Chapter 8. Dementia and Mild Neurocognitive Disorders
© American Psychiatric Publishing
Dementia is a clinical syndrome that can be caused by a range of diseases or injuries to the brain. Although it can affect young people, it is most commonly seen in older individuals because dementia prevalence increases with age. Alzheimer’s Disease International estimates that approximately 35.6 million individuals were living with dementia worldwide in 2010 (Prince et al. 2013); considering its high prevalence and worldwide distribution, dementia should now be considered a pandemic. Given the dramatic growth of the older population (for instance by 2050, the number of people ages 60 years and older worldwide will have increased by 1.25 billion and account for 22% of the world’s population), the number of people living with dementia worldwide is expected to approximately double every 20 years to 65.7 million in 2030 and 115.4 million in 2050 (Prince et al. 2013) (Figure 8–1). The Alzheimer’s Association (Theis et al. 2013) estimates that 5.2 million Americans are living with Alzheimer’s disease (AD), the single most common cause of dementia. About 11% of people ages 65 years and older and about 32% of the oldest old (those age 85 and older) has AD. AD is the sixth leading cause of death in the United States (Theis et al. 2013). Given the chronicity of dementia, with estimates of its duration ranging from 3–4 years in community settings (Graham et al. 1997) to 10–12 years in clinical settings (Rabins et al. 2006), it poses a unique public health problem with serious effects on its victims, their families, and society at large. For example, the Alzheimer’s Association (Theis et al. 2013) estimated that in the United States, annual direct and indirect expenses of caring for people with AD and other dementias will soar from an estimated $203 billion in 2013 to a projected $1.2 trillion annually by 2050.
Projected prevalence of dementia worldwide.
Source. Data from Prince M, Bryce R, Albanese E, et al.: “The Global Prevalence of Dementia: A Systematic Review and Metaanalysis.” Alzheimer’s and Dementia 9(1):63–75, 2013.
In this chapter, we discuss definitions, clinical presentation, evaluation, and differential diagnosis of dementia and related cognitive disorders; describe specific dementia syndromes according to their etiology; and discuss treatment approaches, including treatments that may be on the horizon. For an in-depth discussion of the clinical management of dementia, we recommend Practical Dementia Care by Rabins et al. (2006).
Definitions
Table 8–1 provides definitions espoused by the American Association for Geriatric Psychiatry (Lyketsos et al. 2006). Clinical syndromes such as dementia and cognitive impairment not dementia (CIND) are differentiated from clinical subsyndromes such as mild cognitive impairment (MCI). The table also clarifies that AD refers to a process of characteristic pathological changes in the brain that presumably causes (or influences) the observed dementia syndrome. Although these definitions are important to the clinical world, one should recognize that uncertainty remains about linking cognitive decline to brain pathology. Many studies demonstrate relationships between specific anatomical distributions of neuropathological markers and specific domains of cognitive function (e.g., the presence of medial temporal neurofibrillary tangles affects primarily episodic memory) (Dowling et al. 2011). Other studies show that even older individuals without cognitive impairment can accumulate significant neuropathological changes of AD, cerebral infarctions, and Lewy bodies (Bennett et al. 2012; Negash et al. 2011). In fact, in a study undertaken to examine the relationship of AD pathology, cerebral infarcts, and Lewy body pathology to cognition in individuals without cognitive impairment, nearly all individuals had AD pathology (more than 75% exhibiting amyloid) and a significant percentage had macroscopic infarctions (22%), microscopic infarctions (24%), and Lewy body pathology (13%) (Bennett et al. 2012). Furthermore, up to one-third of individuals without dementia can have AD lesions that meet criteria for intermediate or even high likelihood of AD (Negash et al. 2011). In community settings, up to 88% of individuals with dementia or cognitive impairment who come to autopsy have mixed rather than unitary brain pathologies, including a combination of AD lesions (neocortical neurofibrillary tangles and neuritic plaques), microvascular infarcts (microinfarcts and lacunar infarcts), neocortical Lewy bodies, hippocampal sclerosis, and generalized brain atrophy (White 2009). Although microvascular infarcts predominate as the sole or dominant lesion in 33.8% of patients with dementia or cognitive impairment, AD lesions predominate in 18.6% of these individuals and codominant lesions (most often AD and microvascular) predominate in 14.2% (White 2009).
Definitions Definitions related to dementia
Alzheimer’s dementia
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A dementia syndrome that has gradual onset and slow progression and is best explained as caused by Alzheimer’s disease.
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Alzheimer’s disease
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A brain disease characterized by plaques, tangles, and neuronal loss.
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Cognitive impairment not dementia (CIND)
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A clinical syndrome consisting of apparent or measurable decline in memory or other cognitive abilities, with little impact on day-to-day functioning. Does not meet criteria for dementia.
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Dementia
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A clinical syndrome consisting of global cognitive decline and memory deficits, plus at least one other area of cognition affected. Significant effect on day-to-day functioning. Syndrome is present in the absence of delirium.
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Mild cognitive impairment
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A clinical subsyndrome of CIND, most likely the prodrome to Alzheimer’s dementia. Can be amnestic (having memory deficits) or nonamnestic.
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Source. Adapted from Lyketsos CG, Colenda CC, Beck C, et al.: “Position Statement of the American Association for Geriatric Psychiatry Regarding Principles of Care for Patients With Dementia Resulting From Alzheimer Disease.” American Journal of Geriatric Psychiatry 14:561–572, 2006. Used with permission.
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Clinical Presentation, Evaluation, and Differential Diagnosis
Dementia, being a syndrome, is defined entirely on clinical grounds. Table 8–2 lists the four critical elements of the dementia syndrome. First, dementia affects cognition, which is defined as the mental processes used to obtain knowledge or to become aware of and interact with the environment. These processes include perception, imagination, judgment, memory, and language, as well as the processes people use to think, organize, and learn. Second, cognition is affected globally, meaning that for the dementia syndrome to be present, several areas of cognition (e.g., complex attention, learning, procedural or explicit memory, language, social awareness) must be affected. Third, to differentiate dementia from mental retardation, the cognitive symptoms must represent a cognitive decline for the individual. The decline must be substantial enough to be of concern to an individual, a knowledgeable informant, or the clinician; be quantitatively demonstrable by standardized neuropsychological testing or clinical assessment; and affect the person’s daily functioning, operationalized as basic or instrumental activities of daily living (ADLs). Fourth, because delirium can cause the full range of cognitive symptoms associated with dementia, it is critical that the cognitive syndrome be present in the absence of delirium.
Clinical Presentation of the Dementia Syndrome The four key elements of the dementia syndrome
1. Dementia affects cognition.
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2. Cognition is affected globally.
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3. Decline from prior baseline significantly affects functioning.
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4. Delirium is absent.
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DSM-5 (American Psychiatric Association 2013) has largely moved away from the term dementia in favor of major neurocognitive disorder. However, it acknowledges that the two terms are substantially congruent. The diagnostic criteria for major neurocognitive disorder, which parallel the key elements of the dementia syndrome, are listed in Table 8–3. Clinicians have recently started to deemphasize the concept of the four A’s of cognitive impairment (amnesia, aphasia, apraxia, and agnosia) in favor of the following cognitive domains: complex attention, executive function, learning and memory, language, perceptual-motor, and social cognition. Patients must demonstrate significant decline in cognitive function in one or more of these cognitive domains for a diagnosis of major or mild neurocognitive disorder. The exception is major neurocognitive disorder due to AD, in which a decline in at least two domains is required. DSM-5 primarily subtypes major neurocognitive disorders based on the known or presumed etiology or pathological entity (e.g., AD, frontotemporal lobar degeneration, Lewy body disease) underlying the cognitive decline. The degree of functional impairment determines the severity of the dementia (mild, moderate, or severe).
Clinical Presentation of the Dementia Syndrome DSM-5 diagnostic criteria for major neurocognitive disorder
A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:
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1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and
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2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.
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B. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with complex instrumental activities of daily living such as paying bills or managing medications).
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C. The cognitive deficits do not occur exclusively in the context of a delirium.
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D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia).
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Specify whether due to:
Alzheimer’s disease
Frontotemporal lobar degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson’s disease
Huntington’s disease
Another medical condition
Multiple etiologies
Unspecified
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Specify:
Without behavioral disturbance
With behavioral disturbance
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Specify current severity:
Mild
Moderate
Severe
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Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.
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Source. DSM-5 criteria for major neurocognitive disorder reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 602–605. Used with permission. Copyright © 2013 American Psychiatric Association.
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Although the dementia syndrome is defined around cognitive disturbances, patients with dementia have a wider range of impairments that are of relevance to themselves, their daily life, and their caregivers. These include functional, neuropsychiatric (behavioral), and neurological impairments.
Functional Impairments
Patients with dementia have problems in their social and interpersonal functioning and in their ability to live independently. Patients with milder dementia have difficulties with instrumental activities of daily living (IADLs), such as preparing a meal, balancing a checkbook, shopping, and driving. Patients with more severe dementia develop impairments in their basic ADLs, such as eating, toileting, dressing, and transferring. Changes in functional abilities are associated with cognitive decline (Royall et al. 2007). Furthermore, they have prognostic significance because declining functional abilities impact caregiver burden and are associated with institutionalization (Massoud 2007).
Neuropsychiatric Impairments
Dementia has also been associated with neuropsychiatric symptoms (NPSs). These are generally grouped into four types: 1) affective and motivational symptoms, such as depression (affecting up to 50% of individuals with dementia), apathy, anxiety, and irritability; 2) psychotic symptoms, such as delusions or perceptual disturbances; 3) disturbances of basic drives, including feeding, sleep, and sexuality; and 4) unexpected, socially inappropriate, or disinhibited behaviors. The latter behaviors, such as spontaneous violence, uncharacteristic vocalizations, intrusiveness, and wandering, typically arise in more severe dementia; they represent behavioral manifestations of loss of executive control, sometimes referred to as executive dysfunction syndrome (Lyketsos et al. 2004). Research has found that over the course of a progressive dementia, essentially all patients develop one or more of the NPSs (Okura et al. 2010; Steinberg et al. 2008). These symptoms are associated with a decline in function and cognition among patients that may ultimately lead to increased mortality (Levy et al. 2012). Furthermore, the severity of NPSs is a strong predictor of caregiver burden (Bergvall et al. 2011), with increased rates of depression, anxiety, stress, loss of sleep, medical illness, and mortality among caregivers (Levy et al. 2012). Caregiver burden, in turn, results in greater usage of institutionalization for patients with dementia (Levy et al. 2012).
Neurological Impairments
Patients with dementia develop a range of neurological impairments. Depending on the cause of dementia and specifically on the parts of the brain affected over time, a range of neurological symptoms may occur. Most common are gait disorders, especially unstable, ataxic, or labored gait. Other symptoms include incontinence, focal findings, seizures, and, less commonly, cranial nerve findings.
Epidemiological studies have found that large numbers of older people have mild decline in one or more cognitive domains, such as memory, attention, and thinking, that do not compromise everyday activities and functioning—that is, their independence is preserved—and thus do not satisfy criteria for dementia. Nevertheless, the cognitive impairment is greater than expected for the person’s age and education such that tasks require more time or effort to complete than previously. Impairments may be demonstrable on cognitive assessments and are often troubling to the individual or to family members. The population-based Mayo Clinic Study of Aging reported the prevalence of mild impairments to be 16% among elderly subjects ages 70–89 years and free of dementia (Petersen et al. 2009). Several terms have evolved to refer to these impairments: age-associated memory impairment, age-associated cognitive decline, CIND, and MCI. Impairments can be further divided into amnestic or nonamnestic subtypes, depending on whether significant impairments in memory are present. The core clinical features of MCI, as identified by the National Institute on Aging–Alzheimer’s Association (NIA-AA), are listed in Table 8–4 (Albert et al. 2011). Paralleling the change from favoring the term major neurocognitive disorder over dementia, DSM-5 has largely moved away from the term mild cognitive impairment in favor of mild neurocognitive disorder, while acknowledging the congruency of the two terms. The DSM-5 diagnostic criteria for mild neurocognitive disorder are listed in Table 8–5. NPSs are more common in patients with MCI than in individuals with normal cognition. These symptoms include depression (most common), irritability, anxiety, agitation, apathy, and delusions. In one population-based study in Cache County, Utah, the presence of at least one NPS (even of mild severity) was a risk factor for conversion from CIND to all-cause dementia (Peters et al. 2013). Few individual NPSs had predictive value of conversion; however, nighttime behaviors were a risk factor for all-cause dementia and for AD, and hallucinations were a risk factor for vascular dementia. Several prior studies have also linked specific NPSs, such as major depression and anxiety, to conversion of CIND/MCI to dementia. For instance, in one study, increasing levels of anxiety doubled the risk of conversion (Palmer et al. 2007).
Clinical Presentation of Milder Cognitive Syndromes National Institute on Aging—Alzheimer’s Association’s proposed clinical and cognitive criteria for mild cognitive impairment
Cognitive concern reflecting a historical or observed decline in cognition over time, as reported by a patient, informant, or clinician
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Objective evidence of impairment in one or more cognitive domains (typically including memory)
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Preservation of independence in functional abilities
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No dementia
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Source. Adapted from Albert et al. 2011.
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Clinical Presentation of Milder Cognitive Syndromes DSM-5 diagnostic criteria for mild neurocognitive disorder
A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:
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1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and
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2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.
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B. The cognitive deficits do not interfere with capacity for independence in everyday activities (i.e., complex instrumental activities of daily living such as paying bills or managing medications are preserved, but greater effort, compensatory strategies, or accommodation may be required).
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C. The cognitive deficits do not occur exclusively in the context of a delirium.
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D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia).
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Specify whether due to:
Alzheimer’s disease
Frontotemporal lobar degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson’s disease
Huntington’s disease
Another medical condition
Multiple etiologies
Unspecified
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Specify:
Without behavioral disturbance
With behavioral disturbance
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Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.
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Source. DSM-5 criteria for mild neurocognitive disorder reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 605–606. Used with permission. Copyright © 2013 American Psychiatric Association.
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Long-term follow-up studies suggest that although one-third of individuals with MCI improve to the point that their cognitive impairments are no longer detectable in the next few years, the majority go on to develop dementia (Rosenberg et al. 2006). Approximately 46% of individuals with MCI developed dementia within 3 years, compared with only 3% of individuals of the same age who did not have MCI at the beginning of the study (Tschanz et al. 2006). These findings are consistent with the idea that most patients who develop progressive dementia do so in stages and typically go through a prodromal period of milder cognitive impairment. Pathological studies have confirmed that after long-term follow-up, large numbers of patients who meet criteria for MCI have AD pathology. Risk factors for conversion of MCI to dementia include greater cognitive and functional impairment, advancing age, male gender, marital status (never married), years of education (inverse relationship), being a carrier of the allele producing the ε4 type of apolipoprotein E (APOE*E4), cerebrospinal fluid (CSF) markers or positron emission tomography (PET) scan patterns compatible with AD, positive amyloid imaging, and the presence of anxiety and other NPSs (Palmer et al. 2007; Peters et al. 2013; Petersen et al. 2009; Tschanz et al. 2006).
The prodromal period most often, but not exclusively, starts with cognitive symptoms characteristic of the specific cause of dementia. For example, amnestic MCI, the most common subtype of MCI (Petersen et al. 2009), appears to be a precursor to AD. In fact, the NIA-AA (Albert et al. 2011) has proposed terminology for classifying individuals with MCI due to AD with varying degrees of certainty, based on the presence or absence of AD biomarkers. As with major neurocognitive disorders, DSM-5 primarily subtypes mild neurocognitive disorders based on the known or presumed etiology underlying the cognitive decline. The term vascular cognitive impairment (Bowler and Hachinski 1995; Hachinski 1994, 2007) was coined to refer to nondementia disturbances associated with cerebrovascular disease, likely the prodrome of vascular dementia. Whereas MCI, the prodrome of AD, appears to have primarily cortical features, vascular cognitive impairment, the prodrome of vascular dementia, typically affects executive functions (Hayden et al. 2006).
Conducting an Evaluation
Although a detailed discussion of how to evaluate a patient with suspected dementia is beyond the scope of this chapter, we highlight critical aspects of the evaluation, with a focus on taking a history, conducting a cognitive assessment, and using diagnostic tests. A thorough discussion of the evaluation of the patient with suspected dementia, including reasons for doing an evaluation, the setting for the evaluation, and ways to communicate the diagnosis to the patient and caregiver, is provided in Practical Dementia Care (Rabins et al. 2006).
History Taking
Because dementia is diagnosed clinically, a thorough medical history is essential. A patient with suspected dementia may have difficulty providing history due to language problems, memory disturbance, or anosognosia (lack of insight). Therefore, it is critical to involve a reliable informant during history taking. Informants need to be people who know the patient well, such as family members. Because informants themselves can be influenced by their own mental states, such as depression or denial of the situation, it is often useful to speak with more than one informant to confirm or challenge discrepancies between the history and the evaluation of the patient.
It is critical to date and elucidate the type of onset of cognitive symptoms (e.g., insidious onset, abrupt onset following traumatic brain injury [TBI]), as well as establish the progression of symptoms over time (e.g., gradual, stepwise, or nonprogressive decline). Comparing the severity of the patient’s current impairment with its duration often influences the differential diagnosis. For instance, a slowly progressive dementia over years with insidious onset may point to Alzheimer’s dementia, whereas a dementia that progresses rapidly over months may point to dementia due to prion disease. Clinicians need to resolve discrepancies in reports of severity and duration because they portend different prognoses and recommendations. It is often more feasible to determine when the patient was last well rather than when symptoms first started. Many times, informants minimize early symptoms by attributing them to “normal aging.” It is also important to remember that the history should systematically evaluate for the presence or absence of the broader dementia syndrome presentation, as discussed in the earlier section “Clinical Presentation of the Dementia Syndrome.” Therefore, the history should assess for cortical and subcortical cognitive symptoms; functional losses in social, interpersonal, and daily functioning; the full range of NPSs; and neurological deficits.
