diagnostic criteria, clinical features that may suggest the diagnosis VCI include onset of temporal cognitive deficit in two or more cognitive domains particularly in complex attention and frontal-executive function, abrupt onset of symptoms followed by a stepwise deterioration, and findings on physical examination that are consistent with a previous stroke.[1, 27, 29] Neuropathology in VCI shows focal, multifocal, or diffuse lesions, including white matter lesions (WMLs), lacunar and other cerebral microbleeds (CMBs), and hippocampal atrophy.[13, 27]

Frontotemporal dementia

Pathologically, frontotemporal dementia (FTD) is characterized by focal atrophy of the frontal and temporal lobes, in the absence of findings consistent with AD.[34] Specific regions of atrophy correlate with the clinical and neuropathological syndrome.[35] These regions often show decreased perfusion on single photon emission computed tomography, fluoro-deoxyglucose positron emission tomography (FDG-PET), and perfusion MRI.[36, 37, 38] Although mutations in the tau gene on chromosome 17 have been implicated in familial FTD, the pathogenesis of nonfamilial FTD remains unclear.[39, 40] Autopsy, neuroimaging, and cerebrospinal fluid studies suggest that FTD is characterized by a serotonergic deficit, which likely contributes to the behavioral abnormalities associated with FTD.[41]

There are three distinct clinical subtypes of FTD: behavioral, language, and motor.[42, 43] The behavioral subtype is the most common form of FTD, with 90% of patients developing personality changes during the course of their illness. The personality change is often dramatic and is characterized by social inappropriateness, poor judgment, and disinhibition.[44] Impairment of executive function, insight, and memory are also common features in behavioral FTD.[45, 46] Individuals affected by the behavioral-variant FTD often develop symptoms around age 60, younger than many patients typically diagnosed with dementia syndromes. Findings on perfusion imaging studies often correlate with behavioral symptoms. For example, prominent frontal hypoperfusion is associated with apathy and poor hygiene and self-care, and prominent temporal hypoperfusion is associated with hypomania and compulsive behaviors.[37]

Early progressive language dysfunction or “primary progressive aphasia” is the second most common phenotype in FTD and is characterized by three subtypes: progressive nonfluent aphasia (or nonfluent/agrammatic aphasia); progressive fluent aphasia (or semantic dementia); and progressive mixed aphasia (or logopenic aphasia). Progressive nonfluent aphasia is characterized pathologically by prominent inferior lobe atrophy and clinically by difficulty with interruption in speech. With progression, logorrhea (abundant unfocused speech) may develop. Progressive fluent aphasia is associated with marked anterior temporal lobe atrophy that may lead to white matter tract enervation, thereby inhibiting communication. Patients often present with difficulty in naming and in understanding words (secondary to involvement of the left temporal lobe) or with difficulty in face and object recognition but with normal speech (secondary to involvement of right temporal lobe). Progressive mixed aphasia is characterized pathologically by prominent parietal lobe atrophy and clinically by word-finding difficulty and inability to produce meaningful use (phonemic paraphasia).[47] Further studies are needed regarding the sensitivity of this new subtyping criteria.

The third type of FTD involves a prominent motor component on presentation. Patients demonstrate extra pyramidal motor symptoms or signs of bulbar or spinal motor neuron disease. Patients with bulbar or spinal motor neuron disease (FTD–motor neuron disease) often have motor symptoms within 12 months of disease onset and generally have a rapidly progressive disease course.[45]

Dementia with parkinsonism

A number of parkinsonian disorders are associated with dementia. The two most common forms of dementia with parkinsonism are dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Atypical parkinsonian syndromes such as progressive supranuclear palsy (PSP), multisystem atrophy, and corticobasilar ganglionic degeneration also produce dementia syndromes.

Creutzfeldt-Jakob disease

Human prion disease consists of a rare group of neurodegenerative diseases resulting from a misfolded protein (prion) that causes the brain to malfunction. Subtypes include Creutzfeldt-Jakob disease (sporadic CJD), variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, Kuru, and fatal insomnia.[68, 69] However, Creutzfeldt-Jakob disease (sporadic CJD) accounts for approximately 85% of prion disease.

