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IV. Disease Definition, Natural History, and Epidemiology

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Many types of dementias exist, and they have a number of features in common. This section contains a discussion of dementia in general and brief descriptions of some of the more common types of dementias.

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A. Definition of Dementia

The essential features of a dementia are acquired multiple cognitive deficits that usually include memory impairment and at least one of the following phenomena in the absence of a delirium that might explain the deficit: aphasia, apraxia, agnosia, or a disturbance in executive functioning (the ability to think abstractly and to plan, initiate, sequence, monitor, and stop complex behavior). The order of onset and relative prominence of the cognitive disturbances and associated symptoms vary with the specific type of dementia, as discussed in Section IV.F.

Memory impairment is often a prominent early symptom. Individuals with dementia have difficulty learning new material. These short-term memory problems commonly result in losing valuables such as wallets and keys or forgetting food cooking on the stove. In more severe dementia, individuals also forget previously learned material, including the names of loved ones. Individuals with dementia may have difficulty with spatial tasks, such as navigating around the house or in the immediate neighborhood. Poor judgment and poor insight are common as well. Individuals may exhibit little or no awareness of memory loss or other cognitive deficits. They may make unrealistic assessments of their abilities, underestimate the risks involved in activities such as driving, and make plans that are incongruent with their deficits and prognosis (e.g., planning to start a new business).

In order for a diagnosis of dementia to be made, the cognitive deficits must be sufficiently severe to cause impairment in occupational or social functioning and must represent a decline from a previous level of functioning. The nature and degree of impairment are variable and often depend on the particular social setting of the individual. For example, mild dementia may significantly impair an individual's ability to perform a complex job but not a less demanding one. When memory impairments and/or other cognitive deficits are present in the setting of intact functional status, the patient is usually given a diagnosis of mild cognitive impairment (390) (see Section IV.F.2). There is not yet a general consensus on the criteria for defining and diagnosing mild cognitive impairment (391).

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B. Associated Features

Some individuals with dementia experience a variety of neuropsychiatric symptoms that may include disinhibited behavior, making inappropriate jokes, neglecting personal hygiene, exhibiting undue familiarity with strangers, or disregarding conventional rules of social conduct. They may also demonstrate apathy, amotivation, and withdrawal. Depressed mood, with or without neurovegetative changes, is quite common, as are sleep disturbances and anxiety independent of depression. Suicidal behavior may occur, especially in mildly impaired individuals, who are more likely to have insight into their deficits and to be capable of formulating and carrying out a plan of action. Some patients manifest "catastrophic reactions," overwhelming emotional responses to relatively minor stressors, such as changes in routine or environment. Occasionally, they may harm others by striking out. Delusions can occur, especially those involving themes of spousal infidelity and persecution such as the belief that misplaced possessions have been stolen. Misidentifications of familiar people as unfamiliar (or vice versa) frequently occur. Delusions that a spouse or caregiver is an imposter are particularly difficult for patients and their families. Hallucinations can occur in all sensory modalities, but visual hallucinations are most common. Some patients exhibit a peak period of agitation (or other behavioral disturbances) during the evening hours, which is sometimes referred to as "sundowning."

Individuals with dementia are especially vulnerable to the effects of change and psychosocial stressors (such as bereavement or going to the hospital), and these stressors can worsen intellectual deficits and exacerbate neuropsychiatric symptoms. Patients with dementia are particularly susceptible to developing delirium, as discussed in Section III.B.2. Dementia may be accompanied by neurological symptoms such as gait difficulties, dysarthria, swallowing difficulty with consequent choking or aspiration, urinary and fecal incontinence, seizures, tremor, myoclonus, and other abnormal movements.