Cognitive Assessment
Conducting a cognitive assessment is the central aspect of the evaluation. Many specialists tend to use the Mini-Mental State Examination (MMSE; Folstein et al. 1975) as their primary tool because it is brief, easy to use, and well known. The MMSE, however, is inefficient in evaluating patients with milder cognitive symptoms or mild dementia, especially those with subcortical features. This is because the MMSE has ceiling effects, especially for premorbidly well-educated and intelligent individuals, and has limitations in evaluating executive control function. Furthermore, the MMSE is unable to discriminate subtle degrees of impairment in severe dementia. We recommend that specialists in geriatric psychiatry and other clinicians who work with patients broaden their use of bedside standardized assessments. The Modified Mini-Mental State (3MS; Teng and Chui 1987) and the Montreal Cognitive Assessment (MoCA; Nasreddine et al. 2005) are two bedside cognitive tests that provide a more comprehensive assessment of cognition. The 3MS and MoCA have many advantages: several translations exist, and they have been validated in various languages; they assess abstract thinking, delayed recall, and verbal fluency better than the MMSE; and they have well-known population norms. In addition, for closer assessments of executive functioning, geriatric psychiatrists should consider incorporating the following three measures in every dementia evaluation: the Clock Drawing test (van der Burg et al. 2004), the Frontal Assessment Battery (Dubois et al. 2000), and the Mental Alternation Test (Jones et al. 1993).
Neuropsychological testing is often useful for differentiating dementia from milder cognitive syndromes or normal aging or for clarifying the etiology of the cognitive disorder. However, neuropsychological testing is not needed in every case, assuming that the clinician conducts a standardized assessment using tools similar to those discussed above. If neuropsychological testing is needed, the clinician should have in mind specific questions that he or she wishes to address, such as how to clarify the differential diagnosis or how to set the stage for monitoring prognosis or response to treatment.
Differential Diagnosis and Diagnostic Testing
A key aspect of the dementia evaluation is forming a complete differential diagnosis of the syndrome. Figure 8–2 provides a useful flowchart for this purpose. The first decision is whether any of the observed cognitive changes are disproportionate to normal aging. This can be determined by reviewing the patient’s history or by assessing the patient’s performance against well-known norms for age and education. If the cognitive changes are beyond age appropriate, the next question is whether the patient meets criteria for major neurocognitive disorder such as those listed in DSM-5. If the patient does not meet these criteria, then either CIND (which might be further subtyped as MCI or vascular cognitive impairment) or delirium is present. If dementia is present, the geriatric psychiatrist will determine whether it is cortical or subcortical; consider whether it is progressive or nonprogressive; rate its severity; and assess the degree of functional impairments, the presence or absence of NPSs and their specific phenomenology, and the presence or absence of motor and other neurological symptoms. Finally, the clinician establishes the presumptive cause of the dementia.
Flowchart in the diagnosis of dementia.
Note. CIND = cognitive impairment not dementia; MCI = mild cognitive impairment; NPS = neuropsychiatric symptoms; VCI = vascular cognitive impairment.
The severity of the dementia, typically labeled mild, moderate, or severe, is guided by the score on the MMSE (or equivalent such as the MoCA) or degree of functional impairment. An MMSE score of 20–24 or difficulties with IADLs suggest mild dementia; an MMSE score of 13–20 or difficulties with basic ADLs suggest moderate dementia; and an MMSE score of 12 or less or complete functional dependence indicates severe dementia. NPSs can be assessed by history, mental status examination, and/or standardized tools such as the Neuropsychiatric Inventory—Clinician rating scale (NPI-C; de Medeiros et al. 2010). Occupational therapists are skilled at assessing functional impairment and often use scales such as the Assessment of Motor and Processing Skills (AMPS; Fisher 2003). A complete neurological evaluation is central to assessing neurological conditions that may cause or be the sequelae of a cognitive disorder.
Further workup using laboratory studies and brain imaging is needed in most cases of dementia. A basic dementia screen typically involves laboratory studies and brain imaging. The American Academy of Neurology (Knopman et al. 2001) and the National Institute for Health and Care Excellence (2011) recommend obtaining a metabolic panel, liver function test, complete blood count, thyroid function studies, vitamin B12 levels, and folate levels. In at-risk populations or if the clinical picture indicates, the clinician may consider additional tests, such as heavy metal screen, HIV, syphilis serology, toxicology, electrocardiogram, and chest radiograph, to determine possible underlying pathology.
Urinalysis is useful when the clinician suspects delirium as part of the differential diagnosis. CSF analysis is not routinely part of a dementia workup unless the clinician suspects Creutzfeldt-Jakob disease (CJD) or other forms of rapidly progressive dementias. Likewise, electroencephalography is not part of a routine dementia workup unless frontotemporal lobar degeneration (FTLD), CJD, or delirium is suspected. Brain biopsies are indicated only in cases in which dementia is thought to be secondary to a potentially reversible condition that cannot be diagnosed in any other way (National Institute for Health and Care Excellence 2012).
The type of brain imaging to be used remains controversial. Most clinicians suggest that computed tomography (CT) of the head is adequate to exclude other cerebral pathologies; others feel it is important to perform magnetic resonance imaging (MRI), especially when cortical or subcortical vascular disease may be involved. In the near future, quantification of specific MRI components, such as hippocampal or medial parietal cortical atrophy, will provide information that is important to the differential diagnosis, prognosis, and treatment options. Functional brain imaging using functional MRI (fMRI), PET, or single-photon emission computed tomography (SPECT) has come into broader use and is reimbursed by Medicare under specific circumstances. These types of imaging reveal distinct regions of low metabolism and hypoperfusion and are most useful in the differential diagnosis of dementia caused by AD, cerebrovascular disease, Lewy body disease, or FTLD, if the rest of the clinical picture is inconclusive. Various amyloid PET tracers, such as 18F-AV-45 (also known as florbetapir) and Pittsburgh compound B (PiB), which measure amyloid lesion burden in the brain by binding to amyloid-β (Aβ), can aid in the diagnosis and prognosis of AD, and differentiate AD from other causes of dementia. In 2012, the U.S. Food and Drug Administration (FDA) approved florbetapir for this purpose. The long half-life of 18F allows florbetapir to accumulate considerably more in the brains of patients with AD (Wong et al. 2010). In 2013, the FDA also approved 18F-flutemetamol, an 18F-labeled derivative of the parent molecule PiB.
Other biomarkers, such as CSF tau and Aβ levels, continue to be used in research and will likely have clinical applications in the future. The same is true for genetic testing. Although APOE genotyping is not used in clinical settings universally, it might have greater utility in the near future for tailoring treatment options. Some studies suggest that certain medications may be more effective in specific APOE subgroups (Petersen et al. 2005). Testing for specific genetic mutations associated with AD also has its place in the rare instances in which there is a clear familial autosomal dominant case of Alzheimer’s dementia and knowledge of the specific genetic mutation involved might be useful to the patient or the patient’s progeny following appropriate counseling.
Over 100 different disease processes have been associated with dementia (Rabins et al. 2006). Most cases of dementia can be adequately assessed through the patient’s history and the diagnostic testing approach discussed previously in this section. In the past, dementias were often categorized as either treatable or nontreatable. This differentiation is no longer useful for two reasons. First, the reversibility of a “treatable dementia” depends on the severity of brain damage that has occurred. For example, dementia resulting from moderate to severe vitamin B12 deficiency, hypothyroidism, or normal-pressure hydrocephalus does not reverse when treated. Second, the implication that AD, vascular dementia, and other dementias are not treatable is incorrect. Although these cases tend to be progressive despite available treatments, applying treatments makes a big difference to patients, caregivers, and families, because treatments may attenuate progression, reduce symptoms, and improve quality of life.
Specific Dementias
The more common causes of dementia are listed in Table 8–6. AD is generally considered to be the most prevalent cause of dementia. Other common causes include cerebrovascular disease, Lewy body disease, and FTLD. Less common causes include normal-pressure hydrocephalus, prion diseases (e.g., CJD), TBI (common in the young, however), AIDS, Huntington disease, primary progressive aphasia, corticobasal degeneration, and dementia of depression (previously referred to as pseudodementia). In this section, we highlight the most common, as well as some of the less common, causes of dementia. An extended discussion of all of the above causes of dementia is beyond the scope of this chapter.
Specific Dementias The most common causes of dementia
Causes | Hallmark features |
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Alzheimer’s disease
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A brain disease characterized by plaques, tangles, and neuronal loss. Insidious onset. Slow progressive cognitive and functional decline. Neuropsychiatric symptoms are nearly universal.
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Cerebrovascular disease
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Known as vascular dementia or multi-infarct dementia. Controversial nosological entity due to lack of agreed-upon neuropathological definition. Heterogeneous group of dementias. Stepwise progression with variable rates of decline. Symptoms overlap with those of Alzheimer’s disease. Focal neurological signs. Apathy and depression are common.
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Lewy body disorders
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Examples include Parkinson’s disease dementia and dementia with Lewy bodies. α-Synuclein aggregates in neurons. Progressive cognitive decline, fluctuating cognition, visual hallucinations, parkinsonian features, rapid eye movement sleep disorder, and severe neuroleptic sensitivity are common.
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Frontotemporal lobar degeneration
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Previously referred to as Pick’s disease. Clinically and pathologically heterogeneous. Most common presentations are behavioral variant frontotemporal dementia and primary progressive aphasia. Focal degeneration of frontal and temporal lobes. Hyperphosphorylated tau protein or transactive response DNA binding protein TDP-43 inclusions. Knife-edge atrophy on magnetic resonance imaging. Progressive change in personality, behavior, and language. Motor impairment syndromes co-occur. Typically a more rapid rate of decline than with Alzheimer’s disease.
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Dementia Due to Alzheimer’s Disease
Alzheimer’s dementia is the most common form of dementia. Depending on the population series, 50%–70% of people with dementia are diagnosed clinically as having dementia due to AD (Ranginwala et al. 2008). Experts can typically make the clinical diagnosis of AD reliably. However, whereas the vast majority of patients meet pathological criteria for AD, a significant number have other pathological findings, such as cerebrovascular infarcts, Lewy bodies, and lacunes.
The prevalence of Alzheimer’s dementia is closely tied to age, which is the primary risk factor. Other reported risk factors include head injury or TBI, reduced cognitive reserve capacity of the brain, limited educational or occupational attainment, cerebrovascular disease, hyperlipidemia, hypertension, atherosclerosis, coronary heart disease, atrial fibrillation, smoking, obesity, and diabetes. A possible risk factor is homocysteinemia. Some but not all epidemiological studies have suggested that dietary intake of folate and vitamin B12, antioxidants (especially vitamins C and D), moderate alcohol (especially red wine), nonsteroidal anti-inflammatory agents, and estrogen during the perimenopausal period are associated with reduced risk of AD.
A major risk factor for AD is genetics, with 70%–80% of the disease being heritable, as supported by twin studies (Blennow et al. 2006). AD is a heterogeneous genetic disorder with familial and sporadic forms. The familial forms follow classical autosomal dominant inheritance and typically have their onset before age 65 years. The familial forms are linked with several mutations in genes associated with amyloid precursor protein (APP) on chromosome 21, the presenilin 1 gene PSEN1 on chromosome 14, or the presenilin 2 gene PSEN2 on chromosome 1 (Figure 8–3). Mutations in PSEN1 account for 18%–55% of early-onset familial AD cases, whereas mutations in PSEN2 and APP are less common (Nowrangi et al. 2011). Taken together, these genes account for one-half to two-thirds of the familial cases, suggesting that many autosomal dominant genes are unknown. Researchers are currently studying the mechanisms by which these genetic loci interact.
Pathways implicated in Alzheimer’s disease (AD).
The familial form of AD is linked with several mutations in genes associated with PSEN1, PSEN2, and APP, all involved in the amyloid processing pathway (“the amyloid cascade”). Various pathways (cholesterol metabolism, endocytosis, and immune system) are linked with the more common nonfamilial, late-onset AD (LOAD). Each of these pathways is represented by candidate genes as shown in the figure.
Note. FAD = familial Alzheimer’s disease; LOAD = late-onset Alzheimer’s disease.
Source. Reprinted from Medway C, Morgan K: “Review: The Genetics of Alzheimer’s Disease: Putting Flesh on the Bones.” Neuropathology and Applied Neurobiology 40(2):97–105, 2014.
Many genes, most unidentified, likely increase risk but do not determine the absolute occurrence of sporadic, late-onset AD (LOAD). The most well-known gene, APOE, is a genetic risk factor for LOAD. APOE*E4 is associated with more than 50% of cases of AD (Nowrangi et al. 2011). Individuals who are heterozygous carriers of APOE*E4 have three times the risk of developing AD, whereas individuals who are homozygous APOE*E4 carriers have 15 times the risk compared with non-APOE*E4 carriers. APOE*E4 probably operates mainly by modifying the age at onset through uncertain molecular mechanisms (Breitner et al. 1999). Another major gene associated with LOAD is the sortilin-related receptor gene SORL1. This gene, which is probably involved in amyloid clearance, has also been identified as a risk factor (Rogaeva et al. 2007). The SORL1 protein may alter intracellular trafficking of APP, causing aggregated Aβ to accumulate, and ultimately causing cell death (Nowrangi et al. 2011).
Since 2009, genome-wide association studies (GWASs) have revolutionized the ability to identify biological pathways potentially involved in AD (Medway and Morgan 2014). GWAS studies compare the entire genome of patients with a disease to those without, to determine whether specific alleles occur in greater frequency in patients with the disease and are thus more likely to be associated with the disease. Determining a causal allele strengthens the ability to identify candidate genes that increase the risk of specific disease phenotypes and to attribute risk to each gene. GWASs have led to the discovery of new LOAD alleles, each common (minor allele frequency of greater than 5%) and transmitting modest genetic effects (Medway and Morgan 2014). In the largest GWAS meta-analysis of LOAD to date, the International Genomics of Alzheimer’s Project recently reported 11 new Alzheimer’s susceptibility loci (CASS4, CELF1, FERMT2, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, NME8, PTK2B, SLC24A4/RIN3, SORL1, and ZCWPW1) (Lambert et al. 2013). The study also confirmed eight (CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, and ABCA7) of the nine previously reported genome-wide associations in addition to APOE. Drawing on over 74,000 samples, the meta-analysis was sufficiently powered to reveal new risk alleles previously concealed due to low frequency or weak genetic effects. Although some genes cannot be attributed to pathways that are biologically relevant to LOAD, many susceptibility loci can be linked to pathways involving cholesterol metabolism, synaptic vesicle recycling/endocytosis, and immune system function (see Figure 8–3). These pathways may modify amyloid aggregation and/or clearance. Alternatively, some of these genes may act through non-amyloid mechanisms. Although GWASs are useful at detecting common variants with weak to modest effects, these studies have limitations in detecting rare variants that may confer large genetic effects. Alternative technology (e.g., next-generation sequencing) may be used in tandem with GWASs to detect these uncommon variants in small cohorts (Medway and Morgan 2014).
The current hypothesis is that Alzheimer’s dementia is a heterogeneous condition representing a range of etiologies involving different interactions between different sets of genetic and environmental risk factors (Blennow et al. 2006). At one end of the spectrum are individuals with familial disease, for whom genes such as APOE influence the age at onset and who will develop the disease if they live long enough. At the other end of the spectrum are individuals with a weak predisposition, perhaps carriers of few or no risk genes but in whom the occurrence of environmental risk factors is critical to the onset of Alzheimer’s pathology and the later dementia. As an example of gene-environment interactions, individuals with TBI may be at increased risk of progressive dementia if they also carry one or more APOE*E4 alleles (Isoniemi et al. 2006).
The natural history of Alzheimer’s dementia has been well described from tertiary clinical centers. Time from diagnosis to death in these settings is on the order of 10–12 years, with considerable variability around this median estimate. Population studies from Canada and the United States suggest that a significant proportion of patients with dementia do not make it to clinical centers and that if all patients in this group are included, the median time from onset of symptoms to death in patients with dementia is on the order of 3–5 years (Wolfson et al. 2001). A significant number of patients exhibit slow progression after the onset of dementia. In the Cache County Memory Study, 25%–30% of individuals with AD exhibited limited to no progression from milder stages of dementia even 3–5 years after onset (Tschanz et al. 2011). Likewise, only about 25% of individuals with AD ever progressed to severe dementia, with the majority dying prior to that point (Rabins et al. 2013).
There is also significant variability of cognitive and functional decline in Alzheimer’s dementia. For instance, although the annual rate of cognitive decline on the MMSE as reported in most studies is 3 points, the mean rate of decline in the Cache County Memory Study was 1.5 points (Tschanz et al. 2013). Furthermore, 30%–56% of individuals in this study exhibited a slow rate of decline in one or more domains (cognitive, functional, and behavioral), declining no more than 1 point per year on the measures of each domain (Tschanz et al. 2011).
In the Cache County Memory Study, many factors appeared to influence the progression of Alzheimer’s dementia cognitively, functionally, and behaviorally. Women and individuals in both the youngest and oldest age-at-onset cohorts exhibited faster declines (Rabins et al. 2013; Tschanz et al. 2013). It is possible that factors such as a more severe form of AD in younger persons and/or greater comorbidity in the oldest cohort influence the rate of progression. Neither being a carrier of APOE*E4 nor years of education affected the rate of progression in any of the three domains (Rabins et al. 2013). Other studies reported mixed results for both risk factors (see Tschanz et al. 2013). Individuals with unstable or poorly controlled general health performed cognitively and behaviorally worse over the course of dementia (Tschanz et al. 2013). Specifically, hypertension, atrial fibrillation, angina, and myocardial infarctions were all associated with faster cognitive and functional decline, particularly among older individuals. Several medical treatments—statins, antihypertensive medications, and history of coronary artery bypass graft—are associated with slower rates of cognitive and functional decline in AD. In general, cholinesterase inhibitors and memantine, taken by approximately 22% of the cohort, were associated with higher baseline cognitive scores but did not affect rate of decline (Tschanz et al. 2011). However, among women APOE*E4 carriers, greater duration of treatment with a cholinesterase inhibitor was associated with slower cognitive and functional decline (Tschanz et al. 2013).
Caregiver and care environment factors influenced the clinical course of individuals with AD in the Cache County Memory Study (Tschanz et al. 2013). Participant engagement in more cognitively stimulating activities was associated with slower cognitive decline early in the course of AD. Likewise, a closer caregiver and care recipient relationship was associated with both slower cognitive and functional decline. AD participants cared for by an adult child with a neurotic personality trait exhibited faster cognitive decline. Conversely, AD participants cared for by an adult child with high extraversion scores exhibited slower rates of decline, and AD participants whose caregivers reported regular use of problem-solving coping strategies demonstrated a slower rate of cognitive and functional decline.