Clinically, sporadic CJD presents with a rapid onset of cognitive impairment as well as motor deficits and seizures; mean age of onset is approximately 65 years old.[69] It should be suspected in any patient presenting with a rapidly progressive dementia, visual disturbance, change in personality, and ataxia.[69, 70] Mean duration of illness is eight months.[69]

Variant Creutzfeldt-Jakob disease is the second common type of prion disease and usually affects young adults. The primary risk factor is consumption of contaminated cattle affected by “mad cow” disease. Clinical presentation is a gradual onset associated with psychiatric and neurological manifestations.[68, 69] Electroencephalography, cerebrospinal fluid studies, and gray matter abnormalities on diffusion MRI can be helpful in determining the diagnosis.[71–73]

Reversible dementia

Although potentially reversible causes of dementia account for less than 10% of cases of dementia, identifying and treating these disorders remain a top priority.[74–76] Vitamin deficiencies, thyroid dysfunction, depression, and normal-pressure hydrocephalus (NPH) have all been identified as more common reversible causes of dementia to consider in the initial differential diagnosis (see Table 10.2) of a patient presenting with cognitive impairment, but there are numerous causes of potentially reversible dementias in an expanded differential (see Table 10.3). Although these syndromes are considered “potentially” reversible, it is important to note that the majority of patients with these syndromes do not improve even when these disorders are promptly discovered and treated. Rates of reversal range from only 0.6% to 11% of cases.[76, 77]

Normal-pressure hydrocephalus

Patients with NPH often present with a triad of gait disturbance (“magnetic gait”), urinary incontinence, and cognitive dysfunction. Although NPH should be considered in patients with these symptoms, it is also important to recognize that many older adults have one or more of these symptoms in the absence of NPH. Nevertheless, NPH is amenable to treatment with a surgical shunt and, therefore, should still be considered in patients who fit the clinical scenario. Risk factors include patients with a history of brain hemorrhage and meningitis. Confirmatory studies include imaging studies, radioisotope diffusion studies, and the Fisher test, which involves gait assessment before and after the removal of 30 mL of cerebrospinal fluid. The Fisher test is also useful in predicting a response to ventriculoperitoneal shunting, the treatment of choice.[14, 77, 78]

Delirium

Delirium, a condition characterized by fluctuating levels of consciousness and inattention, must also be distinguished from dementia. Whereas dementia is characterized by an insidious onset, the onset of delirium is usually abrupt and often precipitated by illness, intoxication, or medication. Delirium is associated with a high morbidity and mortality, but unlike dementia, delirium typically resolves if the underlying cause is addressed.[80, 81] Still, recovery from delirium may be protracted in older adults, and delirium may even become chronic in some patients, making it difficult to distinguish from dementia. (See Chapter 11 for more details.)

Mild cognitive impairment

Mild cognitive impairment (MCI) is a more recent research construct that attempts to define cognitive impairment that does not significantly affect function, a hallmark of dementia. Most experts agree that MCI is a known risk factor for dementia, but studies have demonstrated that progression from MCI into dementia is variable. The prevalence of MCI observed in the Mayo Clinic Study of Aging (MCSA), a prospective study of community-dwelling adults 70–89 years of age without dementia, was 16% with a higher prevalence among men.[82] In another recent study, the incidence of MCI was 64 per 1,000 person-years, with a higher incidence in men.[83]

Neuropsychological testing further categorizes MCI into subtypes – amnestic (aMCI) or nonamestic (naMCI) – and as single-domain (sdMCI) or multiple-domain (mdMCI), dependent on the number of cognitive domain impairments on testing.[82, 83] Patients with aMCI present with subjective or objective concerns regarding memory impairment with or without any cognitive domain deficit on exam and are most likely to transition to AD. Risk factors for aMCI include male gender, lower education level, social inactivity, and increasing age.[82–84] Patients with naMCI present clinically without memory impairment and may progress to dementia not due to AD.[83] A prospective population-based study observed that cardiac risk factors increase the likelihood of naMCI by threefold in women.[82, 85]

Progression of MCI to dementia varies, with an observed annual conversion rate of 5%–10%.[86] Predictors for progression to dementia include APOE epsilon4 allele carriers, amyloid deposition, CSF biomarkers, cerebral glucose hypometabolism, temporal lobe atrophy, and clinical severity of cognitive impairment.[87–93]

History

Most patients with dementia do not present with a subjective complaint of memory loss. Rather, a caregiver or family member often raises the concern of memory loss or behavioral change to the practitioner. For example, informants may report that the patient has had trouble remembering events and preparing finances, has gotten lost in familiar settings, cannot find appropriate words, or has been demonstrating unusual behaviors. Informants play an integral role in helping providers understand the onset, nature, and progression of symptoms.