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C. Differential Diagnosis

The differential diagnosis of dementia is described in detail in DSM-IV-TR and is only summarized here (392, 393). Age-associated memory changes are modest and not associated with functional impairment or depression. Memory impairment occurs in both delirium and dementia. A new diagnosis of dementia cannot be made when delirium is present. Delirium, discussed in Section III.B.2, is characterized by a reduced ability to maintain and shift attention appropriately, fluctuating cognitive deficits, and impaired level of consciousness, whereas the deficits in dementia tend to be stable or progressive, and level of consciousness is unaffected. In addition, the onset of delirium may be acute, and its course is often time limited. Amnestic disorder is characterized by memory impairment without significant impairment in other cognitive domains. Mental retardation has an onset before age 18 years and is characterized by significantly subaverage general intellectual functioning, which may not include memory impairment. Schizophrenia may be associated with multiple cognitive impairments and a decline in functioning, but the cognitive impairment tends to be less severe and occurs against a background of psychotic and behavioral symptoms meeting the established diagnostic criteria.

Major depression is an important element of the differential diagnosis of memory difficulties. Particularly in elderly persons, major depressive disorder may be associated with reports of memory impairment, difficulty concentrating, and a reduction in intellectual abilities described by history or observed on mental status examination. Depression and progressive dementia may sometimes be distinguished on the basis of an assessment of the course and onset of depressive and cognitive symptoms and by response of cognitive symptoms to treatment of the depression. However, even when the onset of depressive symptoms precedes or coincides with the onset of cognitive symptoms and both resolve with antidepressant treatment, more than 50% of patients go on to develop dementia or mild cognitive impairment within several years of the depressive episode (280, 394, 395). In addition, among patients with mild cognitive impairment (see Section IV.F.2), evidence suggests that those who are also depressed have a greater likelihood of developing Alzheimer's disease (396). Dementia must be distinguished from malingering and factitious disorder, which generally manifest patterns of cognitive deficits that are inconsistent over time and are uncharacteristic of those typically seen in dementia.

Dementia must also be distinguished from milder symptoms. Subjective memory complaints are common as people get older. Many individuals with these complaints have subtle, nonprogressive declines in memory, but some have more significant impairment that is more likely to represent the prodromal phase of Alzheimer's disease or another dementia. The category of mild cognitive impairment (390) was developed to describe individuals in this prodromal phase (see Section IV.F.2) (6, 391,397).

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D. Prevalence and Course

Exact estimates of the prevalence of dementia depend on the definition and specific threshold used, but it is clear that the prevalence increases dramatically with age. The syndrome affects approximately 5%–8% of individuals over age 65 years, 15%–20% of individuals over age 75 years, and 25%–50% of individuals over age 85 years (398). Alzheimer's disease is the most common dementia, accounting for 50%–75% of the total number of cases of dementia, with a greater proportion of cases in the higher age ranges. Vascular dementia is probably next most common; prevalence estimates vary widely and depend on the definition of vascular dementia used; pure vascular disease may account for 5%–20% of cases of dementia, and mixed dementia—Alzheimer's disease with vascular dementia—occurs at least as frequently. Dementia with Lewy bodies may present with frequent falls, hallucinations, and cognitive fluctuation as well as mild parkinsonism and may account for up to 20% of individuals with dementia (399, 400).

The mode of onset and subsequent course of dementia depend on the underlying etiology. Typically, Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia have an insidious onset and gradual decline, whereas vascular dementia may be characterized by a more acute onset and stepwise decline. However, since both Alzheimer's disease and vascular dementia are common and the two frequently coexist, a secondary diagnosis of vascular dementia or a diagnosis of mixed dementia is often made when a gradually progressive dementia occurs in the setting of known cerebrovascular disease. Other dementias may be progressive, static, or occasionally remitting. The reversibility of a dementia is a function of the underlying etiology and of the availability and timely application of effective treatment.

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E. Staging of Dementia

Progressive dementias are generally staged globally according to the level of cognitive and functional impairment, and the same categories may be used to describe the degree of severity of any dementia (401, 402). However, the staging criteria have not been well validated for non-Alzheimer's dementias. Specific functional staging (FAST staging) has also been developed, is widely used, and can be very useful in tracking the course of Alzheimer's disease and other dementias (403). The ability to perform a specific function depends on baseline skills, acquired deficits, and the social environment. Consequently, the severity of illness should be assessed in the context of past functioning in several domains. Behavioral and neuropsychiatric symptoms are not stage specific.