Despite the variability in their rate of decline, patients who progress show a typical pattern, with loss of memory occurring fairly early, followed by the development of agnosia, apraxia, and aphasia. Patients also follow predictable progression in functional impairments and, in later stages, universally develop problems with mobility and continence. In terminal stages, patients with AD may live a long time, sometimes years, in near-vegetative states if they are in good general health and receive good care.
NPSs are nearly universal. They tend to be persistent in that around 80% of individuals with NPSs at baseline will show at least one symptom over an 18-month interval (Tschanz et al. 2013). Over time, the prevalence of NPSs increases; the most common symptoms are depression, apathy, agitation, and restlessness (at least one of these symptoms is manifested in approximately 75% of individuals), followed by sundowning and verbal outbursts (manifested in approximately 50% of individuals) (Scarmeas et al. 2007; Steinberg et al. 2008; Tschanz et al. 2011). Several cohort studies suggest that affective, psychotic, and sleep symptoms relapse and remit through the course of Alzheimer’s dementia and are very troubling for patients and caregivers (Rabins et al. 2006; Steinberg et al. 2008). Apathy, in contrast, appears to be a steadily accumulating symptom in that many, but not all, patients gradually develop persistent and pervasive apathy (Steinberg et al. 2008). Overall, the presence of NPSs tends to increase over time (Scarmeas et al. 2007).
During the past several decades, studies have explored the possibility of neuropsychiatric subsyndromes in Alzheimer’s dementia (Canevelli et al. 2013). For example, increasing evidence over the past 10 years suggests that AD with psychosis may represent a distinct phenotype with a genetic basis (Geda et al. 2013). By examining the internal structure of the Neuropsychiatric Inventory, researchers have classified NPSs into specific clusters. The practical implications of identifying possible clusters or subsyndromes include more adequately comprehending neurobiological correlates and psychosocial determinants of NPSs, as well as tailoring therapeutic interventions to specific phenotypes and subsyndromes (Canevelli et al. 2013). Neurobiological data support the notion of specific clusters of NPSs by recognizing that there are three major neurobiological models relevant to NPSs in AD: the frontal-subcortical circuits, corticocortical networks, and the monoaminergic system (Geda et al. 2013). Specific NPSs have been associated with lesions involving crucial structures or tracks in a network mediating a particular behavior (Geda et al. 2013). For instance, disinhibition or apathy can be observed from lesions involving the frontal-subcortical circuits, even if the lesion is far away from the frontal cortex (Geda et al. 2013). Reflecting the evidence that NPSs tend to cluster into distinct groups, the Neuropsychiatric Syndromes of AD Professional Interest Area (NPS-PIA) of the International Society to Advance Alzheimer’s Research and Treatment organized NPSs around five syndromic areas: depression, apathy, sleep, agitation, and psychosis (Geda et al. 2013). The NPS-PIA has prepared specific reviews and recommendations for each syndrome, while recognizing that syndromes will overlap with one another (Geda et al. 2013).
Depression affects up to 50% of persons with dementia over the course of the illness (Schwarz et al. 2012). It is the most common symptom early in the course of dementia, affecting 29% of individuals (Tschanz et al. 2013). A potentially devastating and debilitating illness, depression tends to be underrecognized and highly correlated with increased health care utilization, increased risk of suicide, decreased quality of life for the affected individual and caregiver, and greater severity and acceleration of cognitive impairment (Sepehry et al. 2012). Among individuals with AD, the risk for depression increases with older age, female gender, and less education (Treiber et al. 2008).
Apathy affects a large proportion of individuals with dementia. In the Cache County Study, apathy was among the most frequently reported NPSs, with 20% of individuals exhibiting apathy at baseline and 51% exhibiting the symptom at 5-year follow-up (Steinberg et al. 2008). It was consistently the most severe symptom at each evaluated time point. Apathy affects up to 70% of individuals with mild to moderate AD and up to 90% of individuals with late-stage AD (Berman et al. 2012). It tends to appear early in dementia, increase with illness severity, and persist throughout the illness. Risk factors for apathy include greater severity of cognitive and functional impairment, older age, and stroke (Treiber et al. 2008). Strokes may damage areas such as the prefrontal cortex or related neural pathways involved in planning and execution of goal-directed behaviors (Treiber et al. 2008). Apathy is significantly associated with subsequent development of depression, consisting of inactivity, loss of confidence, learned helplessness, and poor response to rehabilitation due to lack of motivation (Berman et al. 2012). Understandably, apathy is associated with poorer quality of life for patients and caregivers (Berman et al. 2012).
Up to half of all individuals with AD experience sleep disorders (Camargos et al. 2014; Roth 2012). Sleep disorders reduce patients’ quality of life, can magnify their cognitive impairments and mood dysregulation, contribute to loss of function, are a primary reason for institutionalization, and increase caregivers’ burden. The most common sleep disorder associated with AD is irregular sleep-wake rhythm, a circadian rhythm disorder (Roth 2012). Patients with irregular sleep-wake rhythm lack a well-defined sleep period (e.g., they might alternate between sleeping for 2–3 hours and remaining awake for 2–3 hours throughout an entire 24-hour cycle). Other common sleep disorders among individuals with AD include sundowning, nighttime wandering, difficulty with sleep onset and/or maintenance, and an increased diurnal distribution of sleep (as opposed to an overall decreased amount of sleep) (Camargos et al. 2014; Roth 2012). Electroencephalograms (EEGs) of individuals with AD demonstrate increased stage I sleep, non–rapid eye movement dedifferentiation in later stages, and reduced rapid eye movement quantity in late stages. Causes of sleep disorders in AD are multifactorial. Various brain hormones and systems (e.g., suprachiasmatic nucleus, vasopressin, pineal gland, and melatonin systems) critical for the regulation of the sleep-wake cycle are affected by the disease. For instance, in some patients with AD, the suprachiasmatic nucleus demonstrates tangles and neuronal cell loss with reactive gliosis (Roth 2012). Also, individuals with AD who are homozygous APOE*E4 carriers demonstrate greater reductions in melatonin levels compared with those who have the alleles APOE*E3 and APOE*E4. On the other hand, individuals with AD often have changes in zeitgebers (environmental cues critical for reinforcing circadian rhythm patterns), such as disturbed patterns of light exposure, as a consequence of inactivity and inadequate stimulation at home or in nursing homes.
Detailed discussions of the causes and common presentations of agitation and psychosis in dementia appear in Chapter 19, “Agitation and Suspiciousness,” and Chapter 11, “Schizophrenia Spectrum and Other Psychotic Disorders,” respectively.
The Predictors Study, a population-based study that recruited individuals mostly in relatively early stages of AD, demonstrated that symptoms such as agitation, restlessness, and wandering, were associated with faster cognitive decline (Scarmeas et al. 2007). Agitation and restlessness were also associated with faster functional decline, whereas wandering was associated with faster functional decline and institutionalization. Other studies demonstrated that apathy, depression, and psychosis predict subsequent rapid cognitive decline. In the Cache County Memory Study, individuals who demonstrated clinically significant symptoms in at least one domain on the Neuropsychiatric Inventory were more likely to progress to severe AD and progressed more rapidly than individuals with only mild symptoms or no symptoms at all (Rabins et al. 2013).
Several studies have reported that genetic factors (most notably APOE*E4) confer an increased risk of NPSs in AD, including aggression, depression, and psychosis. However, the majority of studies have not demonstrated a relationship between APOE genotype and NPSs (Treiber et al. 2008).
What is unclear is whether there is a causal relationship between NPSs and disease severity or between treatments targeting symptoms and disease severity, or whether symptoms and treatments interact together to influence disease severity. Also, it is unknown whether pharmacological or nonpharmacological interventions targeting NPSs influence the rate of progression to severe AD. Whether there is an association between NPSs and mortality remains controversial (Rabins et al. 2013; Scarmeas et al. 2007).
The brain changes seen in Alzheimer’s dementia are well known. Even in early stages of the disease, brain imaging studies show volume reduction in the hippocampus bilaterally, and this reduction appears to progress with the illness. In early stages of the disease, brain imaging using fluorodeoxyglucose PET typically shows bitemporoparietal and often frontal hypoperfusion. This hypoperfusion eventually spreads throughout the brain as the disease progresses. PET or SPECT of neurotransmitters involving the cholinergic, dopaminergic, and serotonergic systems shows neurotransmitter loss even in living patients in early stages of Alzheimer’s dementia (Sabbagh et al. 2006). More recently, researchers and clinicians have been able to image amyloid deposition in the brain using florbetapir, PiB, FDDNP, and other PET or SPECT ligands. Using these ligands, researchers have found that by the time dementia begins, there is already an abundant deposition of amyloid, which does not necessarily increase over time and is not necessarily specific to Alzheimer’s dementia (Engler et al. 2006). The deposition of amyloid may be fairly extensive by the time early symptoms appear, suggesting a time course of many years, perhaps decades, of brain changes between pathological onset and clinical expression of dementia (Blennow et al. 2006).
Pathologically, the characteristic lesions of AD include senile or neuritic plaques containing Aβ and neurofibrillary tangles comprised of hyperphosphorylated tau proteins, with associated loss of neurons in several neurotransmitter systems: cholinergic, serotonergic, and dopaminergic. These changes typically occur early in the disease and affect both the nuclei and the cortical projections of neurons. Over time, these changes result in synaptic dysfunction. Until recently, the dominant hypothesis about etiopathogenesis suggested an amyloid cascade in which the increased production or decreased clearance of Aβ in the brain causes the disease, as shown in Figure 8–4A (Pimplikar 2009). Aβ40 and Aβ42 peptides accumulate, resulting in aggregation and formation of insoluble plaques; this triggers a cascade of deleterious changes, resulting in neuronal death (Pimplikar 2009). This hypothesis, which dominated research for over 20 years (Selkoe 1991), is now evolving to that depicted in Figure 8–4B (Morelli et al. 2012; Mucke and Selkoe 2012; Pimplikar 2009).
Reassessing the amyloid hypothesis.
(A) The classical view of the amyloid hypothesis. Aβ is the primary cause of AD. Increased production or decreased degradation results in accumulation of Aβ, triggering downstream deleterious events. Over time, these events result in synaptic dysfunction and cause AD. The working model is that blocking the effects of Aβ will prevent all downstream events and prevent AD. (B) A modified amyloid hypothesis, more consistent with the presently available data. Both Aβ and non-Aβ factors (green boxes) cause deleterious events leading to AD. Aβ no longer occupies the top position and is not considered to be the sole instigator of downstream events. One corollary of this theory is that blocking the effects of Aβ will not necessarily prevent AD.
Note. Aβ = amyloid-beta.
Source. Reprinted from Pimplikar SW: “Reassessing the Amyloid Cascade Hypothesis of Alzheimer’s Disease.” International Journal of Biochemistry and Cell Biology 41(6):1261–1268, 2009. Used with permission.
Aβ peptides are derived in the amyloidogenic pathway of APP (Morelli et al. 2012). APP, a transmembrane glycoprotein, is present on most neurons. Its function is unknown. In the nonamyloidogenic APP pathway, α-secretase followed by γ-secretase cleaves APP within the Aβ peptide region, preventing Aβ generation (Morelli et al. 2012). In the amyloidogenic pathway, APP undergoes site-specific sequential proteolysis by β-secretase followed by γ-secretase (the core proteins of which are presenilins 1 and 2) (Morelli et al. 2012). APP is rapidly processed (speed in excess of 10 molecules/neuron/second), and the vast majority of its metabolism is deposited in the extracellular space (Moghekar et al. 2011). Aβ40 and Aβ42 peptides predominate in the fragments released following proteolysis by β-secretase and γ-secretase. Aβ is likewise secreted into the extracellular space at extremely high rates (2–4 molecules/neuron/second) (Moghekar et al. 2011). Aβ42, a longer form of Aβ, is more prone to aggregate and to form plaques (see Figure 8–5) (Pimplikar 2009). Aβ42 accumulates close to the synaptic cleft and is thought to lead over time to synaptic disconnection, the loss of neurotransmitter systems, and the emergence of symptoms. Plaques contain other proteins, such as APOE. One hypothesis is that some APOE*E4, in particular, acts as an amyloid catalyst or “pathological chaperone” (Morelli et al. 2012). Although many mutations in APP or presenilin 1 result in increased levels of Aβ42, some mutations in presenilin 1 decrease the Aβ40 levels, thus effectively changing the ratio of Aβ40 to Aβ42 (Pimplikar 2009). There is evidence to suggest that the increase in the ratio of Aβ42 to Aβ40, rather than the absolute level of Aβ42, is pathogenic and triggers events ultimately leading to the disease (Figure 8–5) (Pimplikar 2009). Indeed, some studies suggest that the increased ratio of Aβ42 to Aβ40 is inversely related to the age at onset of AD (Bentahir et al. 2006).
Main tenets of the amyloid hypothesis in the pathogenesis of Alzheimer’s disease.
The amyloid hypothesis suggests that Aβ is the primary cause of AD. The original proposal was that increased levels of Aβ resulted in plaque formation (1), causing AD. Subsequent observations suggested that it is the increased levels of Aβ42 that are pathogenic and cause AD (2). Other research suggests that the ratio of Aβ42 to Aβ40 is pathogenic (3). Newer research has focused on the idea that Aβ forms soluble oligomers that are pathogenic and cause AD (4).
Note. Aβ = amyloid-beta; AD = Alzheimer’s disease.
Source. Reprinted from Pimplikar SW: “Reassessing the Amyloid Cascade Hypothesis of Alzheimer’s Disease.” International Journal of Biochemistry and Cell Biology 41(6):1261–1268, 2009. Used with permission.
Patients may develop end-stage dementia despite having no evidence of amyloid plaque (Holmes et al. 2008). Moreover, cognitively normal individuals may demonstrate substantial amounts of senile plaques (Villemagne et al. 2008). There are also increasing data to support that insoluble plaques are not necessarily the cause of the disease (Pimplikar 2009). Newer research has focused on soluble forms of Aβ, referred to as Aβ oligomers. Aβ oligomers are believed to be a particularly biologically active form of Aβ, and there is evidence to indicate that it is the disease-causing pathogenic agent (see Figure 8–5) (Walsh and Selkoe 2007). Other data suggest that presenilin 1 mutations alone can trigger the toxic events seen in AD and that the increased concentration of Aβ and senile plaques may only be a secondary effect (Pimplikar 2009).
The manifestation of AD symptomatology probably depends more on the brain location and neurotransmitter systems affected than on the cause of the pathology present (Lyketsos 2006). Neuritic plaques first begin in the frontal cortex before spreading over the entire cortical region; on the other hand, tau and neurofibrillary tangles first appear in the limbic system before spreading to the cortex (Pimplikar 2009). Although Aβ is associated with brain neuronal changes, it may also bind to other brain cells, such as microglia, and cause neuronal injury (Mucke and Selkoe 2012). High levels of Aβ can structurally and functionally alter microglia, astrocytes, and the endothelial and smooth muscle cells of cerebral blood vessels (Mucke and Selkoe 2012). Other downstream factors involved in progression include glutamatergic toxicity, lipid peroxidation products, and the loss of trophic factor. The precise mechanisms by which Aβ contributes to neuronal dysfunction and ultimately death are still unknown (Mucke and Selkoe 2012).
Because Alzheimer’s pathology likely begins many years and perhaps decades before the onset of symptoms, there is an opportunity for prevention once future advances make it possible to diagnose the disease through the use of biomarkers before symptom onset. Also, the distribution of the neuropathology appears to change with the course of the disease such that it begins in the mesial temporal lobe and then disseminates widely throughout the brain. The tissue loss that follows can become extensive, so that patients dying with advanced AD have atrophic brains and significantly enlarged ventricles. These changes during the course of the disease may mean that different treatments will have differential efficacy at different phases of the disease.
Dementia Due to Cerebrovascular Disease (Vascular Dementia)
Vascular dementia continues to be a controversial nosological entity, in part because of the absence of clear neuropathological agreement about it. Also, it is difficult to differentiate on clinical grounds alone those patients who have dementia due to AD from those who have vascular dementia. Further complicating the differentiation, abundant evidence suggests that cerebrovascular risk factors and diseases influence both the progression of dementia due to AD (e.g., Mielke et al. 2007) and the emergence of Alzheimer’s pathology in the brain (e.g., Beach et al. 2007). Most patients with vascular dementia who come to autopsy have mixed pathology, often with significant AD pathology (Jellinger and Attems 2006).
Vascular dementia, therefore, is best understood as a heterogeneous group of dementias. At one end of the spectrum are patients with pure genetic forms, such as 1) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 2) mitochondrial encephalopathy with lactic acidosis and strokelike episodes. At the other end are patients who develop dementia after multiple strokes in which significant portions of the brain are damaged. Between those two endpoints are patients with mixtures of pathologies and clinical presentations that impact one another (e.g., smaller strokes or chronic subcortical hypoxia might both damage brain tissue and lead to the onset and progression of Alzheimer’s pathology). Genes and risk factors that predispose individuals to cerebrovascular disorders are also risk factors for vascular dementia. These include diseases of the large and small vessels of the brain, diabetes, hypertension, and atrial fibrillation and other cardiac diseases.
The clinical presentation of vascular dementia is variable. More often than not, it can resemble that of AD. Typically, it presents in fits and spurts, often with acute or subacute onset after a cerebrovascular event. A mix of symptoms is usually present, often including apathy, depression, and motor symptoms. Among patients with vascular dementia or dementia due to AD who have similar MMSE scores, those with vascular dementia are usually more functionally impaired. Gait disorders, parkinsonism, and incontinence are early features of vascular dementia.
The diagnosis of vascular dementia is based on a typical clinical history and associated physical examination findings. The diagnosis requires brain imaging that shows completed infarcts or lacunes in brain areas associated with the cognitive changes. One should be able to demonstrate a temporal relationship between the brain vascular disease and the cognitive changes, but this might be difficult. Radiological findings of white matter change alone, with no evidence of completed strokes or associated examination findings (e.g., focal motor symptoms or a gait disorder), are not supportive of a diagnosis of vascular dementia. White matter changes, as seen on MRI, are common in cognitively normal older people (Longstreth et al. 2005). The diagnosis becomes more complex when patients with established Alzheimer’s dementia develop strokes; many such patients also meet criteria for a diagnosis of vascular dementia. Results from the Nun Study (Snowdon et al. 1997) and the Religious Order Study (Schneider et al. 2004) suggested that for a given degree of Alzheimer’s pathology, dementia is more severe in the presence of comorbid cerebrovascular disease.