A thorough history also hinges on a systematic review of prescription and over-the-counter medication use. Use of medications that may impair cognition, such as anticholinergics, psychotropics, and sedative hypnotics, should be determined. Performing a functional assessment is another key step in the evaluation of patients with dementia. Functional impairment is often assessed by asking the patient and family members or informants about instrumental ADLs (i.e., managing finances, household chores, and taking medications) and ADLs (i.e., dressing, grooming, and toileting). The Global Deterioration Scale and Functional Assessment Staging is another standardized tool that can be used to measure dementia-related dependency.[65]

Physical examination

A comprehensive history and functional assessment should be followed by a complete physical examination. During the physical exam, special attention should be given to the neurologic examination to evaluate other possible causes of memory impairment. Focal neurological deficits consistent with previous stroke, signs of parkinsonism, and abnormal gait and eye movements may be particularly revealing.

Cognitive assessment

Although agreement between history and physical examination is suggestive of a diagnosis of dementia, a cognitive assessment is necessary to diagnose and differentiate dementia syndromes. Cognitive performance, however, is influenced by numerous factors, not all of which are indicative of dementia. For example, inefficient learning strategies, slowed processing, decreased attention, and sensory deficits may affect the results of cognitive testing. Age, education, and demographic factors may alter performance and must be incorporated into the analyses of test results.[96]

The Mini-Mental Status Examination (MMSE) is the most commonly used screening test for dementia. The examination tests orientation, registration, attention, and calculation, and it is used to diagnose and stratify patients into mild, moderate, and severe dementia. Traditionally, a perfect score is 30; scores of 25–29 suggest MCI; scores of 19–24 indicate mild dementia; scores of 15–19 indicate moderate dementia; and scores of 14 or less are consistent with severe dementia. Using a cut-off of 23/24, the MMSE has a sensitivity of 79% and a specificity of 95%.[97] Studies assessing the use of the MMSE have been done with relatively small sample sizes, and the MMSE is not as sensitive for mild dementia as it is for more moderate or sever impairment. In addition, the MMSE is influenced by age, education, language, and motor and/or visual impairments. Tools that incorporate age, sex, and educational attainment are now available to help correct the interpretation of these results.[98, 99] For example, in patients with less than nine years of education, a score of 17 or less is consistent with mild, not moderate, impairment.

MMSE testing can be used not only to diagnose cognitive impairment or dementia, but also to follow its progression. Over time, most patients will display a steady deterioration in their MMSE testing scores. For example, in patients with AD, the average decline in MMSE is two to four points per year. More recently, the MMSE has also been used to assess decision-making competency. Studies suggest that scores higher than 23 or scores lower than 19 are reliable in distinguishing competency from incompetency. Intermediate scores may require a more complete evaluation.[100, 101]

The clock-drawing test (CDT) is a quick screen for cognitive impairment, taking less than five minutes to perform. During this test, the patient is asked to draw a clock face with all of the numbers and label the face with a specified time, such as “10 minutes to 2 o’clock.” The person is given one point for labeling all 12 numbers, three points for placing the 12 at the top, one point for drawing two hands, and one point for the correct identification of the time. A score of fewer than four points indicates impairment.[102] The CDT is appealing because of ease of administration, but like the MMSE, it is not sensitive to mild impairment.[103]

The Mini-Cog is another brief screening test that combines the CDT and the three-item recall from the MMSE. Patients who recall none of the three words are classified as demented, those who recall all of the three words are nondemented, and those who recall one or two of the three words are classified as either demented or nondemented based on the results of their CDT.[104] A retrospective analysis and a post-hoc examination suggests that the sensitivity and specificity of the Mini-Cog is similar to that of the MMSE.[104, 105] The advantage of the Mini-Cog is its high sensitivity, ease of administration, and lack of influence by the patient’s education level.