The CDR is a commonly used scale to stage dementia severity (401). Individuals with a CDR of "questionable" (CDR of 0.5) show mild deficits in memory and sometimes in other areas and have doubtful or mild functional impairment. When such individuals present for clinical evaluation, they tend to have fairly significant memory impairment that is evident on objective testing as well, and they are typically assigned a diagnosis of mild cognitive impairment (see Section IV.F.2) or mild dementia. The Global Deterioration Scale (GDS) distinguishes three stages in this range (402). A GDS stage of 2 designates normal aging, in which older persons have subjective deficits in cognition and related areas only. Many studies have indicated that persons with these complaints are at increased risk for decline over subsequent years (404–406). The GDS stage 3, which includes subtle but manifest cognitive deficits, generally accompanied by executive level functional deficits, is equivalent to mild cognitive impairment (391). Such individuals should be evaluated over time. Many patients with mild cognitive impairment progress to Alzheimer's disease or another dementia, some patients' deficits remain stable without progression, and a few return to normal functioning (6). In community settings, this group of individuals is heterogeneous; some are similar to those who would be given a diagnosis of mild cognitive impairment in a memory clinic, whereas others have much more subtle symptoms that may be consistent with normal aging. Patients who have been systematically diagnosed as having mild cognitive impairment in memory clinics tend to be more homogeneous and more likely to progress to dementia.

Individuals with "mild" dementia (MMSE score of >18, GDS or FAST stage 4, CDR of 1) are likely to have difficulties with balancing a checkbook, preparing a complex meal, or managing a difficult medication schedule. Those with "moderate" impairment (MMSE score of 10–18, GDS or FAST stages 5 and 6, CDR of 2) also have difficulties with simpler food preparation, household cleanup, and yard work and may require assistance with some aspects of self-care (e.g., picking out the proper clothing to wear). Those whose dementia is "severe" (MMSE score of <10, GDS or FAST stages 6 and 7, CDR of 3) require considerable or total assistance with personal care, such as dressing, bathing, and toileting. Research has shown that measurable cognitive abilities remain throughout the course of severe dementia (407). In the terminal phase, patients become bed bound, develop contractures (408), require constant care, and may be susceptible to accidents and infectious diseases, which ultimately prove fatal.

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F. Specific Dementias

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1. Dementia of the Alzheimer's Type

Dementia of the Alzheimer's type, commonly referred to as Alzheimer's disease, has an insidious onset and gradual progression. Various patterns of deficits are seen, but the disorder begins most commonly with deficits in recent memory, which are followed by aphasia, visuospatial perceptual impairments, apraxia, and agnosia after several years. Deficits in executive function (e.g., performing tasks involving multiple steps, such as balancing a checkbook or preparing a meal) are also typically seen early in the course of the disease. Neuropsychiatric symptoms are common in Alzheimer's disease. Depression, anxiety, irritability, apathy, and even subtle personality changes are fairly common in the early stages of the disease, whereas in the middle and later stages of the disease psychotic symptoms and behavioral disturbances are more common. Patients usually develop incontinence and gait and motor disturbances, and eventually become mute and bed bound. Seizures and myoclonus may also occur late in the disease.

The diagnosis of Alzheimer's disease should be made only when the patient exhibits the typical symptom profile of Alzheimer's disease and when other etiologies for the dementia have been ruled out by careful history, physical and neurological examinations, and clinical and laboratory tests. A definitive diagnosis of Alzheimer's disease requires both the clinical syndrome and microscopic examination of the brain at autopsy, at which time the characteristic plaques and neurofibrillary tangles widely distributed in the cerebral cortex will be seen. A careful clinical diagnosis of Alzheimer's disease conforms to the pathological diagnosis 70%–90% of the time.