Little is known about the progression of clinically diagnosed vascular dementia. Therefore, we can only make speculative comments here. Clinical anecdotes suggest that many patients with vascular dementia can have a nonprogressive condition for many years as long as they do not have other strokes. However, other patients decline rather precipitously, and most patients have variably slower rates of progressive decline.
Lewy Body Disorders
In 2007, a consensus panel (Lippa et al. 2007) proposed the term Lewy body disorders as an umbrella term for Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB). This proposal appropriately recognizes the existence of a spectrum of dementias associated with Lewy body disease of the brain whose shared pathology involves impairments in α-synuclein metabolism. In these three conditions, also termed synucleinopathies, α-synuclein aggregates to form insoluble fibrils. α-Synuclein, a synaptic protein, is the primary structural component of Lewy body filaments. Lewy bodies, in turn, are cytoplasmic, eosinophilic, round or oblong neuronal inclusions. Lewy bodies (as well as Lewy neurites, related proteinaceous structures comprised of α-synuclein) develop in discrete regions throughout the brain stem, diencephalon, basal ganglia, and neocortex (Ballard et al. 2013). Neuronal degeneration, cognitive impairment, and eventually dementia ensue in all Lewy body disorders. The sequence of events involved is poorly known.
One of the complicating factors in determining a diagnosis is that many patients with Lewy body pathologies have coexisting pathologies, in particular Alzheimer’s and vascular pathologies. For instance, approximately half of PDD patients meet neuropathological criteria for AD (Sabbagh et al. 2009). Amyloid plaques are typically seen in DLB (although not as dense as in AD), and neurofibrillary tangles can be found in some DLB cases. Parkinsonian features can be seen in AD although typically late in the disease course. Furthermore, patients with AD are often treated with psychotropic medications that cause long-lasting extrapyramidal side effects, even after the drugs are discontinued. The clinical presentations of PDD and DLB can be similar. Patients develop a progressive subcortical dementia with the following hallmark features: executive dysfunction, cognitive fluctuations, inattention, visuospatial dysfunction, parkinsonism, visual hallucinations, and sleep disturbances (McKeith et al. 2005).
Dementia With Lewy Bodies
Dementia with Lewy bodies is the second most common type of progressive dementia after AD. DLB accounts for approximately 20% of late-onset dementia cases (Ballard et al. 2013), generally affects individuals age 60 or older, and becomes more prevalent with age. The Dementia With Lewy Bodies Consortium continues to systematically update diagnostic and management recommendations for DLB. The third report of the consortium highlights the central, core, and suggestive features that comprise the diagnostic criteria for probable and possible DLB (McKeith et al. 2005). The central feature is a progressive cognitive decline that eventually ends in dementia. Whereas AD typically presents with memory loss initially, DLB’s early deficits are in attention, executive, and visuospatial abilities. Core features include fluctuating cognition with variations in attention and levels of alertness, recurrent well-formed visual hallucinations, and parkinsonian features. Suggestive features include rapid eye movement (REM) sleep behavior disorder, severe sensitivity to neuroleptics, and low dopamine transporter uptake in the basal ganglia as demonstrated on PET or SPECT imaging. The diagnostic criteria for probable DLB require one of the following:
- The presence of dementia plus at least two core features
- The presence of dementia plus one core feature and one suggestive feature
The diagnostic criteria for possible DLB require the presence of dementia plus one core or suggestive feature. The DLB Consortium also provided a long list of supportive features which lack diagnostic specificity but can support the clinical diagnosis of DLB (McKeith et al. 2005). Examples of such supportive features include falls, syncope, transient and unexplained loss of consciousness, severe autonomic dysfunction, hallucinations (other than visual) or delusions, depression, or brain imaging or EEG findings consistent with the diagnosis.
Fluctuating cognition occurs in about 60%–80% of people with DLB (McKeith et al. 1996) and is often mistaken for delirium. The symptoms and their duration vary between individuals and even within the same person. Symptoms range widely from episodes resembling blackouts of absence seizures to speech changes seen in strokes. They can last from seconds to days. Recurrent visual hallucinations occur in over half of DLB cases (Simard and van Reekum 2004) and are the most frequently reported psychotic symptom. Hallucinations tend to be images of people, animals, or objects (Ballard et al. 2013) but can be as simple as shapes in the corner of one’s eye. They can occur at any time but are more common at night and are not typically distressing unless accompanied by delusions or occurring in severely demented individuals (Ballard et al. 2013). Parkinsonian features are similar to those found in PD (e.g., dyskinesias, rigidity, gait disorders, tremor) and occur in almost 70% of individuals with DLB (Aarsland et al. 2001).
If dementia and parkinsonism coexist, the differential diagnosis is sorted out by examining the relative course of the cognitive and motor symptoms. The emergence of dementia after many years of motor symptoms supports a diagnosis of PDD. In contrast, the early presence of dementia in a patient with motor parkinsonism supports a diagnosis of DLB. Researchers use a 1-year interval between onset of PD and onset of dementia to differentiate PDD from DLB.
Many patients with Alzheimer’s dementia develop a clinical DLB picture, reflected in the neuropathology, and many DLB patients have concurrent Alzheimer’s dementia pathology. Daytime drowsiness and naps, staring spells, and episodes of disorganized speech have high positive predictive value for the diagnosis of DLB over Alzheimer’s dementia (Ferman et al. 2004). Both visual hallucinations and delusions are more common in DLB (as well as in PDD) than in Alzheimer’s dementia and have high positive predictive value. In fact, visual hallucinations may be the most clinically useful feature to distinguish DLB from AD (Tiraboschi et al. 2006). Neuroleptic sensitivity is much more common and severe in DLB than in AD. Autonomic dysfunction, such as urinary incontinence, tends to be an early sign in DLB, whereas it often occurs in late stages of AD.
Although the progression of DLB tends to be similar overall to that of Alzheimer’s dementia, the course of DLB is more variable. Because many patients have a more fulminant course, some experts believe that DLB has a worse prognosis than Alzheimer’s dementia (McKeith et al. 2004). DLB is associated with considerable suffering for patients and families, in part because of common, difficult-to-treat, and persistent NPSs (hallucinations, delusions, and affective symptoms). Patients also tend to become affected early with balance, sleep, and motor disorders and to become confined in their mobility.
Parkinson’s Disease Dementia
PDD refers to patients who have had PD for many years and then develop dementia most likely caused by the PD itself. With the advent of the use of l-dopa to help control Parkinson’s motoric symptoms, it has become apparent that some of the most common and impairing symptoms of PD are in the cognitive realm. PDD is associated with excess disability, reduced quality of life, increased risk for psychosis, increased nursing home admission and therefore disease-related costs, increased mortality, and increased caregiver burden (Emre 2003). Patients with PD typically show impairments in executive functioning (e.g., problem solving, set shifting, and planning), deficiencies in attention, and poor fluency. They also have memory impairments, affecting working memory and the organization and retrieval of explicit memory. Memory retrieval is often improved by cuing. Some individuals have visuospatial difficulties arising out of problems with set shifting and the need for high executive demand to complete visuospatial tests.
The average time from onset of PD to the development of dementia is approximately 10 years (Hughes et al. 2000). At least 75% of patients with PD who survive for more than 10 years will develop dementia. Risk factors for the development of dementia in individuals with PD include old age, PD onset after age 60 years, duration of PD, severity of motor symptoms (particularly postural and gait disturbances), REM sleep behavior disorder, visual hallucinations (which increase the risk of developing dementia by 20-fold) (Galvin et al. 2006), and MCI. Once individuals with PD begin to demonstrate cognitive impairment, their MMSE scores decline by an average of 2.4 points per year (Kandiah et al. 2009). However, because the MMSE is not very sensitive to detecting executive dysfunction, patients may have significant cognitive impairment even with normal MMSE scores. The MoCA may be a more sensitive tool for identifying early cognitive impairment in PD (Zadikoff et al. 2008).
Classically, neuropathological staging of PD is based in part on a predictable neuroanatomical spread of Lewy body pathology, starting with the olfactory system and lower brain stem and eventually progressing to the cortex (Braak et al. 2004). Although the neuropathological stage of PD generally correlates with the severity of dementia, some patients may develop cognitive decline despite mild cortical pathology, whereas others may have normal cognitive function despite widespread cortical pathology (Braak et al. 2005). Although high rates of Alzheimer’s pathology appear to be present in patients with PD and dementia, this linkage remains controversial because of the different findings in various autopsy series. One proposed theory linking PD and AD is that the pathways of β-amyloid, tau, and α-synuclein aggregation may potentiate each other, leading to neuronal dysfunction and cell death (Figure 8–6) (Shulman and De Jager 2009). Metzler-Baddeley (2007) provides more information.
Common pathways linking Parkinson’s disease with Alzheimer’s disease.
Source. Reprinted by permission from Macmillan Publishers LTD: Nature Genetics (Shulman JM, De Jager PL: “Evidence for a Common Pathway Linking Neurodegenerative Diseases.” Nature Genetics 41(12):1261–1262, 2009), copyright 2009.
Cognitive impairment in PD has been associated with deficits in several neurotransmitter systems, including dopaminergic, cholinergic, serotonergic, and noradrenergic. Many studies have demonstrated a relationship between frontostriatal dopaminergic pathways and working memory (e.g., Cools and D’Esposito 2011). Although dopaminergic medications may promote mild improvement on short-term memory tests early in the disease course, they are unlikely to be helpful in moderate to severe cases of PDD (Morrison et al. 2004). Cholinergic systems appear to have an important role in the cognitive decline associated with PDD. PET scans have demonstrated cholinergic dysfunction in the cerebral cortex, beginning in early PD and becoming more widespread in PDD (Shimada et al. 2009). Cholinesterase inhibitors modestly improve cognitive function in PDD, leading to the FDA’s approval of the cholinesterase inhibitor rivastigmine for treatment of PDD.
NPSs are common in PD both with and without dementia. These symptoms include depression, psychosis, anxiety, impulse control disorders, disorders of sleep and wakefulness, and apathy (Weintraub and Burn 2011). Depression can be seen in up to 40% of patients. Sleep disorders occur in up to 30% of patients and include rapid eye movement sleep behavior disorders, nightmares, sleep fragmentation, and daytime sleepiness. Visual hallucinations can be seen in up to 50% of patients. Persecutory delusions are also quite common. Many medications used to treat PD, such as anticholinergic agents, amantadine, dopaminergic agents, and catechol O-methyltransferase (COMT) inhibitors, can exacerbate visual hallucinations and delusions.
Dementia Due to Frontotemporal Lobar Degeneration
FTLD is in many ways the paradigmatic non-Alzheimer’s dementia and has become a major focus of interest because of the appreciation that in individuals younger than 65 years, FTLD is the second most common form of dementia, with a rate of occurrence that is close to that of Alzheimer’s dementia (Neary et al. 2005). Previously referred to as Pick’s disease, FTLD is a clinically and pathologically heterogeneous disorder characterized by a progressive change in personality, behavior, and language, and focal degeneration of the frontal and/or temporal lobes. Less commonly, FTLD can also present with progressive motor decline in addition to behavior and language deficits. As the condition progresses and global dementia ensues, however, symptoms overlap and it becomes increasingly difficult to group patients into one category of FTLD or another.
The most common presentation of FTLD is the behavioral variant (bvFTLD) (Kertesz et al. 2007). It is characterized by progressive changes in personality and behavior, as well as cognitive dysfunction. Patients may exhibit an amalgam of executive dysfunction, such as social inappropriateness and disinhibition, poor insight, hyperorality, changes in affect, emotional blunting and apathy, and stereotyped behaviors. Because of the prevalence of apathy in this variant, bvFTLD is often misdiagnosed as depression (Bertoux et al. 2012). Cognitive tests, such as the MMSE, may not be able to reveal cognitive deficits early in the course of bvFTLD.
The second most common presentation of FTLD is primary progressive aphasia (PPA) (Kertesz et al. 2007). PPA is characterized by a prominent progressive impairment in speech and language of insidious onset, with deficits in speech production, naming, grammar, and/or word comprehension. Behavioral features often develop in individuals with PPA. The three main variants of PPA are progressive nonfluent aphasia, semantic dementia, and logopenic progressive aphasia. Patients with progressive nonfluent aphasia demonstrate anomia, impaired fluency, paraphasic errors, and agrammatism with telegraphic speech. Language comprehension and repetition are spared early in the course. Patients ultimately progress to mutism. Those with the semantic dementia variant present with anomia, impaired single-word comprehension, and semantic paraphasic errors. Semantic memory is also affected. Speech production and repetition are spared. The third variant, logopenic progressive aphasia, is characterized by a paucity of and slowed rate of speech, impairment in single-word retrieval and repetition, and phonological paraphasias. Episodic memory and calculation are often affected. Speech production, grammar, and single-word comprehension are spared, at least early on.
Approximately 10%–15% of patients with FTLD also have motor neuron disease. Individuals with the bvFTLD type are most often affected, and motor symptoms can either precede or follow changes in behavior and personality. Patients present with progressive lower motor neuron signs of muscular atrophy and fasciculations preferentially affecting bulbar and upper extremity muscles. The progression to death is hastened. One motor impairment syndrome that co-occurs with FTLD is amyotrophic lateral sclerosis (ALS). Some patients with FTLD develop ALS presentations (known as FTLD-ALS) as their disease progresses, whereas some patients with ALS develop FTLD over their disease course.
There is significant clinical, pathological, and genetic overlap between FTLD-ALS and two atypical parkinsonian syndromes, progressive supranuclear palsy and corticobasal syndrome (Seltman and Matthews 2012). Both progressive supranuclear palsy and corticobasal syndrome have cognitive and behavioral features that overlap with FTLD and are often classified in the spectrum of FTLD clinical syndromes. Clinical features of progressive supranuclear palsy include postural instability, axial rigidity, frequent falls, bradykinesia, dysarthria, and supranuclear gaze deficits, as well as progressive cognitive decline and apathy. Clinical features of corticobasal syndrome include the simultaneous occurrence of asymmetrical cortical signs (e.g., limb apraxia, myoclonus, alien limb phenomenon) and extrapyramidal signs (e.g., bradykinesia, tremor, limb rigidity, dystonia). Although progressive supranuclear palsy is characterized by neuronal loss and atrophy in the basal ganglia with relative sparing of the frontal cortex, the pattern of frontal lobe atrophy in corticobasal syndrome closely resembles the pattern of FTLD. Because some individuals with FTLD may manifest both extrapyramidal symptoms and psychosis, they are not infrequently diagnosed as having DLB. Individuals with FTLD may also exhibit hypersomnia, fluctuating cognition, and sleep disorders (Claassen et al. 2008), leading to diagnosis of DLB. Clinicopathological studies can be helpful in understanding the underlying neurodegenerative process in patients who meet criteria for both FTLD and DLB.
A revised consensus of neuropathological criteria takes into account advances in both genetics and biochemistry and reflects the diversity of pathological pictures (Cairns et al. 2007). Pathologically, FTLD is characterized by knife-edge lobar atrophy, typically in the anterior temporal and posterior inferior areas of the frontal lobes. Microscopically, neurons appear enlarged and vacuolar, with extensive gliosis and loss of myelin. Neurons and glial cells may contain abnormal cytoplasmic and/or nuclear protein inclusions. Inclusions tend to comprise either hyperphosphorylated tau protein or transactive response DNA binding protein 43 (TDP-43). Inclusions containing tau protein can be seen in various disorders such as FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and hippocampal sclerosis. Collectively, these disorders are known as tauopathies.
FTLD is familial in a considerable number of patients, often in an autosomal dominant pattern of inheritance. Mutations in the tau, progranulin, and ubiquitin genes have been associated with the condition. Familial TDP-43 proteinopathy is associated with defects in multiple genes and several neuropathological types (Cairns et al. 2007).
FTLD is a clinical diagnosis. Although neuroimaging is not necessary to establish the diagnosis of FTLD, it may support the diagnosis and is necessary to exclude alternative pathology. FTLD is sometimes misdiagnosed as Alzheimer’s dementia; however, clinicians can differentiate FTLD from Alzheimer’s dementia via the early age at onset of FTLD (average age at onset is in the late 50s or early 60s), early prominent NPSs, and lack of significant memory or visual spatial impairments. Other symptoms that support a diagnosis of FTLD over Alzheimer’s dementia include abnormal eating behaviors, social inappropriateness, degree of apathy, and stereotyped behaviors. FTLD is almost invariably progressive, especially if language symptoms occur early on. In clinical settings, the time from an FTLD diagnosis to death is on the order of 3–5 years, which is shorter than the periods associated with Alzheimer’s dementia (Chow et al. 2006). Also, compared with Alzheimer’s dementia, FTLD is a greater burden to caregivers, given the disinhibited behaviors that are hard to treat and require aggressive supervision to manage.
Less Common Dementias
Dementia Due to Normal-Pressure Hydrocephalus
The dementia of normal-pressure hydrocephalus (NPH) is a subcortical dementia associated with a characteristic magnetic-like gait disorder, incontinence, and cognitive dysfunction. Little is known about its epidemiology and progression. It is estimated to have an annual incidence of 0.5–2 per million individuals (Wilson and Williams 2006). Idiopathic NPH is most common after age 60 years. Cognitive symptoms may include psychomotor slowing, executive dysfunction, personality changes, inattention, impaired recall, and decreased fine motor speed (Finney 2009). The condition is suspected when patients present with the classic triad of findings and brain imaging reveals enlarged ventricles disproportionate to cortical atrophy. The diagnosis is confirmed by a patient’s response to either lumbar puncture drainage of a large volume (40–50 mL) of CSF, response to an extended CSF drainage trial through a lumbar spinal catheter, or measurement of resistance to CSF outflow during a lumbar puncture. NPH is difficult to diagnose because gait difficulty, cognitive decline, urinary incontinence, and enlarged ventricles (ventricle size increases with age) are all common in the elderly and can have many causes; furthermore, there is no combination of cardinal findings that is pathognomonic or specific for NPH (Graff-Radford 2007). Because NPH is often seen in the elderly, a factor complicating the diagnosis of NPH is that 75% of patients with idiopathic NPH also meet clinical criteria for AD or vascular dementia (Bech-Azeddine et al. 2007). Moreover, a significant percentage of patients with idiopathic NPH demonstrate positivity for biomarkers typically found in AD, such as Aβ (Leinonen et al. 2012). Much interest has focused on efforts to diagnose and treat NPH using shunts, as discussed in “Disease-Modifying Therapies” later in this chapter.