The Montreal Cognitive Assessment (MoCA) was designed to screen for mild cognitive impairment. The MoCA takes approximately 10 minutes to administer, and it is used to evaluate memory, attention, concentration, executive functions, language, visuospatial skills, and orientation. Similar to the MMSE, a perfect score is 30, adjusting for education; a cut-off score of 25/26 had 100% sensitivity and 87% specificity for detecting MCI.[106] The tool is freely available online with instructions for use and interpretation of results, including normative data (www.mocatest.org). Further research is needed to validate the use of MoCA as a screening tool in primary care. Studies comparing MoCA to MMSE demonstrated good sensitivity and moderate specificity in detecting MCI.[107, 108] MoCA may also be particularly helpful in detecting vascular dementia.[109–111]

Neuropsychological testing encompasses a wide array of tests and involves a more extensive evaluation of multiple cognitive domains. In a practice parameter from 2001, the American Academy of Neurology (AAN) concluded that neuropsychological testing is useful in distinguishing MCI from dementia in patients presenting with memory loss and in distinguishing different dementia syndromes. The five instruments deemed most reliable by the AAN were the animal-naming test, the Modified Boston Naming test, the MMSE, Constructional Praxis, and Word List Memory.[112] An aggregate total score from these five tests has been shown to differentiate accurately patients undergoing normal aging from patients with AD.[113]

Finally, an assessment of premorbid literacy is crucial to determining the extent of dementia in a patient. The National Adult Reading Test involves the pronunciation of 50 English words and has been validated as an estimator of premorbid ability in a study of 80-year-olds.[114] This test is often administered prior to a full neuropsychiatric evaluation.

Laboratory evaluation

The only laboratory evaluation recommended for all patients with suspected dementia includes screening for hypothyroidism and B12 deficiency.[14] Tailored laboratory evaluation is otherwise guided by clinical findings and may include assessment of the complete blood count, liver function studies, electrolytes, syphilis and Lyme serology, and human immunodeficiency virus status. The cost-effectiveness of obtaining multiple laboratory studies has been called into question because of the low likelihood of detecting a reversible dementia.[115]

Recently, plasma phospholipids have been identified as a possible biomarker for the diagnosis of preclinical AD. Accuracy is approximately 90% for predicating progression to MCI or AD within two to three years in individuals without cognitive impairment.[116] Currently biomarker testing is not recommended as part of a routine laboratory evaluation, but extensive research in this area is underway.

Genetic testing

Genetic testing for most patients with dementia is not recommended. However, the American College of Medical Genetics and the National Society of Genetic Counselors do recommend genetic testing when familial AD is suspected (e.g., individuals or multiple family members have a history of early onset AD or have a relative with a known history for a mutated gene associated with early onset AD).[117] Although screening for the presence of the APO E4 allele has garnered much research interest because it is a known risk factor for AD, its utility as a diagnostic test is limited because not all persons who are homozygote for the allele develop AD.[118] Until more research is available in this area, the potential for harm based on over-diagnosis of the disease is tremendous.[119]

Neuroimaging

The role of neuroimaging in patients with suspected dementia is in evolution. Although many clinical prediction rules do not recommend routine screening with neuroimaging, the AAN recommends neuroimaging in the initial evaluation of all patients with dementia.[14] The Alzheimer’s Association Position Statement recommends the use of MRI in clinical diagnosis of dementia and cognitive impairment to identify small lacunar infarcts, white matter ischemic changes, hippocampal atrophy, and volumetric changes.[120] MRI findings can lend support to a presumed diagnosis; for example, generalized or focal atrophy may be suggestive of AD, and white matter lesions may indicate ischemic disease.[14] Several studies suggest that hippocampal atrophy might allow for early detection of AD, may help in following the course of the disease, and may guide future treatment decisions.[121, 122] The Alzheimer’s Disease Neuroimaging Initiative is a large, multisite study that is now underway and is designed to evaluate the specific role of neuroimaging in the diagnosis of AD and in monitoring the progression of MCI.[123]

The use of functional imaging studies, such as PET, single photon emission computerized tomography, and functional MRI (fMRI) in the diagnosis of dementia is currently being studied.[123] Fluorodeoxyglucose (FDG)-PET preliminary findings suggest that functional studies may detect temporoparietal deficits in early AD that shift to the frontal region with progression of AD.[123, 124] In 2005, the Centers for Medicare and Medicaid (CMS) approved reimbursement for FDG-PET as an adjunctive diagnostic tool for dementia. There is no evidence, however, that the additional diagnostic accuracy provided by PET leads to improved patient outcomes or cost-effective medical care. At present, The Alzheimer’s Association and the National Institute on Aging (NIA) do not advocate routine use of PET imaging for a presumed diagnosis of dementia and cognitive impairment; however, PET usage is recommended for research in preclinical AD.[125]