Onset of Alzheimer's disease generally occurs in late life, most commonly in the 60s, 70s, and 80s and beyond, but in rare instances the disorder appears in the 40s and 50s. The incidence of Alzheimer's disease also increases with age, and it is estimated at 0.5% per year from age 65–69 years, 1% per year from age 70–74 years, 2% per year from age 75–79 years, 3% per year from age 80–84 years, and 8% per year from age 85 years onward (409). Progression is gradual but steadily downward, with an average duration from onset of symptoms to death of 8–10 years. Plateaus may occur, but progression generally resumes after 1 to several years.

In DSM-IV-TR, Alzheimer's disease is subdivided into the subtypes "With Early Onset" and "With Late Onset," as well as "With and Without Behavioral Disturbance." Other predominant features of the current clinical presentation such as psychosis, mood disorder, or personality change, are coded with their own Axis I code.

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2. Mild Cognitive Impairment

Mild cognitive impairment is a term used to represent a variety of mild cognitive syndromes manifested by a modest but detectable decline in cognitive function in the setting of largely intact functional status (391). Because it is expected that new treatments will be better at preserving than restoring neuronal function, early recognition of these mild syndromes, particularly those thought to represent the prodromal phase of Alzheimer's disease and other neurodegenerative dementias, are a major focus of current research. Mild cognitive impairment is conceived of as a transitional state between normal aging and dementia (particularly Alzheimer's disease) in which cognitive deficits are present but function is preserved. As such, the population of patients meeting the criteria for mild cognitive impairment is inherently unstable, as many patients progress to meet the criteria for dementia. Moreover, because mild cognitive impairment lies along a continuum between normal aging and dementia, its precise upper and lower boundaries are difficult to determine. A variety of research definitions for mild cognitive impairment are in place, but there is no consensus on the optimal definition. The most widely accepted definition requires the following: 1) subjective cognitive complaints, 2) evidence of objective deficits in cognitive function based on age- and education-adjusted norms on standardized neuropsychological tests, 3) intact daily functioning, 4) evidence of cognitive decline from a prior level, and 5) evidence of not meeting the criteria for dementia (410).

Mild cognitive impairment is sometimes divided into subtypes based on the most prominent symptoms. One subtype, referred to as "amnestic mild cognitive impairment," may be the prodromal stage of Alzheimer's disease (410). A large proportion of patients who meet the criteria for mild cognitive impairment probably have the prodromal phase of Alzheimer's disease, particularly when short-term memory loss dominates the clinical picture (173). However, it should be noted that, no matter how it is defined, mild cognitive impairment is a heterogeneous category that includes some individuals with nonprogressive deficits, some with prodromal Alzheimer's disease and other dementias, and some for whom a diagnosis of early Alzheimer's disease or another dementia would be more appropriate.

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3. Vascular Dementia

Vascular dementia results from the effects of cerebrovascular disease on cognitive function. Several cerebrovascular mechanisms can lead to cerebral injury, including large vessel infarctions, multiple lacunar infarctions, extensive subcortical and periventricular white matter disease, and microvascular changes. These types of tissue injuries are usually due to atherosclerotic disease or amyloid angiopathy. Autoimmune mechanisms are far less likely.

The full range of clinical symptoms in vascular dementia is not well understood. The best known syndrome is cognitive impairment that occurs shortly after a clinically recognized stroke (within 3 months), with evidence of infarctions in brain areas relevant to the impaired cognitive functions. Neurological signs and symptoms consistent with cerebrovascular damage (hemiparesis or hemianopia) are usually present. There is no specific cognitive profile of vascular dementia, although executive and attentional deficits may be more pronounced than impairment in short-term memory. The pattern of cognitive deficits is often patchy, depending on which regions of the brain have been damaged (411).