Rapidly progressive dementias (RPDs) represent a heterogeneous group of disorders that can be categorized by their underlying pathophysiology, including neurodegenerative, inflammatory, vascular, toxic, metabolic, neoplastic, and infectious causes (Woodruff 2007). Although relatively rare, human transmissible spongiform encephalopathies, or prion diseases, are probably foremost in the minds of clinicians when evaluating RPDs (Woodruff 2007). Prion diseases represent a large portion of neurodegenerative causes of RPD (Appleby and Lyketsos 2011; Geschwind et al. 2008). However, out of a University of California, San Francisco, cohort of 178 patients with suspected prion disease or other RPDs, 38% of patients were diagnosed with a nonprion condition (Geschwind et al. 2008). The largest group of nonprion patients in the cohort had neurodegenerative diseases (14.6% of the entire cohort and 39% of all nonprion cases). These diseases included AD, DLB, FTLD, corticobasal syndrome, and progressive supranuclear palsy. The second most common group had autoimmune conditions (8.4% of the entire cohort and 22% of nonprion cases). These included Hashimoto’s encephalopathy, antibody-mediated limbic encephalitis associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic), multiple sclerosis, and neurosarcoidosis. The third most common diagnosis was dementia of unknown cause (4.5% of the entire cohort and 12% of nonprion cases). Several patients had encephalitis of presumed viral etiology (enterovirus was confirmed in one patient). Other nonprion causes of RPD included toxic-metabolic causes (e.g., methylmalonic acidemia, encephalopathy secondary to alcohol intoxication, methotrexate toxicity), encephalopathy associated with cancer but without evidence of autoantibodies, and psychiatric conditions, among others.
Recent knowledge regarding prion protein transmission across species has led to concerns about animal-to-human transmission of these proteins through the diet, followed by incurable RPD. In the United States the annual incidence of CJD, the most common human prion dementia, is roughly 1 per million individuals (Holman et al. 2010). The incidence peaks between ages 65 and 74 years (Holman et al. 2010). Although most cases (75%–85%) of CJD are sporadic, other forms include genetic (10%–22%) and acquired (iatrogenic and variant CJD) (< 1%–3%) (Appleby and Lyketsos 2011; Geschwind et al. 2008).
The basic pathophysiology of the disease, partly worked out by Stanley Prusiner (who won the Nobel Prize in Medicine for this work), is thought to involve abnormal transformation of prion protein (PrPc) from its α-helical form to a β-sheet form. The pathological prion protein (PrPres) reuses itself as a template (prions do not require nucleic acids to replicate) to convert more PrPc to PrPres. This leads to a snowball cascade with widespread dissemination of these proteins, which become clumpy and toxic, leading to the classic spongiform appearance of the nervous system. How this is brought about is uncertain. It might occur spontaneously or result from interactions with mutant prion proteins or those of other species that make their way into the human brain. Some cases have resulted from transplanting affected organs. Little is known about factors that initiate or accelerate these transitions, although some of the familial cases appear to have been initiated by biological stress to the brain through stroke, hypoxia, or TBI (Lyketsos 1999). At present, this disease is incurable. The familial forms are a target of genetic counseling.
All mammals, including humans, carry the prion protein gene PRNP on the short arm of chromosome 20. Several mutations in this gene have been reported and are associated with a familial progressive dementia (Michalczyk and Ziman 2007), sometimes referred to as Gerstmann-Sträussler-Scheinker syndrome. In 1996, variant CJD was discovered in the United Kingdom. It was linked to bovine spongiform encephalopathy, which was most likely transmitted to humans by eating affected beef. By the end of 2005, approximately 190 human cases had been identified (Collee et al. 2006). This epidemic appears to have subsided.
CJD and Gerstmann-Sträussler-Scheinker syndrome have variable clinical presentations, although the most characteristic presentation is that of RPD, prominent gait disorder (e.g., ataxic gait), extrapyramidal symptoms, and motor findings (e.g., myoclonus) early on. Early cognitive deficits involve memory, concentration, judgment, and language (e.g., aphasia). Sleep disturbances, such as insomnia, and visual disturbances, ranging from field defects to cortical blindness, can occur as well (Puoti et al. 2012). Patients may display a gaze that expresses apprehension or fear and may be hypersensitive (Puoti et al. 2012). Patients become disabled rapidly and may experience difficulty in obtaining a diagnosis because they often present with psychiatric symptoms such as depression, anxiety, apathy, and executive dysfunction. In one-third of individuals, vague complaints of fatigue, headache, sleep disturbance, vertigo, malaise, weight loss, pain, depression, or behavioral changes precede the dementia by weeks to months (Geschwind et al. 2008). However, obvious impairments in gait, behavior, and cognition can be apparent over a matter of days (Puoti et al. 2012). The median survival is 5 months, and approximately 85% of patients die within 1 year of symptom onset (Geschwind et al. 2008). Although the time course of CJD is almost invariably rapid, cases in the literature have been reported with longer courses, sometimes lasting years. The familial cases, in particular, tend to run longer courses, as long as a decade in younger individuals (Lyketsos 1999).
The only way to definitively confirm a diagnosis of sporadic prion disease in living patients is through brain tissue biopsy. However, the combination of a clinical assessment and either CSF assay or MRI imaging has sufficient sensitivity and specificity to accurately diagnose the disease (Puoti et al. 2012). That said, often up to 80% of prion disease cases, including genetic forms, are initially misdiagnosed (Appleby and Lyketsos 2011). The rarity of the disease often delays diagnosis. Furthermore, diagnostic patterns vary by country and/or clinical center (e.g., community hospital vs. university hospital) (Appleby and Lyketsos 2011). The Centers for Disease Control and Prevention (2010) has published criteria for probable sporadic CJD, which are outlined in Table 8–7.
Dementia Due to Prion Diseases and Other Rapidly Progressive Dementias CDC criteria for probable sporadic Creutzfeldt-Jakob disease
Rapidly progressive dementia
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And
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At least two of the following four features:
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Myoclonus
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Visual or cerebellar signs
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Extrapyramidal or pyramidal signs
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Akinetic mutism
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And
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A positive result on at least one of the following three laboratory tests:
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Periodic sharp wave complexes on electroencephalogram during a disease of any duration
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Positive 14-3-3 cerebrospinal fluid assay in patients with a disease duration of less than 2 years
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Magnetic resonance imaging signal abnormalities in the caudate nucleus and/or putamen on diffusion-weighted imaging or fluid-attenuated inversion recovery
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And
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Routine investigations should not suggest an alternative diagnosis
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Source. Adapted from Centers for Disease Control and Prevention 2010.
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Although neurodegenerative dementias such as AD, DLB, and FTLD are typically characterized by gradual onset and insidious progression, they can sometimes present in a fulminant form, developing over months, with death occurring in less than 3 years (Geschwind et al. 2008). These neurodegenerative dementias can resemble CJD because of an overlap of motor symptoms (particularly gait disturbances, extrapyramidal signs, and myoclonus) and cognitive, behavioral, and psychiatric manifestations. EEG and CSF abnormalities can likewise overlap. For instance, the periodic 1- to 2-Hz triphasic sharp waves characteristically seen on EEG in CJD can also be seen, although rarely, in end stages of AD or DLB, as well as in toxic-metabolic conditions and in Hashimoto’s encephalopathy. Furthermore, this electroencephalographic finding usually appears only in the later stages of CJD. Thus, the EEG lacks sensitivity and specificity and misses many early and some late cases. CSF findings in CJD are likewise neither sensitive nor specific for the disease. False-positive results for CSF 14-3-3 protein can be seen in fulminant AD cases. A more sensitive and specific test for CJD could be the combination of fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) MRI sequences (Geschwind et al. 2008).
Autoimmune diseases of the brain causing limbic encephalopathy can also resemble CJD. Symptoms include memory loss, depression, anxiety, personality changes, emotional lability, and seizures. The clinician should consider a paraneoplastic syndrome when there is a subacute or rapid development of dementia, cancer risk factors, extrapyramidal or cerebellar symptoms, other neurological symptoms, evidence of inflammation in CSF analysis, or a family history of cancer (Geschwind et al. 2008). Detection of paraneoplastic antibodies should prompt the clinician to aggressively investigate for the corresponding tumors. Primary central nervous system vasculitis often presents with headache, altered mentation, focal neurological signs, and CSF pleocytosis (Geschwind et al. 2008). Vasculitides can be distinguished from CJD and other RPDs by the presence of systemic manifestations or by specific brain MRI abnormalities, such as brain hemorrhage or multiple infarctions of different ages. Notably, even in the absence of gastrointestinal symptoms, celiac disease can cause ataxia, NPSs, seizures, headaches, neuropathy, and dementia. Geschwind et al. 2008) and Woodruff (2007) provide further information regarding various causes of RPD, as well as diagnostic approaches, screening tests, representative imaging abnormalities, and treatment options.
Treatment
Treatment for Milder Cognitive Syndromes
Memory clinics and primary care physicians anecdotally report that because of the increased public awareness of dementia, patients are presenting with increasingly milder cognitive symptoms to request diagnosis and treatment. At present, there is little empirical knowledge about how to manage these patients clinically. Most experts recommend continued observation and the use of nonpharmacological therapies such as controlling vascular risk factors (e.g., healthy diet, exercise, smoking cessation), due to the relationship of cardiovascular health to cognitive health; meditation; cognitive stimulation; and cognitive rehabilitation (e.g., using memory cues and organizational aids).
Cooper et al. (2013) reviewed nonpharmacological interventions for MCI to identify which had the best treatment evidence. The only type of nonpharmacological intervention for which they found preliminary evidence was a long-term group program of memory training, reminiscence and cognitive stimulation, recreation, and social interaction, which improved cognition over 6 months. They found limited evidence that individual aerobic exercise programs improve executive functioning and category fluency, or that computerized cognitive training programs improve delayed recall. However, the studies using computerized programs had multiple secondary outcomes, increasing the possibility of a chance finding. Furthermore, Cooper and colleagues questioned the clinical benefit of isolated improvements in these cognitive domains. Nonetheless, exercise has been associated with favorable effects on neuronal survivability and function, neuroinflammation, vascularization, neuroendocrine response to stress, and brain amyloid burden (Baker et al. 2010). Cooper et al. highlighted the limited generalizability of the nonpharmacological interventions that they reviewed, most of which were underpowered and lacked sufficient evidence of efficacy. A Cochrane review found that, compared with no treatment, specific neuropsychological (“brain”) exercises designed to strengthen memory in people with MCI did improve immediate and delayed verbal recall (Martin et al. 2011); however, the effects were lost when the group receiving exercises was compared with an active control group.
Various vitamins (e.g., vitamin B6, vitamin B12, folate, vitamin E), supplements (e.g., Gingko biloba), and nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., rofecoxib, triflusal) have not been shown to reliably improve cognition in patients with MCI or to prevent conversion to dementia. Nicotine patches improved attention (and verbal recall as a secondary outcome) but not global functioning over 6 months in a small study of nonsmokers (Newhouse et al. 2012). In one study, piribedil, a dopamine receptor agonist, was more effective than placebo on a cognitive primary outcome (defined as change in MMSE score) over 3 months (Nagaraja and Jayashree 2001); however, the criteria for MCI were not strict and the authors acknowledged that some participants may have had dementia.
The results of at least one randomized trial suggest that the cholinesterase inhibitor donepezil may delay progression to dementia, especially in patients who are APOE*E4 carriers (Petersen et al. 2005), but this has not been replicated or supported by other trials (Rosenberg et al. 2006). More recent reviews and meta-analyses (e.g., Cooper et al. 2013; Russ and Morling 2012) found very little evidence that cholinesterase inhibitors either affected progression to dementia or improved cognitive scores in patients with MCI. Furthermore, there was an increased risk of adverse events, particularly gastrointestinal, in those who received cholinesterase inhibitors, as well as an unexplained increased mortality rate with galantamine specifically (Cooper et al. 2013). Thus, in most cases, cholinesterase inhibitors should not be clinically prescribed for individuals with MCI (Cooper et al. 2013; National Institute for Health and Care Excellence 2012). We recommend initiating pharmacological therapy only in cases in which there is strong evidence of likely benefit—for example, when the patient appears to be about to transition to Alzheimer’s dementia or when the cognitive impairment is particularly worrisome to the patient. Rosenberg et al. (2006) and Cooper et al. (2013) provide more detailed approaches to this issue.
The Four Pillars of Dementia Care
Dementia care has four basic elements, or pillars (Lyketsos et al. 2006). The first pillar relates to management of key aspects of the disease with the goal of reversing its effects or delaying its progression in the brain. Although few disease therapies exist at present, several therapies are being developed for different types of dementia targeted at underlying pathophysiological mechanisms. The second pillar of dementia care relates to the management of its symptoms, whether they are cognitive, neuropsychiatric, or functional. The final two pillars involve providing supportive care to patients and caregivers in ways that are systematic and evidence based.
The overall premise of this approach is that an effective, systematic care model exists for patients with dementia resulting from AD (Lyketsos et al. 2006). This care model also has implications for patients suffering from other forms of dementia. Until recently, dementia care interventions were few and were provided on faith, with limited evidence of effectiveness. Evidence from randomized trials now indicates that a dementia care “package” provides significant benefits to patients and caregivers. Although rigorous well-controlled trials to evaluate the efficacy of care interventions are sparse, several high-quality trials of care coordination in dementia demonstrate modest to moderate effects on patient quality of life, improving care quality, reduction of NPSs, and reduction of caregiver burden, unmet needs, and depression (Samus et al. 2014). Based on results from a randomized trial, Callahan et al. (2006) reported that in primary care settings, guideline-based dementia care led to better patient and caregiver outcomes, likely due to the more appropriate use of medications and interventions that targeted both caregivers and patients. Long-term follow-up studies (e.g., Mittelman et al. 2006) have demonstrated that caregiver-targeted interventions (e.g., counseling and support programs) can prolong the time patients spend in the community. An observational cohort (Lyketsos et al. 2007) from the Maryland Assisted Living Study supported these findings, suggesting that treatment for dementia might delay discharge from assisted living facilities by as much as 7 months.
Multicomponent supportive dementia care programs can improve the patient’s ability to age in place. In a recent 18-month randomized controlled study (Maximizing Independence [MIND] at Home) of 303 community-living elders, home-based dementia care delivered by community-based nonclinical coordinators, supervised by geriatric clinicians, led to delays in transitioning from home, reduced unmet needs, and improved self-reported quality of life (Samus et al. 2014). The intervention was considered to be low risk with no intervention-related adverse events. Over 18 months, participants in the intervention group had a 51-day mean delay of transition out of their home, with a 228-day median delay over an extended follow-up period (median of 26 months) compared with control participants. Given the positive effect of being able to stay at home versus costly facilities (e.g., nursing homes or assisted living placements), the findings imply a cost savings (Samus et al. 2014). Furthermore, most contacts (72%) between the community-based coordinator and another person (e.g., patient, study partner, health provider, clinician) were phone based, which implies that benefits can be achieved in a potentially cost-efficient manner (Samus et al. 2014). Tremont et al. (2013) is currently investigating a cost-effective, telephone-based, multicomponent dementia intervention to reduce distress in dementia caregivers. Nevertheless, in-person visits are likely essential to visually identify a wide range of home and personal safety needs (e.g., fall risk, medication use adherence, wander risk) and the physical condition of participants and study partners (Samus et al. 2014).
An optimal dementia care team includes dementia care specialist, occupational and physical therapists, nurse, psychologist, social worker, and case manager, working closely with the primary care physician and caregivers. One of the roles of the dementia care specialist, who is often a gerontologist or geriatric psychiatrist, is to manage, both pharmacologically and nonpharmacologically, the cognitive and neuropsychiatric symptoms that accompany dementia. Nonpharmacological strategies can be very effective and avoid risks and side effects associated with medications. Over time, however, medications often become a necessary and integral part of symptom management. A particularly useful and well-known adage for medication management in geriatric patients is to start low and go slow. When initiating or titrating medications, the care specialist should be mindful of the following:
- Elderly patients have decreased renal clearance and slowed hepatic metabolism.
- Because elderly patients often have multiple medical illnesses and are taking multiple medications, the clinician must evaluate potential drug-drug interactions.
- Because geriatric patients are at increased risk of orthostasis and falls in part due to decreased vascular tone, medications contributing to orthostasis should be used cautiously.
- Deliriogenic medications (e.g., anticholinergics and benzodiazepines) should be used judiciously and sparingly.
Disease-Modifying Therapies
Alzheimer’s Disease
As articulated in the principles of care of the American Association for Geriatric Psychiatry (AAGP) (Lyketsos et al. 2006), estrogen, anti-inflammatory agents (e.g., prednisone, NSAIDs), and Ginkgo biloba are not effective treatments for Alzheimer’s dementia. One large randomized controlled trial (RCT) demonstrated that high doses of the antioxidant vitamin E delays progression of Alzheimer’s dementia, lengthening the time before onset of the next phase by 2 years (Sano et al. 1997). Given safety concerns about dosing, the AAGP recommended considering vitamin E for Alzheimer’s dementia but avoiding doses above 400 IU/day. In a recent study evaluating the use of high-dose (2,000 IU/day) vitamin E in patients with mild to moderate AD, Dysken et al. (2014) found that vitamin E may slow functional decline and decrease caregiver burden for some patients. Under investigation are the usefulness of other antioxidants (vitamins C and D), folate to reduce homocystinemia, and dietary modifications.
One of the most effective therapies for AD is the aggressive management of associated vascular risk factors such as blood pressure (particularly keeping systolic blood pressure below 160 mm Hg), high cholesterol, diabetes, obesity, and sedentary lifestyle (Mielke et al. 2007). Although statins have shown promise as treatments for cognitive decline and dementia in observational studies, several large RCTs (e.g., Trompet et al. 2010) did not show any significant effect on cognition.