Molecular neuroimaging using amyloid imaging tracers is a primary research focus to improve detection of AD before changes in brain structures occur. This may help to assess disease progression as well as efficacy of disease modifying medications in the future.[2] One agent, the Pittsburgh Compound-B (PIB), has demonstrated good binding to amyloid B peptide in areas with significant amyloid deposition in postmortem studies of the human brain.[126] A longitudinal study with PIB observed that amyloid deposition independent of brain atrophy does not accurately identify AD; however, it might be useful in conjunction with MRI to improve diagnostic accuracy of dementia.[126, 127]

Brain biopsy

The brain biopsy as a diagnostic tool has become nearly obsolete. It is rarely used in younger patients with acute onset of cognitive impairment or those with an atypical clinical presentation suggesting a reversible disorder. Brain biopsy is invasive, carries a low diagnostic yield, and rarely leads to specific treatment interventions.

Screening guidelines

Despite the availability of guidelines for the diagnosis of dementia, routine screening of all older adults is not widely recommended. In 2010, the Alzheimer’s Association and Medicare Detection of Cognitive Impairment recommended that cognitive impairment assessment should be included in the annual wellness visit (AWV).[128] However, the US Preventive Services Task Forces has concluded that there is insufficient evidence (I recommendation) to support routine screening for dementia in older adults.[129] There are currently insufficient data to support a beneficial effect of early diagnosis and treatment. Also, the feasibility, cost-effectiveness, and potential harms of routine screening of all older adults are largely unknown.

Treatment of dementia

Advances in understanding the pathophysiology of dementia have allowed for development of more targeted pharmacological therapies; however, the cornerstone of the management of dementia is still symptomatic and geared largely toward minimizing functional disability, addressing behavioral disturbances, and preventing injury. Despite a number of setbacks, the search for effective disease-specific and disease-modifying therapies holds promise.

Pharmacological management

Nonpharmacological management

Many nonpharmacologic interventions have been studied for the treatment of individuals with dementia. Cochrane reviews of 25 categories of nonpharmacologic therapies found evidence to support a beneficial effect for cognitive training, cognitive stimulation, and ADL training for patients with dementia.

Behavioral disturbances

The prevalence of neuropsychiatric symptoms in patients with dementia is common, occurring in nearly 60% of patients. This often accounts for significant caregiver burden.[175–177] Behavioral and psychological symptoms are often the most challenging management issue for caregivers and are predictive of nursing home placement;[176] therefore, attention to these behaviors is paramount in the care of patients with dementia. Longitudinal interventions tailored to the needs of the patient and the caregiver (including activity planning and environmental redesign as well as skills training, education, and support for caregivers) can help to decrease these symptoms.[178]

Improving communication and patient perception is one strategy to reduce behavioral disturbances. Reduction of sensory impairment is imperative in communicating with patients with dementia; glasses and hearing aids should always be available and environmental noise and visual disturbances should be minimized. Caregivers should be encouraged to interact with the patient at eye level, avoid threatening stances or gestures, and to speak softly and slowly.

Caregiver training to identify antecedents, response, and consequences of a problematic behavior may also be helpful. Using an “ABC” method, caregivers are asked first to identify the antecedents (A) or triggers for certain behavior such as a change in schedule, interpersonal conflict, or physical stressor; once identified, these antecedents can be avoided or minimized. The caregiver is then asked to describe the behavior (B) elicited by the antecedent and to understand when, where, and how often it occurs. Finally, the caregiver notes the consequences (C) of the behavior, such as how the caregivers reinforce or deter the activity and what happens after the behavioral disturbance.[179]

Another strategy to address behavioral disturbance is to approach the patient from a social, environmental, and medical perspective.[180] Tailored behavioral strategies in a randomized study of 272 caregivers and people with dementia demonstrated a 68% improvement in behavioral symptoms as well as alleviating depressive symptoms in a majority of caregivers.[181] A meta-analysis of 23 high-quality trials for multipronged caregiver intervention studies revealed a significant reduction in patient behavioral issues as well as caregiver stress reduction.[178]

Affective symptoms, such as apathy, depression, anxiety, and sleep disturbance occur in up to one-quarter of all demented patients.[182] Depressive symptoms may be modified by increasing time spent at pleasant events, increasing social interaction, and increasing activity level. Behavioral interventions to minimize sleep disturbance include improving sleep hygiene as well as addressing nighttime pain and nocturia.