The incidence and prevalence of vascular dementia mirror those of Alzheimer's disease in that vascular dementia becomes increasingly common with advanced age (412–414). The relationship between Alzheimer's disease and vascular dementia is complex. Alzheimer's disease and strokes are both common and frequently coexist (although often only one diagnosis is recognized during a person's life). In addition, a wide variety of evidence from neuroimaging, neuropathological, epidemiological, and genetic studies suggests that the two share common risk factors, such as hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia, as well as others (415). There is also considerable neuropathological overlap between the two conditions. Many patients with typical pathological signs of Alzheimer's disease have cerebrovascular disease as well, whereas other patients with clear strokes also have pathological signs of Alzheimer's disease. The degree to which strokes alone are responsible for dementia is unclear; estimates for the fraction of dementia caused by "pure" vascular dementia range from 5% to 20% (416). Early treatment of hypertension and vascular disease may prevent further progression. Vascular dementia associated with autoimmune disease occurs in concert with other symptoms of the specific illness and in the age group characteristic of the specific disease (e.g., systemic lupus erythematosus, giant cell arteritis).

Like Alzheimer's disease, vascular dementia is subtyped by DSM-IV-TR according to certain clinical features. Subtypes available for vascular dementia include "With Delirium," "With Delusions," "With Depressed Mood," and "Uncomplicated." Clinically significant behavioral disturbances can be coded as a modifier but are not considered a separate subtype. No subtyping based on age of onset is used. More formal diagnostic criteria, typically focused on differentiating pure vascular dementia from a mixture of Alzheimer's disease and vascular pathology, are used in the research setting (417). These criteria vary widely, particularly to the extent that they stress clinical versus radiographic evidence for stroke, and there is no consensus on optimal criteria for vascular dementia at this time (5, 418, 419).

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4. Dementia of Parkinson's Disease and Dementia With Lewy Bodies

Lewy bodies are commonly found at autopsy in individuals with late-life dementia. There are two subtypes of Lewy body disease depending on whether Parkinson's disease precedes cognitive impairment by more than 1 year (Parkinson's disease dementia) or whether the cognitive impairment is the dominant symptom (dementia with Lewy bodies). Whether or not these entities are best classified as one condition or as distinct ones is still unresolved. Parkinson's disease is a slowly progressive neurological condition characterized by tremor, rigidity, bradykinesia, and postural instability; its onset is typically in middle to late life. Estimates of the prevalence of dementia in Parkinson's disease vary. One large longitudinal study found that dementia developed in nearly 80% of patients followed for 8 years (420). The dementia associated with Parkinson's disease has an insidious onset and slow progression and is characterized by cognitive and motor slowing, executive dysfunction, and impairments in memory retrieval and flexibility. Parkinson's disease is important to psychiatrists because of the high prevalence of associated depression and the frequent occurrence of psychotic symptoms such as visual hallucinations during pharmacological treatment of the primary motor deficit.

Dementia with Lewy bodies has been recognized clinically only in the last 10–15 years (421, 422). In many ways it is clinically similar to Alzheimer's disease. Important clinical differences that distinguish dementia with Lewy bodies include visual hallucinations that appear earlier in the disease course and tend to be more prominent, parkinsonian features such as postural instability and falls that appear early in the disease course, cognitive fluctuations lasting days to weeks, and a somewhat more rapid evolution. Patients with dementia with Lewy bodies are markedly sensitive to the extrapyramidal effects of antipsychotic medications, and these medications should be used only with the utmost caution in these patients. Dementia with Lewy bodies may account for as many as 7%–26% of dementia cases, depending on the criteria used (423, 424). The disorder is particularly likely to come to psychiatric attention because of a patient's prominent psychotic symptoms and sensitivity to antipsychotic medications.

The neuropathology of Parkinson's disease and dementia with Lewy bodies are identical and include an abundance of Lewy inclusion bodies in both subcortical and cortical regions (422). Because autopsies often reveal both the neuropathologies of dementia with Lewy bodies and Alzheimer's disease, controversy exists about the independence of the two diseases. The development of valid clinical and pathological diagnostic criteria for dementia with Lewy bodies is an area of active research.