A better understanding of the etiopathogenesis of Alzheimer’s dementia has led to the development of therapies targeting amyloid precursor protein metabolism, Aβ1–42 deposition or clearance, and ways by which amyloid injures neurons. For example, inhibition of the enzymes β-secretase and β-secretase targets the metabolism of amyloid precursor protein. Two types of immunotherapies under investigation include injecting amyloid to create host immunity (active immunization) or injecting intravenous immunoglobulin antibodies to clear amyloid from the brain (passive immunization). Examples of the latter include bapineuzumab and solanezumab, monoclonal antibodies that bind to soluble Aβ and promote Aβ removal from the brain through the bloodstream. Lastly, there are antitau therapies targeting tau hyperphosphorylation and the inhibition of tau aggregation. Mangialasche et al. (2010) published a summary of FDA clinical trials of disease-modifying agents.
For the most part, clinical trials have not been successful at producing safe disease-modifying therapies for AD. Given the complexity of AD, the central hypothesis of “one protein, one drug, one disease” needs to be modified (Mangialasche et al. 2010). There are complex interactions at every level of the human body, from genes to organs, as well as interactions between the person and the environment. Few people have “pure” AD; amyloid plaques and Lewy bodies may interact in yet unknown ways. It is difficult to account for these nonlinear and rather unpredictable interactions in clinical trials. Many clinical trials aim to find a selective compound that acts on a specific disease target (e.g., Aβ) to produce a desired clinical effect. However, some RCTs demonstrate that even when therapies completely remove amyloid plaques, patients may still develop end-stage dementia, suggesting that clearing amyloid plaques alone cannot repair already damaged neurons or stop clinical progression of AD (Holmes et al. 2008). Researchers neither completely understand the functions of Aβ nor know the upper and lower safe limits of Aβ (Carrillo et al. 2013). Many drugs bind to more than one target, increasing the risk of unforeseen and unwanted complications. On the other hand, many enzymes, such as β-secretase, have many substrates. It is challenging to design a drug to target β-secretase because of its many substrates, as well as because of its wide substrate-binding domain and the need for drugs to be able to cross the blood-brain barrier to modulate the enzyme (Mangialasche et al. 2010).
Mangialasche et al. (2010) highlight other barriers to producing successful disease-modifying therapies, including the following:
- RCT protocols can be costly and time-consuming for the patient and the caregiver, thus increasing withdrawal rates.
- There is a lack of validated biomarkers with established cutoffs.
- Studies that have unsuccessful preclinical and clinical results are not always published, leading to repetition of errors.
- Some drugs with positive results in preclinical and early clinical testing failed large phase 3 RCTs.
- Designing selective compounds without intolerable and potentially toxic side effects is difficult.
- Some drugs are hindered by the inability to reach a therapeutic dosage, or treatment duration may have been too short to result in an effect.
- There are genetic differences among patients (e.g., APOE*E4 carriers or cytochrome P450 variability).
- Reliable evaluation of patients requires adequate training and monitoring of RCT raters.
- Even if a drug targets mild to moderate stages of AD, the disease could have already advanced too far for detection of a disease-modifying effect.
Indeed, even by the time MCI develops, the pathological process may have advanced too far for treatments to be preventive, and it may be necessary to target the disease earlier, at the stage of subjective memory impairment (Cooper et al. 2013).
Given that disease-modifying therapies have largely been unsuccessful, that targeting patients even in early stages of dementia may prove too late, and that physicians are increasingly able to diagnose AD in very early stages (i.e., in a presymptomatic phase) using biomarkers, trials have started targeting prevention of AD. Carrillo et al. (2013) describe various ongoing trials in their early phases. The following are some examples:
- The Anti-Amyloid Treatment for Asymptomatic AD Trial targets cognitively normal adults ages 65–80 years with PET evidence of Aβ. Because the subjects have evidence of Aβ, they are more likely to demonstrate cognitive decline over time during the trial, making them a good target population for prevention. Subjects will be randomly assigned to receive solanezumab or placebo. The primary outcome measure will be the rate of cognitive decline.
- The Centre for Studies on Prevention of AD at the Douglas Institute in Montreal, Quebec, is testing various preventive interventions in people older than 60 years with a family history of AD. Interventions include medications such as intranasal insulin and naproxen, and lifestyle modifications such as aerobic exercise and dietary changes. The goals are to find optimal biomarker end points and to identify interventions that move biomarkers or mitigate their progression.
- The Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging is investigating the interaction between vascular and AD pathologies and exploring the possibility of delaying AD by reducing vascular risk factors through physical activity. The target population is individuals older than 60 years with subjective memory complaints or a diagnosis of MCI and at least one cardiovascular risk factor.
- The Multidomain Alzheimer Preventive Trial in France is testing the protective effects of a multifactorial intervention consisting of nutritional advice, cognitive and physical activity, and omega-3 treatment. The targeted population includes frail (because of evidence linking frailty with cognitive decline) or prefrail individuals without dementia, ages 70 years and older, with subjective memory complaints and a limitation in at least one IADL.
Many risk factors contributing to the development of late-life dementia are modifiable. Cognitive stimulation, complexity of occupation, an engaged lifestyle, and a reduction of vascular risk factors (e.g., cholesterol and smoking) may have protective effects (Carrillo et al. 2013).
Various prevention trials focus on different populations such as asymptomatic individuals with AD pathology and presymptomatic individuals with dominant mutations or other risk factors that increase the likelihood of developing AD (Carrillo et al. 2013). However, these trials may not necessarily be generalizable because they may represent two different pathological processes that may respond differently to a given treatment. Furthermore, ethical issues arise in prevention studies. At this point in time, we cannot predict whether a person with AD pathology will definitively develop dementia. Both false positives and false negatives can have detrimental effects on a person and his or her family.
Other Diseases
There are no disease-modifying treatments available for DLB, PDD, FTLD, or CJD. Management of stroke risk, typically with anticoagulants and by mitigating vascular risk factors, is fully indicated in treating patients with vascular dementia or possibly Alzheimer’s dementia with relevant vascular comorbidities. l-Dopa agonists may be effective at treating PDD. Some patients with DLB may also have a partial response. Although l-dopa can precipitate or exacerbate psychosis and somnolence, this risk is lower than with dopamine agonists (Fernandez et al. 2003).
Although many patients with NPH have favorable outcomes that can be enduring after shunt insertion, the beneficial effects typically involve gait and continence but not cognition (Klassen and Ahlskog 2011). The response of patients with NPH or AD to shunt insertion is poorer than that of patients without neurodegenerative pathology (Hamilton et al. 2010). Indicators of positive response to shunting include improvement in gait after a high-volume lumbar puncture or high CSF flow pressure on continuous monitoring (Graff-Radford 2007). Other positive prognostic factors include 1) short duration of cognitive impairment, 2) a mild impairment in cognition, 3) the appearance of gait disturbance prior to the onset of cognitive impairment, and 4) the presence of a secondary cause for NPH (Graff-Radford 2007). Indicators of negative response to shunting include 1) moderate or severe cognitive impairment, 2) the presence of dementia for more than 2 years, 3) the appearance of cognitive impairment before gait disturbance, 4) the presence of aphasia, and 5) the patient’s abuse of alcohol (Graff-Radford 2007). The size of ventricle or the severity of gait disorder is not a good predictor of outcome (Meier et al. 2006). Up to 40%–50% of shunt patients experience complications from shunting. In a Dutch study (Vanneste et al. 1992), the largest outcome study to date, notable mortality was observed after shunt placement, with the risks of shunting outweighing the benefits. No RCT has been conducted to evaluate the long-term benefit of shunting. Although confirmatory diagnostic tests for NPH are available, shunting for patients with NPH remains controversial due to an absence of trials demonstrating long-term benefit.
Several RPDs already have disease-modifying treatments that can potentially halt or reverse their disease process. However, no disease-modifying treatments for prion diseases are as yet available. Appleby and Lyketsos (2011) highlighted experimental trials of treatments for prion diseases. Researchers are identifying potential novel approaches to treatment, such as vaccines, RNA interference, and anti-inflammatory agents. One of the most popular approaches to treatment is to block neuronal PrPc, which has been done successfully in animal models. Most treatment studies of human prion diseases are case reports or case series. They are hampered by disease heterogeneity, lack of standardized outcome measures, low prevalence and statistical power, and rapid progression. Furthermore, families may decline noncurative treatments due to the rapid progression and severity of neurocognitive decline seen in prion diseases. Individuals at risk of developing prion diseases (e.g., genetic forms of prion diseases) are most likely to receive the greatest benefit from treatments. Thus, the most important aspect of establishing treatment for RPD is an early and accurate diagnosis. For instance, a brain fluorodeoxyglucose–PET scan study of fatal familial insomnia mutation carriers demonstrated hypometabolism in the thalamus 13–21 months prior to clinical symptoms (Cortelli et al. 2006). Once therapeutics become available, early detection of prion diseases using biomarkers could enable clinicians to administer effective treatments in presymptomatic stages or prior to severe brain damage, allowing for a better quality of life for patients.
The cholinesterase inhibitors, donepezil, rivastigmine, galantamine, and tacrine, and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine are all approved by the FDA for the symptomatic treatment of cognitive symptoms in AD. These medications provide only modest and temporary stabilization of the changes to cognition and ADLs associated with the disease. They do not reverse or stop the degenerative process. Furthermore, the data are mixed as to whether these medications improve long-term outcomes, such as the need for nursing home admission.
Cholinesterase inhibitors inhibit the enzymes that degrade acetylcholine (acetylcholinesterase and/or butyrylcholinesterase), effectively increasing the concentration of acetylcholine at synaptic clefts in the brain. Acetylcholine is a neurotransmitter hypothesized to be important in cognition. Donepezil, rivastigmine, and galantamine are all approved for the treatment of mild to moderate AD. Donepezil and the patch preparation of rivastigmine are approved for the treatment of severe AD. Tacrine, the first agent approved for use in AD, is no longer available in the United States because it can cause hepatotoxicity, specifically a transient and reversible transaminitis. These medications are available in a variety of formulations: oral immediate-release tablet or capsule, once-daily dosing tablet (donepezil only), extended-release preparations (memantine and galantamine), oral-disintegrating tablet (donepezil only), solution (rivastigmine and galantamine), and transdermal patch form (rivastigmine only).
Researchers have studied another cholinesterase inhibitor, huperzine, an over-the-counter Chinese herb extract whose safety is poorly understood. A recent meta-analysis (Yang et al. 2013) suggests that huperzine may have some beneficial effects on cognitive function, daily living activities, and global clinical assessment in patients with AD; however, the study acknowledges that its findings should be interpreted with caution due to the poor methodological quality of the trials included.
Memantine, which is hypothesized to work by preventing the excitotoxic effects of glutamate in the brain, is approved for the treatment of moderate to severe AD. It is available in oral immediate-release, extended-release, and solution preparations.
A summary of the four FDA-approved medications available in the United States for the treatment of cognitive symptoms is provided in Table 8–8.
Therapies for Cognitive Symptoms Associated With Dementia FDA-approved medications available in the United States for the treatment of cognitive symptoms in Alzheimer’s dementia
Drug | Disease stage | Preparations | Dosing | Common side effects and dosing tips |
|---|---|---|---|---|
Donepezil
|
All stages of AD
|
Oral tablet
Once-daily tablet
Oral-disintegrating tablet
|
Initially 5 mg/day. May increase to 10 mg/day after 4–6 weeks.
|
Nausea, vomiting, diarrhea, anorexia, weight loss, dyspepsia, insomnia, and vagotonic effects leading to bradycardia and heart block. Dosage may have to be reduced in cases of hepatic impairment.
|
Rivastigmine
|
Mild to moderate AD
Transdermal patch also approved for severe AD
Oral tablet and transdermal patch also approved for mild to moderate Parkinson’s disease dementia
|
Oral capsule
Oral solution
Transdermal patch
|
Initially 1.5 mg twice daily. Increase by 3 mg every 2 weeks as tolerated to maximum dose of 6 mg twice daily.
|
Nausea, vomiting, diarrhea, anorexia, abdominal pain, weight loss, dyspepsia, dizziness, headache, extrapyramidal symptoms, central nervous system depression, and vagotonic effects leading to bradycardia and heart block. Gastrointestinal side effects may be reduced if taken with food and dosage titrated slowly. If treatment stopped for more than several days, start titration over with initial dosage.
|
Galantamine
|
Mild to moderate AD
|
Oral tablet
Extended-release capsule
Oral solution
|
Initially 4 mg twice daily. Increase to 8 mg twice daily after 4 weeks. May increase to 12 mg twice daily if indicated.
|
Nausea, vomiting, diarrhea, anorexia, weight loss, dyspepsia, muscle cramps, and vagotonic effects leading to bradycardia and heart block. Associated with increased mortality, mainly due to cardiovascular events, in some placebo-controlled trials. Gastrointestinal side effects may be reduced if taken with food and dosage titrated slowly. Caution in patients with renal or hepatic impairments.
|
Memantine
|
Moderate to severe AD (monotherapy and in combination with acetylcholinesterase inhibitor)
|
Oral tablet
Extended-release capsule
Oral solution
|
Initially 5 mg/day. May increase by 5 mg weekly to maximum dose of 20 mg twice daily. Dosages over 5 mg should be divided.
|
Dizziness, headache, confusion, constipation, and fatigue. Caution in patients with renal or hepatic impairments. Dosage may have to be reduced in cases of renal impairment.
|
Note. AD = Alzheimer’s disease; FDA = U.S. Food and Drug Administration.
| ||||
Source. Data from Stahl SM: Essential Psychopharmacology: The Prescriber’s Guide, Revised and Updated Edition. New York, Cambridge University Press, 2006.
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The approved cholinesterase inhibitors appear to have comparable efficacy. However, because each of the medications has individual pharmacological particularities as well as pharmacokinetic and pharmacodynamic properties that make them distinct, a patient may respond to one medication over another (Massoud et al. 2011). Prior to the development of the patch delivery form of rivastigmine, approved in the United States in 2007, and the extended-release form of galantamine, there were important differences in toxicity that entered into the clinical decision about which medication to use first. Rivastigmine also has biological activity against butyrylcholinesterase. Galantamine is also an allosteric modulator of the nicotinic receptors. Despite differences in biological activity, in the absence of solid relevant clinical data, the choice of agent continues to be driven by ease of use and titration, cost, and physician experience.
There is ample evidence to recommend initiating a cholinesterase inhibitor for the treatment of mild to moderate AD, provided that the agent appears to have a worthwhile effect on cognitive, global, functional, or neuropsychiatric symptoms, and that a dementia care specialist initiates and routinely reviews treatment (National Institute for Health and Care Excellence 2011). Although memantine is frequently prescribed off-label for mild AD, independent reviews have found no differences between memantine and placebo on any outcome for patients with mild AD (Schwarz et al. 2012). Furthermore, these reviews detected only small differences on some outcomes in patients with moderate AD taking memantine (Schwarz et al. 2012). Thus, many experts recommend against memantine for mild AD but recommend it as an option for moderate AD only for patients who are intolerant of or have a contraindication to cholinesterase inhibitors (National Institute for Health and Care Excellence 2011).
Several RCTs and withdrawal studies suggest that in patients with moderate or severe AD, cholinesterase inhibitors are associated with clinically relevant cognitive and functional benefits (Schwarz et al. 2012). The available evidence also supports the use of memantine in patients with severe AD (National Institute for Health and Care Excellence 2011; Schwarz et al. 2012). There is no consensus, however, on when to switch from cholinesterase inhibitors to memantine in individuals with severe AD (Schwarz et al. 2012).
Most experts recommend and data support initiating and titrating one of these medications to the highest approved and tolerated dose, and assessing response over 6–12 months (Rabins et al. 2006). Cholinesterase inhibitors lead to notable, albeit temporary, symptomatic improvements in 10%–15% of cases. Symptomatic improvements often last for 6–9 months. In clinical practice, the judgment as to the response to treatment relies greatly on the expectations that patients, their families, and their prescribing physicians have with this class of medications (Massoud et al. 2011). Mild improvement or stabilization should be considered an appropriate and realistic goal (Massoud et al. 2011). There is no consensus, however, on how to estimate clinical efficacy (Schwarz et al. 2012).
There is debate, however, about whether patients should continue taking a cholinesterase inhibitor for a longer period of time. In primary care settings in the United States, most patients who start a prescription do not continue taking it for more than a few months. Nevertheless, many experts recommend continuing therapy once it begins because patients may develop a rapid cognitive and functional decline when a cholinesterase inhibitor is discontinued (Schwarz et al. 2012). It is unclear whether clinical deterioration following discontinuation of a cholinesterase inhibitor is due to a loss of therapeutic effect or withdrawal from the medication (Schwarz et al. 2012).
Other experts point out that some patients do well after a discontinuation trial and that many benefit from switching agents. Massoud et al. (2011) reviewed eight open-label or retrospective switching studies involving patients in the mild to moderate stages of AD. In general, more than 50% of patients switched for unsatisfactory response showed stabilization or improvement in global evaluations, cognitive measures, and functional measures. Additionally, more than 50% of individuals switched for intolerance tolerated the second agent. The authors concluded that because cholinesterase inhibitors have individual pharmacological properties, switching is a valid clinical choice for patients with AD who either do not tolerate or have a lack of response to the initial agent. They considered significant deterioration within the first 6 months of treatment to represent a “lack of efficacy” and deterioration beyond the first 6 months of treatment to represent “loss of efficacy” (measured by a decline of at least 2 points on the MMSE, as well as a documented deterioration in functional autonomy, global impression, or behavior). The authors suggested that either a lack or a loss of efficacy was a reasonable justification for switching agents. On the other hand, they did not recommend switching for loss of response with the initial cholinesterase inhibitors beyond 1 year of use, because this is most often due to the natural course of AD (most evident during the transition from mild to moderate or from moderate to severe stages). In these latter cases, the authors recommended adding memantine to the cholinesterase inhibitor. In practice, however, less than one-third of patients actually switch cholinesterase inhibitors. One of the authors of this chapter (CGL) has followed a patient who benefited from sequential use of four of the cholinesterase agents (huperzine, donepezil, rivastigmine, and galantamine). Although clearly that was an extreme case, which is probably quite rare, it points out that the issue of long-term therapy is not a settled matter.