Verbally disruptive behaviors, such as screaming, abusive language, and repetition, may result from cortical disinhibition, but may also signal untreated pain, sensory deprivation, or social isolation. Social interaction and sensory stimulation may improve this behavior. Sundowning, or confusion that increases at nighttime, is common among many elderly patients with dementia, especially in the acute care setting. Food, brief personal contact, music, improved hearing and vision, aromatherapy, light therapy, physical activity, and maintenance of a daily routine have been shown to reduce sundowning.[183, 184]

Aggressive behavior particularly during personal care is also common in patients with dementia; this behavior is often a self-protective response and may be secondary to confusion or misunderstanding. Helping caregivers to understand that this behavior is not intended to be harmful may be beneficial. Also, employing assistance during bathing and other personal care efforts has been shown to be successful.[185]

Wandering and pacing can pose safety issues for many patients with dementia because of the associated potential for getting lost and for injury. Addressing unmet needs such as hunger, pain, and toileting may minimize pacing. Also, engaging the patient in low-risk exercise or structured physical therapy may help to reduce wandering. Finally, continuous supervision may be necessary to ensure patient safety.

Assessment of the etiology of agitation should be evaluated and treated initially. In the absence of other effective therapies, medications may be needed to address certain behavioral disturbances. In one large multicenter, randomized clinical trial (CitAD), adding citalopram 30 mg daily and a psychosocial intervention improved agitation in patients as well as decreased caregiver distress. However, adverse effects of citalopram include QT prolongation and worsening cognition and may limit use.[186] In the absence of other effective therapies, antipsychotic medications may be needed to address certain behavioral disturbances. In the setting of acute agitation or aggression that is not responsive to behavioral interventions, haloperidol has often been considered the drug of choice; however, recent studies have shown an increased risk of QT prolongation and torsade de pointes with intravenous and high dose haloperidol. Many experts now recommend an atypical antipsychotic agent as first line when an antipsychotic is indicated.[187, 188]

Atypical antipsychotic agents include clozapine, olanzapine, risperidone, aripiprazole, risperidone, and quetiapine.[188] For acute management of behavioral and psychological disturbances, a trial of atypical antipsychotics including clozapine, olanzapine, risperidone, and quetiapine may be warranted. Several reviews suggest that these agents have, at most, modest efficacy.[189–191] The 2006 Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study suggests that adverse effects leading to intolerability may offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with AD.[189]

Despite higher expense, atypical antipsychotic agents do have a lower risk of extrapyramidal side effects than traditional antipsychotic medications. Still, adverse effects are common with these medications and include extrapyramidal symptoms, somnolence, and gait dysfunction. To offset some of these adverse effects, low doses are recommended. Olanzapine is started at 2.5 mg daily and titrated to a maximum of 5 mg twice a day. Of note, olanzapine has been associated with significant weight gain and insulin resistance and requires monitoring of fasting blood glucose. Quetiapine is started at 25 mg at bedtime and titrated to a maximum of 100 mg or 125 mg daily. Risperidone is started at 0.5 mg a day and titrated to 1 mg a day. At higher doses, significant extrapyramidal side effects may become a problem with risperidone. Clozapine is rarely used now because it carries a risk of agranulocytosis and requires frequent blood monitoring.

Despite frequent clinical use, atypical antipsychotic agents are not FDA approved for management of behavioral disorders, and these medications carry an associated mortality risk and increased risk of stroke. In April 2005, the FDA issued a public health advisory about the use of second-generation atypical antipsychotic agents because of increased mortality found in elderly patients taking these medications.[192] A subsequent meta-analysis confirmed these results and concerns have since been raised about the mortality risk of conventional antipsychotics as well.[193, 194]

Given the valid safety concerns associated with antipsychotic medications, they should be reserved for patients who are at imminent risk of harming themselves or others or have delusions and hallucinations that are distressing or that disrupt the patients’ care. Practitioners must explain the risks and benefits of these medications and obtain informed consent from the patients and/or family members prior to use. Patients with DLB may be particularly sensitive to the extrapyramidal side effects of antipsychotics, so use by these patients should be avoided.