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5. Dementia Due to Frontotemporal Dementia Spectrum Disorders

Frontotemporal dementia (formerly referred to as Pick's disease and sometimes referred to as frontotemporal lobar degeneration) is characterized in its early stages by changes in personality, significant apathy, executive dysfunction, deterioration of social skills, emotional blunting, behavioral disinhibition, and prominent language abnormalities. Difficulties with memory, apraxia, and other features of dementia usually follow later in the course. As the dementia progresses, it may be accompanied by extreme agitation. Individuals may develop such severe problems with language, attention, or behavior that it may be difficult to assess the degree of cognitive impairment. Early prominent changes in personality and behavior, severe apathy, and/or early language deficits help to distinguish this group of disorders from Alzheimer's disease. Two sets of diagnostic criteria for frontotemporal dementia spectrum disorders have been proposed (361, 425). The criteria of McKhann et al. include several disorders previously considered to be distinct: progressive supranuclear palsy, corticobasal ganglionic degeneration, amyotrophic lateral sclerosis with dementia, and hippocampal sclerosis (361, 426). Argyrophilic grain disease may also be included in this group of conditions (427). In frontotemporal dementia spectrum disorders, structural brain imaging typically reveals prominent frontal and/or temporal atrophy, with relative sparing of the parietal and occipital lobes. The formal diagnosis of Pick's disease, which is only one of the numerous neuropathological subtypes of this condition, depends on the neuropathological finding of Pick inclusion bodies (361). About one-third of cases are familial, and a number of specific genetic defects have been identified (29). The disorder most commonly manifests in patients ages 50–60 years, although it can occur among older or younger individuals. The course is progressive and can be more rapid than that of Alzheimer's disease, although there is significant heterogeneity. Once thought to be rare, these conditions have been found to be more common, and careful assessment may reveal cases previously missed. These conditions are important for psychiatrists because they often present with a variety of psychiatric symptoms, including disinhibition, apathy, depression, anxiety, personality change, substance abuse, family conflict, and impaired work performance, that initially overshadow the cognitive impairment, complicating and delaying the proper diagnosis.

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6. Other Progressive Dementing Disorders

Other disorders that can lead to progressive dementia include Huntington's disease and Creutzfeldt-Jakob disease. Huntington's disease is an autosomal dominant disorder that affects the basal ganglia and other subcortical structures and includes motor, behavioral, mood, and cognitive symptoms. Creutzfeldt-Jakob disease is a rapidly progressive spongiform encephalopathy associated with a prion (proteinaceous infectious particle). Variant Creutzfeldt-Jakob disease, thought to be due to introduction into the human food chain of scrapie-like prion disease, usually presents before age 40 years with psychiatric symptoms. Cognitive decline is rapid, with death usually occurring within 1.5 years.

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7. Dementia Due to Other Causes

In addition to the preceding categories, a number of general medical conditions can cause dementia (428). These conditions include structural lesions (e.g., primary or secondary brain tumors, subdural hematoma, slowly progressive or normal-pressure hydrocephalus), head trauma, endocrine conditions (e.g., hypothyroidism, hypercalcemia, hypoglycemia), nutritional conditions (e.g., deficiency of vitamin B12, thiamine, or niacin), other infectious conditions (e.g., HIV, neurosyphilis, Cryptococcus), derangements of renal and hepatic function, neurological conditions (e.g., multiple sclerosis), effects of medications (e.g., benzodiazepines, beta-blockers, anticholinergics), autoimmune diseases (e.g., lupus erythematosus, vasculitis, Hashimoto's encephalopathy, neurosarcoidosis), environmental toxins (e.g., heavy metals, organic hydrocarbons), and the toxic effect of long-standing substance abuse, especially alcohol abuse. It is critical that psychiatrists caring for individuals with dementia be familiar with the general medical and neurological causes of dementia in order to ensure that the diagnosis is accurate and, in particular, that potentially treatable conditions are not missed.

References

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