Although cholinesterase inhibitors and memantine are licensed for monotherapy, combining the two types of drugs could theoretically potentiate their benefits (Schwarz et al. 2012). Even though it is common practice to combine cholinesterase inhibitors with memantine, many experts do not endorse this practice because of a lack of clinical evidence to support additional benefit (National Institute for Health and Care Excellence 2011; Schwarz et al. 2012). Several randomized trials and observational studies demonstrated no additional (or inconclusive) superiority of combination donepezil and memantine over donepezil monotherapy (National Institute for Health and Care Excellence 2011).
Although clinical trials have suggested that cholinesterase inhibitors may be of value in treating vascular dementia, none has been approved by the FDA for that purpose. The results of one study suggest that compared with placebo, donepezil is associated with increased mortality in vascular dementia. The National Institute for Health and Care Excellence (2012) recommends that cholinesterase inhibitors and memantine should not be prescribed clinically for the treatment of cognitive decline in individuals with vascular dementia.
Both oral and transdermal preparations of rivastigmine have been approved for the treatment of mild to moderate dementia in PDD. In a large, parallel-group RCT of rivastigmine in PDD (Emre et al. 2004), patients who received rivastigmine demonstrated an average 1-point advantage on the MMSE over the 24-week treatment period compared with those who received placebo. The treatment group also demonstrated an average advantage of nearly 3 points on the Alzheimer’s Disease Assessment Scale—Cognitive subscale, particularly in areas of attention and executive function; 2 points on an ADLs scale; and 2 points on the total Neuropsychiatric Inventory score. In a Cochrane review of cholinesterase inhibitors for PDD, DLB, and MCI associated with PD, Rolinski et al. (2012) determined that current evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, NPSs, and ADLs. However, evidence from RCTs for cholinesterase inhibitors other than rivastigmine is inconclusive (Ballard et al. 2011). Likewise, although memantine is well tolerated, it does not appear to demonstrate positive effects on nonmotoric symptoms in PDD (Schwarz et al. 2012).
Cholinesterase inhibitors have been effective in treating cognitive impairment in DLB, although this is considered an off-label use. Furthermore, they have demonstrated therapeutic benefit in treating hallucinations and are considered first-line therapy for treating psychosis in DLB. Studies on use of memantine for DLB have been inconclusive (Schwarz et al. 2012). At best, memantine seems to provide modest positive global effects in DLB. However, benefits from memantine treatment are rapidly lost following discontinuation.
Although no cholinesterase inhibitors have demonstrated value in treating cognitive deficits in patients with FTLD, a medication trial is reasonable when the underlying cause of dementia is unclear.
NPSs are nearly universal in patients with dementia, affecting up to 98% of individuals across dementia stages and etiologies (Kales et al. 2014; Lyketsos et al. 2011). They are associated with poor patient outcomes, including excess morbidity and mortality, more rapid disease progression, increased health care utilization, and earlier nursing home placement. NPSs are also associated with negative caregiver outcomes, including stress, depression, reduced employment, and poorer quality of life. Thirty percent of the cost of caring for community-dwelling patients with dementia can be directly attributed to NPS management. Nevertheless, there continues to be uncertainty about how to manage these symptoms. A detailed discussion of the evaluation and management of NPSs in dementia is beyond the scope of this chapter. We articulate a few principles here from Kales et al. (2014) and Lyketsos et al. (2011); Rabins et al. (2006) provide a more in-depth discussion.
A useful mnemonic for the management of NPSs is DICE: Describe, Investigate, Create, and Evaluate (Kales et al. 2014). The describe phase involves an evaluation in which the patient, caregivers, and other relevant informants accurately characterize what is occurring behaviorally. This phase enables the provider to identify underlying patterns or contributory factors to the behavior. Another important goal of this phase is to determine what aspects of the NPSs are most disturbing or problematic for the patient and caregiver, as well as to establish the treatment goal.
During the investigate phase, the clinician examines the patient and identifies potential underlying and modifiable etiologies. Contributing factors include undiagnosed medical conditions (e.g., pain, infections, constipation, dehydration), medication side effects and drug-drug interactions, underlying psychiatric comorbidity (e.g., depressive or anxiety disorders), limitations in functional abilities, poor sleep hygiene, boredom, psychological factors (e.g., feelings of inadequacy, helplessness, fear), sensory impairments (e.g., hearing, vision), and environmental factors (e.g., over- or understimulating environment, lack of predictable routine, diminished pleasurable activities). Table 8–9 lists major components contributing to NPSs. In general, most disturbances are multifactorial, and it is best to address several contributing factors at once. The workup for underlying causes often includes laboratory studies.
Therapies for Neuropsychiatric Symptoms in Dementia Contributing causes of neuropsychiatric symptoms
A biological stress or delirium that accompanies a recurrent or new medical condition (e.g., constipation, urinary or upper respiratory infection, pain, poor dentition, headaches, hunger, thirst)
|
An identifiable psychiatric syndrome that is either recurrent or associated with the dementia
|
Aspects of the cognitive disturbance itself (e.g., a catastrophic reaction due to inability to express oneself vocally)
|
An environmental stressor (e.g., excessive noise or stimulation, unfamiliar surroundings, not enough heat)
|
Unmet needs (e.g., hunger, thirst, feeling lonely)
|
Unsophisticated or intrusive caregiving (e.g., poor communication, being rushed)
|
Medication side effects, whether from new medications or previously prescribed medications
|
In the create phase, the person with dementia, the caregiver, and the treatment team (provider, visiting nurse, social worker, occupational therapist) collaborate to design and implement a treatment plan. The plan consists of behavioral, environmental, pharmacological (prescribing medications and/or discontinuing medications contributing to NPSs), and educational approaches that target the identified causes. For example, a provider might treat a patient’s urinary tract infection or constipation while simultaneously teaching the caregiver not to rush the patient during toileting and to use a combination of scheduled and prompted toileting for incontinence. A provider may educate a caregiver about sleep hygiene while simultaneously tapering the patient’s daytime sedating medications that contribute to excessive napping. The plan should target physical problems (aggressively managing pain, constipation, dehydration, sleep disturbances, sensory impairments, and infections), underlying psychiatric conditions, safety concerns (e.g., putting safety knobs on stoves, eliminating throw rugs, removing weapons, providing sufficient lighting), and other environmental factors (e.g., establish structured routines and meaningful activities for the patient). Caregivers provide important insight as to what has worked for the patient and what has not. Taking into account the patient’s interests, the team can more effectively tailor a patient-specific treatment plan. Providers can assist caregivers by modeling problem solving, giving constructive feedback, providing emotional support, validating that what the caregivers are doing is important, and ensuring that they are taking care of themselves.
Finally, the evaluate phase involves assessing whether an intervention was attempted and whether it was effective. If the caregiver implemented an intervention, it is important to evaluate whether the NPSs improved, whether the intervention helped to decrease the patient’s and caregiver’s distress, and whether there were any unintended side effects or consequences. If the caregiver did not implement an intervention, the provider should attempt to understand why not and brainstorm solutions with the caregiver. If the intervention included a psychotropic medication, the provider and caregiver should sequentially monitor behaviors and potential new side effects, and consider a trial of tapering the dose or discontinuing the medication to ensure that the medication continues to be necessary.
Because of the increased risks inherent in using medications to treat NPSs in patients with dementia, the clinician should consider using nonpharmacological interventions as first-line therapy. The exception is in emergency situations when NPSs could compromise the safety of the patient or others, in which case the standard of care supports psychotropic use (Kales et al. 2014). Small studies have shown modest benefit with aromatherapy, bright light therapy, music therapy, controlled multisensory stimulation (Snoezelen rooms), animal-assisted therapy, exercise programs, physical therapy, occupational therapy, and speech therapy. Some of these therapies are useful during a treatment session but have no longer-term benefits. Behavioral therapy using a behavioral monitoring log can help identify triggers to avoid or manage, and can provide sustained improvements in behavior in individuals with dementia. A Cochrane review and meta-analysis (Moniz Cook et al. 2012) suggested that functional analysis (where a therapist develops an understanding of the function or meaning behind the patient’s distress and symptoms) is associated with a decrease in the frequency of challenging behaviors and an improvement in the caregiver’s reaction to them. However, it is too early to draw conclusions regarding the efficacy of this method. A stable, structured, predictable environment that avoids over- or understimulation can be very beneficial for a patient. Distraction, redirection, removing environmental cues (e.g., car keys) for behaviors caregivers want to discourage (e.g., driving), or offering simple choices can be effective in decreasing agitation and anxiety. Educating caregivers and professional staff about how to manage NPSs can lead to reductions in patients’ behavioral outbursts and less restraint use. Psychotherapy can be a useful strategy, particularly in early dementia, with patients who are anxious, depressed, or demoralized. Interventions with the best evidence to support their use are outlined in Table 8–10.
Therapies for Neuropsychiatric Symptoms in Dementia General nonpharmacological strategies for managing neuropsychiatric symptoms
Domain | Key strategies |
|---|---|
Behavior management
| |
Memory-related problems (e.g., disorientation or confusion with object recognition)
|
Identify self and others if patient does not remember names or is aphasic.
|
Use memory aids (calendar or white board showing current date).
| |
Keep all objects for a task in a labeled container (e.g., grooming).
| |
Supervise medication taking and secure medications.
| |
Present a single object at a time.
| |
Paint doors to identify or disguise them.
| |
Falling and poor balance
|
Remove clutter or unnecessary objects.
|
Use a fall alert system if the patient can remember to activate.
| |
Consider referral to occupational therapy for home safety evaluation and removal of tripping hazards.
| |
Consider referral to physical therapy for simple balance exercise.
| |
Minimize alcohol intake.
| |
Hearing voices or noises (especially at night)
|
Evaluate hearing and adjust amplification of hearing aids.
|
Evaluate quality and severity of auditory disturbances.
| |
If hallucinations are present, evaluate whether they present an actual threat to safety or function in deciding whether to treat with antipsychotics.
| |
Wandering or inability to respond to emergency (difficulty calling for help)
|
Educate caregiver about the need to supervise patient.
|
Inform neighbors, fire department, and police of patient’s condition.
| |
Develop emergency plan involving others if possible.
| |
Outfit with an ID bracelet (e.g., Alzheimer Safe Return Program).
| |
Identify potential triggers for elopement and modify them.
| |
Nighttime wakefulness, turning on lights, awaking caregiver, feeling insecure at night
|
Implement good sleep hygiene.
|
Evaluate environment for disturbances such as temperature, noise, light, shadows, and level of comfort.
| |
Eliminate caffeinated beverages (starting in the afternoon).
| |
Create a structured schedule that includes exercise and activities throughout the day.
| |
Limit daytime napping.
| |
Use night-light.
| |
Create a quiet routine for bedtime that includes a calming activity and calming music.
| |
Address daytime loneliness and boredom that may contribute to nighttime insecurities.
| |
Hire nighttime assistance to enable caregiver to sleep.
| |
Repetitive questioning
|
Respond using a calm, reassuring voice.
|
Use a light touch to reassure, calm, or redirect.
| |
Inform patient of events as they occur (vs. indicating what will happen in the near or far future).
| |
Use distraction.
| |
Care management
| |
Communication
|
Use a calm, reassuring voice.
|
Avoid negative words and tone.
| |
Use a light touch to reassure, calm, or redirect.
| |
Allow patient sufficient time to respond to a question.
| |
Help patient find words to express himself or herself.
| |
Offer simple choices (no more than two at a time).
| |
Simplifying the environment
|
Use labeling or other visual cues.
|
Remove unnecessary objects to reduce confusion with tasks.
| |
Eliminate noise and distractions while you are communicating or when patient is engaging in an activity.
| |
Use simple visual reminders (e.g., arrows pointing to bathroom).
| |
Caregiver education and support
|
Understand that patient behaviors are not intentional.
|
Learn how to relax the rules (e.g., baths do not have to happen daily; there is no right or wrong in performing activities or tasks as long as the patient and caregiver are safe).
| |
Go along with patient’s view of what is true and avoid arguing or trying to reason or convince.
| |
Task structuring
|
Break each task into very simple steps.
|
Provide one- to two-step simple verbal commands.
| |
Use verbal or tactile prompts for each step.
| |
Provide structured daily routines that are predictable.
| |
Activities
|
Engage patient with meaningful activities that tap into preserved capabilities and previous interests.
|
Introduce activities involving repetitive motion (washing windows, folding towels, and putting coins in container).
| |
Guide and cue the patient to initiate, sequence, organize, and complete tasks.
| |
Note. Domains and strategies listed are potential approaches used in randomized clinical trials but are not exhaustive. One strategy may be effective for one patient but not another. Only consider the above strategies following a thorough assessment and diagnostic workup.
| |
Source. Adapted from Gitlin LN, Kales HC, Lyketsos CG: “Nonpharmacologic Management of Behavioral Symptoms in Dementia.” Journal of the American Medical Association 308(19):2020–2029, 2012. Used with permission.
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Although extensive effort has been put into developing nonpharmacological approaches, little controlled evidence is available to suggest that they work, and they are often difficult to implement in real-world settings, especially in primary or institutional care (Livingston et al. 2005). A study of newly admitted nursing home residents demonstrated that within the first 3 months of admission, only 12% received nonpharmacological interventions, whereas 71% received at least one psychotropic medication (Molinari et al. 2010). Furthermore, more than 15% were taking four or more psychotropic medications. Of those treated with psychotropics, 64% had not received psychopharmacological treatment for the 6 months preceding admission and 71% had not received a psychiatric diagnosis during the same time frame.
No pharmacotherapy has FDA approval for dementia-related NPSs. Despite well-known, significant concerns about the safety and efficacy of psychotropic medications in treating NPSs in individuals with dementia, clinicians commonly use these drugs to manage these symptoms. Clinicians routinely prescribe these medications without first methodically assessing potential underlying causes of behaviors. Clinicians may use a “symptom cluster” approach, in which they match a medication to a symptom that resembles a known symptom of an illness (e.g., mood stabilizers for decreased sleep and pressured speech or antidepressants for dysphoria and apathy). Because dementia is usually progressive and NPSs can fluctuate over time, clinicians and caregivers may be trying to hit a “moving target” with psychotropics. Caregivers frequently attempt to manage several NPS disturbances concomitantly, often with more than one medication, contributing to an unpredictable and undecipherable outcome. Even in the few cases where psychotropics, specifically antipsychotics, demonstrate modest efficacy in improving NPSs, the benefits may be negated by significant adverse effects. Psychotropic medications are unlikely to affect poor self-care or refusal of care, memory problems, inattention, unfriendliness, repetitive verbalizations or questioning, shadowing, or wandering (Kales et al. 2014). They are also unlikely to improve behaviors that can ultimately be attributed to apraxia or agnosia (e.g., urinating in a trash can because it resembles a toilet bowl). If medication treatments are indicated, it is important to follow guidelines similar to those outlined in Table 8–11. Sink et al. (2005) published a widely employed algorithm for using medications to treat NPSs in dementia.
Therapies for Neuropsychiatric Symptoms in Dementia Guidelines for use of medications to treat neuropsychiatric symptoms
Differentiate which disturbance is present; they are not all the same.
|
Consider possible contributing causes and the need for medical workup.
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Implement nonpharmacological interventions concomitantly.
|
Use medications cautiously, with defined targets and close monitoring for adverse effects potentially caused by psychotropic medications.
|
Educate caregivers to notify clinicians immediately should the patient develop an adverse drug reaction.
|
Routinely review the risk-benefit ratio of treatment.
|
Avoid knee-jerk prescribing of psychotropics in response to symptoms to better elicit the underlying cause(s).
|
Be mindful that select isolated disturbances are unlikely to respond to medications.
|
Use of psychotropics should always be time limited, because symptoms may resolve over time with or without pharmacological treatment.
|
Have in place a backup plan and a plan to deal with after-hours crises.
|
Source. Adapted from Gitlin LN, Kales HC, Lyketsos CG: “Nonpharmacologic Management of Behavioral Symptoms in Dementia.” Journal of the American Medical Association 308(19):2020–2029, 2012. Used with permission.
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Several different classes of medications have been studied. For some of them, safety concerns exist and efficacy remains uncertain. The use of both conventional and atypical antipsychotics is controversial because their efficacy is modest and they have been associated with side effects (including rapid cognitive decline), a higher risk of cerebrovascular or cardiovascular events, and mortality in patients with dementia (Schneider et al. 2005). The FDA has issued black box warnings regarding the use of antipsychotics in treating patients with dementia-related psychosis (U.S. Food and Drug Administration 2008). Both conventional and atypical antipsychotics carry this increased mortality risk in dementia, whereas other psychotropic medications, such as antidepressants and anticonvulsants, do not.
Antipsychotic medications are the core treatments of agitation and psychosis. In the Clinical Antipsychotic Trial of International Effectiveness—Alzheimer’s Disease, risperidone and olanzapine showed the most, albeit modest, benefit of symptom reduction as assessed by various rating scales. Antipsychotics had no effect on other outcomes such as cognition, functioning, or quality of life (Sultzer et al. 2008). Although these antipsychotics are not contraindicated in dementia, the risk-to-benefit ratio is high, and they should be used with caution (Rabins and Lyketsos 2005). Some RCTs have demonstrated that antipsychotics can be discontinued for the majority of individuals receiving chronic antipsychotic therapy without a worsening of behavior (Seitz et al. 2013). However, the Antipsychotic Discontinuation in AD trial showed that after patients with AD and psychosis or agitation achieved and maintained treatment response with risperidone (mean dose of 0.97 mg/day) for 4–8 months, a switch from risperidone to placebo in a randomized, double-blind manner was associated with a markedly increased risk of relapse relative to continuing risperidone (Devanand et al. 2012). Predictors of successful discontinuation of antipsychotics include lower baseline severity of NPSs and lower dosages of antipsychotics to receive symptom control (Seitz et al. 2013). For a more detailed description of the pharmacological treatment of agitation and psychosis in the context of dementia, see Chapter 19, “Agitation and Suspiciousness,” and Chapter 11, “Schizophrenia Spectrum and Other Psychotic Disorders,” respectively, in this textbook.
Patients with DLB present an additional challenge to antipsychotic therapy because they are extremely sensitive to the extrapyramidal side effects of all antipsychotics except clozapine. Adverse events range from parkinsonism to acute dystonia to neuroleptic malignant syndrome. Clinicians should avoid use of conventional antipsychotics in patients with DLB. Similarly, although antipsychotics can be useful in treating visual hallucinations and delusions associated with PDD, they need to be used with caution due to the inherent risk of exacerbating parkinsonian symptoms. Quetiapine and especially clozapine are the least likely to worsen parkinsonism.
There is evidence to suggest that selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Porsteinsson et al. 2014; Seitz et al. 2013), sertraline (Lyketsos et al. 2003), and escitalopram (Seitz et al. 2013), are efficacious in treating agitation, depression, and apathy in patients with Alzheimer’s dementia. Double-blind trials comparing the serotonin antagonist and reuptake inhibitor trazodone with placebo, however, have not shown benefit in the treatment of NPSs (Ballard and Corbett 2010). Although the rates of adverse events with antidepressants may be less than those observed with antipsychotics, antidepressants should in no way be considered harmless (Seitz et al. 2013). In older adults serotonergic agents are associated with adverse events, including injurious falls (evident even at low doses but increasing by as much as threefold at higher doses), fractures, bleeding, and hyponatremia (Schwarz et al. 2012; Seitz et al. 2013). There are also reports that SSRIs induce an amotivational or apathy syndrome, which is reversible when the medication is stopped or the dose decreased (Berman et al. 2012). Some observational studies have demonstrated an increased risk of stroke and death as well (Seitz et al. 2013).
Recent RCTs have demonstrated that citalopram and escitalopram may be as effective as risperidone or perphenazine and more effective than placebo in hospitalized populations with dementia and NPSs (Seitz et al. 2013). One recent randomized placebo-controlled, double-blind trial, the Citalopram for Agitation in Alzheimer Disease study, evaluated 186 patients with probable AD and clinically significant agitation (Porsteinsson et al. 2014). Over 9 weeks, compared with patients given placebo, patients treated with citalopram 30 mg/day showed a clinically relevant, significant reduction of agitation on several rating scales. This improvement is comparable to that of antipsychotic drugs in other trials (Porsteinsson et al. 2014). Adverse events were modest and consistent with known side effects of SSRIs (e.g., gastrointestinal complaints, respiratory tract infections, falls). Compared with patients given placebo, patients treated with citalopram demonstrated a 1-point greater decline in MMSE scores over 9 weeks. Although the clinical significance of this effect on cognition is unclear, this decline is less than what experts consider to be a minimum clinically significant change (1.4 points). It is also unclear whether the cognitive effect continues beyond 9 weeks and whether citalopram adversely affects the course of AD. One limitation of using citalopram (and escitalopram, the active S-isomer of citalopram), however, is a dose-dependent risk of QT prolongation, potentially leading to torsades de pointes. This risk generated an FDA advisory warning in 2011 stating that citalopram should no longer be used at daily dosages greater than 20 mg/day in individuals older than 60 years because of the potential for cardiac electrical abnormalities (U.S. Food and Drug Administration 2012). There are insufficient data on the efficacy of citalopram for agitation at doses lower than 30 mg/day (Porsteinsson et al. 2014).
Evidence is limited regarding the efficacy of cholinesterase inhibitors and memantine for NPSs, but these drugs may help delay the emergence of symptoms or treat very mild symptoms. In general, they should not be considered first-line agents in managing acute NPSs of moderate or greater severity until better evidence of their efficacy emerges (Weintraub and Katz 2005).
Multiple meta-analyses suggest that evidence to support the use of antidepressants to treat comorbid depression in AD is weak at best (Schwarz et al. 2012; Sepehry et al. 2012). However, these meta-analyses were limited by the heterogeneity of their included studies, with differing criteria for the diagnosis of depression, the compound tested, and outcome measures for depression. Many clinical trials also excluded more severely depressed patients, likely limiting the apparent treatment benefit in these studies (Ballard and Corbett 2010).
Choosing an antidepressant is complicated because of the frailty and susceptibility to side effects of many individuals with dementia (Ballard and Corbett 2010). Tricyclic antidepressants are limited by significant adverse effects (e.g., confusion, falls due to orthostatic hypotension, cardiac arrhythmias). There is only one study looking at venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), in the treatment of depression in dementia. This small placebo-controlled, double-blind, randomized study showed essentially no difference in improvement on a depression rating scale between low-dosage venlafaxine (mean immediate-release doe of 75 mg/day, with a range from 37.5 to 131.25 mg/day) and placebo groups at 6 weeks (de Vasconcelos Cunha et al. 2007). There also was no statistically significant difference in the incidence of adverse events between the groups. No clinical studies have been done of either duloxetine, an SNRI, or bupropion, a norepinephrine-dopamine reuptake inhibitor, for depression in dementia. Randomized placebo-controlled trials of sertraline and mirtazapine have demonstrated an absence of benefit of antidepressants over placebo after 3 months of treatment (Banerjee et al. 2011; Rosenberg et al. 2010; Weintraub et al. 2010). Patients with AD and depression who received antidepressants did not show improvement in global cognition (Sepehry et al. 2012); moreover, patients treated with antidepressants experienced an increased rate of adverse events.
Experts emphasize, however, that the limited evidence of efficacy of antidepressant therapy from clinical trials should not be used as a reason to withhold antidepressant treatment from a patient with AD who is severely depressed (Ballard and Corbett 2010). Various international organizations (e.g., British Psychological Society, Royal College of Psychiatrists, Canadian Consensus Conference on Dementia) recommend treating an individual with dementia and depression with antidepressants (giving preference to an SSRI or to avoiding medications with anticholinergic effects) if the patient has had an inadequate response to nonpharmacological interventions (e.g., increasing pleasant activities and social interactions), after carefully assessing the risk-benefit ratio (Sepehry et al. 2012). Although the duration of treatment is unclear, a general rule of thumb is to treat major depression for at least 6 months.
Little is known about treating depression associated with other types of dementia because most studies have focused on AD. SSRIs may be efficacious in treating depression and anxiety associated with DLB. Observational studies have demonstrated some benefit for SSRIs in reducing disinhibition, anxiety, depression, impulsivity, repetitive behaviors, and eating disorders in patients with FTLD. In the absence of any specific evidence guiding the treatment of depression in other non-AD dementias, clinicians should follow the same treatment approaches as they would for depression in AD (Ballard and Corbett 2010).
Few studies have examined treatments for apathy in dementia. Even fewer have targeted apathy as a primary outcome. These studies tended to be open-label, were underpowered, involved mixed dementias, and had a wide range of definitions for apathy. Cholinesterase inhibitors have the best evidence for improving or stabilizing apathy, with no clear indication that any one cholinesterase inhibitor is superior to the other (Berman et al. 2012). There is some evidence for modest benefits of memantine, mixed evidence for benefits of atypical antipsychotics, and no good evidence to support using antidepressants, antiepileptics, or traditional antipsychotics to treat apathy (Berman et al. 2012). Potential adverse effects limit the use of these classes of medications. Despite a perception that apathy is treatable with stimulants, only a handful of small eligible trials of methylphenidate since 1975 have shown significant improvement. The most recent study to evaluate methylphenidate in dementia, the Apathy in Dementia Methylphenidate Trial, compared methylphenidate 20 mg/day to placebo in a 6-week, randomized, double-blind trial (Rosenberg et al. 2013). Methylphenidate treatment was associated with significant improvement in two out of three efficacy outcomes. Global cognition trended toward improvement with methylphenidate but was not statistically significant. Although the methylphenidate group experienced minimal significant adverse events overall, this group trended toward experiencing weight loss and greater anxiety. Apathy tends to be chronic and progressive; for this reason, it is unclear when to initiate treatment and how long to continue treatment. Treatment may be useful if a patient’s quality of life can potentially be improved, if the patient has excessive disability, or if a patient’s caregiver is significantly distressed or burdened by the repercussions of this symptom (Berman et al. 2012). Long-term therapy may be indicated if a patient demonstrates a positive response to medications.
A comprehensive discussion on the treatment of sleep disorder in dementia is beyond the scope of this chapter. A useful first step is to take an individualized sleep inventory (Roth 2012). A widely used sleep inventory is the Epworth Sleepiness Scale (Johns 1991). After identifying which type of sleep disorder (e.g., difficulty falling asleep at night, excessive daytime sleepiness, restless leg syndrome, obstructive sleep apnea) is present and which symptoms are most pressing to the patient and/or caregiver, the dementia team can tailor treatments to the specific disorder and symptoms. As a general rule, the team should discontinue medications causing the symptoms, implement behavioral/nonpharmacological measures (e.g., sleep hygiene, hiring nighttime assistants to enable the caregiver to sleep, continuous positive airway pressure therapy for obstructive sleep apnea), and attempt to identify underlying problems and target specific issues before treating general symptoms (Camargos et al. 2014; Roth 2012). There is a paucity of studies evaluating pharmacological interventions of sleep disorders in dementia. Many of the extant studies have been limited by a small sample size, retrospective data collection, open-label testing, or the fact that sleep was evaluated as a secondary outcome (Camargos et al. 2014). Trials evaluating the effects of triazolam, haloperidol, and melatonin on sleep have had disappointing results (Camargos et al. 2014). Quetiapine and mirtazapine are sometimes used to treat sleep difficulties (e.g., quetiapine may improve rapid eye movement sleep behavior disorder) but can worsen restless legs syndrome and periodic limb movements of sleep (Roth 2012). The typical starting dose of quetiapine is 12.5 mg/day (increasing in increments of 12.5 mg). The typical starting dose of mirtazapine is 7.5 mg/day, and the dose can be increased by increments of 7.5 mg; however, it is important to remember that higher doses tend to be less sedating (Roth 2012). A recent double-blind, placebo-controlled study of trazodone in AD patients with sleep disorders demonstrated promising results (Camargos et al. 2014). Compared with individuals in the placebo group, individuals who received trazodone 50 mg/day slept 42.5 more minutes per night and experienced no drug effect on daytime sleepiness, naps, cognition, or function. More in-depth discussions of the etiology, evaluation, and treatment of sleep disorders in specific dementias are provided in Chapter 16, “Sleep and Circadian Rhythm Disorders,” and in Roth (2012).
An estimated 60%–70% of older individuals with AD and other dementias live in the community and are cared for by family members and friends (Theis et al. 2013). Nearly all (up to 99%) of community-residing individuals with dementia have unmet needs for care, services, and support (Black et al. 2013). Unmet dementia-related needs increase the risk of undesirable health outcomes, nursing home placement, and death (Black et al. 2013). It is critical to provide systematic supportive care to patients with dementia. The first step is for patients, caregivers, and team members to collaborate to determine unmet care needs. A needs assessment is an efficient tool to help identify these gaps. Once an assessment is completed, the patient, caregiver, and team can prioritize unmet needs by importance and feasibility, and then devise a tailored treatment plan to meet these needs.
The MIND at Home study recently set out to determine the prevalence and correlates of unmet needs in a sample of community-residing individuals with dementia and their informal caregivers (Black et al. 2013). Using a dementia care needs assessment (Black et al. 2008), evaluators were able to determine the proportion of unmet items in six prespecified need categories: evaluation and treatment of memory symptoms, NPS management, home and personal safety, general health and medical care, daily and meaningful activities, and legal issues and advance care planning. Participants, study partners, and primary care physicians received the written results of the assessment, which included recommendations for each identified unmet need. Coordinators then conducted an in-home visit with each participant and study partner; they reviewed and prioritized needs and then developed a care plan. Care components could be individually tailored to unmet needs and updated based on emergent needs of either participants or caregivers. A coordinator helped guide the study partner and/or participant (when appropriate) on implementing the plan. Ninety percent of participants had unmet home and personal safety needs, particularly for wander and fall risk management and for home safety evaluations. More than 60% of participants had unmet general health and medical care needs, including the need to see their primary care provider, medical subspecialist, or a dental, vision, or hearing specialist. Over 50% had unmet meaningful activities needs, including the need for adult day care, attending senior centers, and in-home activities. Forty-eight percent had unmet legal issues and advance care planning needs. Almost 33% of participants had not received a prior evaluation or diagnosis of dementia. Higher unmet needs for individuals with dementia was significantly associated with nonwhite race, lower income, early-stage dementia and less impairment in ADLs, more symptoms of depression, and caregivers with lower education.
Table 8–12 lists supportive areas that a dementia care team should address in every case (Lyketsos et al. 2006). Teams should educate patients, when appropriate, about their condition, including giving them their diagnosis and anticipated course. Early diagnosis can provide opportunities to initiate treatments for dementia symptoms and to help individuals and families plan for future care (Black et al. 2013). When patients, caregivers, and clinicians recognize medical conditions earlier, the costs of care may be lowered, quality of life improved, and hospitalizations prevented (Black et al. 2013). Supportive care for patients should be aimed at preserving their dignity, maintaining optimal physical and mental health, encouraging their abilities to persist for longer periods of time, and making life easier for their caregivers. Teams should work with caregivers to find safe environments that maximize remaining physical and cognitive abilities, within the restrictions of the environment. Ideally, environments would permit patients to be well nourished and hydrated, receive a certain amount of activity and socialization, receive support for their ADLs and IADLs, and maintain good sleep hygiene. In-home activities customized to the interests and capabilities of individuals with dementia can significantly increase their engagement, reduce NPSs, and reduce caregiver burden (Black et al. 2013). An in-home occupational therapy assessment, using a functional assessment method such as the Assessment of Motor and Processing Skills (Fisher 2003), can provide useful data about a patient’s level-of-care needs and about home safety. Additional information about providing supportive care for patients is available in the book The 36-Hour Day by Mace and Rabins (2011) and from the Alzheimer’s Association Web site (www.alz.org).
Supportive Care for Patients Supportive care for patients
Provide comfort and emotional support.
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Address safety concerns with regard to driving, living alone, environmental hazards (eliminating access to dangerous items), medications, falls, and wandering (using a monitoring device).
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Maintain a safe, predictable place to live with graded support (as little help as possible), role modeling, and cueing for activities of daily living and instrumental activities of daily living.
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Provide structure, activity, and stimulation in day-to-day life to maximize remaining abilities and function.
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Provide environmental cues for behaviors (e.g., laying out clothing for self-care).
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Assist with decision making.
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Aggressively manage medical comorbidities.
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Maintain up-to-date advance directives and advance care planning decisions.
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Provide good nursing care in advanced stages.
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Community-dwelling adults with dementia generally receive more care from caregivers as their disease progresses (Theis et al. 2013). The daunting tasks of caregivers include assisting with ADLs, managing the individual’s safety and/or NPSs, identifying and navigating a loose network of long-term care support services, facilitating health care visits, advocating for the patient, and making proxy financial and health care decisions (Black et al. 2013). All of this work occurs within a context of loss—both losses for the individual with dementia and losses for his or her caregiver (Black et al. 2013). These caregivers often face greater burdens and stress than do caregivers of individuals with other illnesses, and depression is common (Black et al. 2013). Caregiver burnout can affect not only the caregiver but also the patient. Stress, deteriorating mental and physical health, and financial hardships can have deleterious effects on the patient. Caregiver stress is predictive of nursing home admission for individuals with dementia, and unmet caregiver needs are associated with lower quality of life (Black et al. 2013). In the MIND at Home study, almost all caregivers (97%) had one or more unmet needs (Black et al. 2013). More than 85% of caregivers had unmet needs for referrals to community resources (e.g., Alzheimer’s Association) and caregiver education (e.g., developing caregiver skills and learning how dementia impacts individuals and their loved ones). More than 40% of caregivers also had unmet needs for mental health care. Nonwhite race, less education, and more symptoms of depression was significantly associated with higher unmet caregiver needs.
Because caregivers are the lifeline of the patient and are greatly affected by dementia, they should be involved intimately in the development and implementation of any dementia care program. As with addressing unmet needs of individuals with dementia, a needs assessment can serve as a useful foundation to gather data on unmet caregiver needs. Table 8–13 lists key intervention areas involving caregivers (Lyketsos et al. 2006; Rabins et al. 2006; Selwood et al. 2007). Mittelman et al. (2006) highlight the importance of the delivery of interventions to caregivers. Their work suggests that caregiver interventions can have effect sizes as large as or larger than medications in delaying out-of-home placement for patients with dementia. Central to good dementia care is making sure that caregivers are educated about dementia, have an understanding of the diagnosis, are able to access resources, use respite appropriately, and have an expert available around the clock to help them in times of crisis.
Supportive Care for Patients Supportive care for the caregiver
Provide comfort and emotional support.
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Educate the caregiver about dementia.
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Instruct caregiver on the skills of caregiving and support him or her with problem-solving techniques.
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Ensure that an expert clinician is always available for consultation, especially for crisis intervention.
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Encourage respite from caregiving.
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Encourage caregiver to maintain a social network.
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Attend to the caregiver’s general and mental health, including scheduling preventive health care visits.
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Key Points
- Dementia is an epidemic clinical syndrome consisting of global cognitive decline and memory deficits, with at least one other area of cognition affected.
- Dementia can be accurately diagnosed and differentiated from cognitive impairment not dementia and mild cognitive impairment.
- Amnestic mild cognitive impairment is likely the prodrome to Alzheimer’s dementia, the most common form of dementia.
- The evaluation and differential diagnosis of dementia and of mild neurocognitive disorders involve an initial focus on defining the phenomenology of the syndrome and its associated features, followed by a workup for a putative clause.
- The four pillars of dementia treatment are disease treatment, symptom treatments, supportive care for the patient, and supportive care for the caregiver. All of these areas must be addressed in contemporary dementia care. A needs assessment is an efficient tool to help identify unmet care needs.
- The concept of treatable and nontreatable dementias is no longer relevant; all dementias are treatable, albeit not necessarily curable. One of the most effective therapies for Alzheimer’s disease is aggressively managing associated vascular risk factors.
- The amyloid cascade hypothesis of Alzheimer’s disease is rapidly evolving, impacting clinical trials. Trials have started targeting prevention of Alzheimer’s disease with antiamyloid therapies.
- Neuropsychiatric symptoms are nearly universal across dementia stages and etiologies. No pharmacotherapy has U.S. Food and Drug Administration approval for dementia-related neuropsychiatric symptoms. Nonpharmacological interventions can be as effective as currently available medications and should be considered first-line therapy except in emergency situations.
- Disease-modifying therapies in Alzheimer’s disease have largely been unsuccessful, and there are no disease-modifying treatments available for dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal lobar degeneration, or Creutzfeldt-Jakob disease. Cholinesterase inhibitors provide only modest and temporary stabilization of the changes to cognition and ADLs associated with the disease. They do not reverse or stop the degenerative process.
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