17. Neurocognitive Disorders
17.1. Delirium
17.2. Major or Mild Neurocognitive Disorders
17.2.1. Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease
17.2.2. Major or Mild Frontotemporal Neurocognitive Disorder
17.2.3. Major or Mild Neurocognitive Disorder With Lewy Bodies
17.2.4. Major or Mild Vascular Neurocognitive Disorder
17.2.5. Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury
17.2.6. Substance/Medication-Induced Major or Mild Neurocognitive Disorder
17.2.7. Major or Mild Neurocognitive Disorder Due to HIV Infection
17.2.8. Major or Mild Neurocognitive Disorder Due to Prion Disease
17.2.9. Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease
17.2.10. Major or Mild Neurocognitive Disorder Due to Huntington’s Disease
The neurocognitive disorders (NCDs) (referred to in DSM-IV as "Dementia, Delirium, Amnestic, and Other Cognitive Disorders") begin with delirium, followed by the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or mild NCD subtypes are NCD due to Alzheimer's disease; vascular NCD; NCD with Lewy bodies; NCD due to Parkinson's disease; frontotemporal NCD; NCD due to traumatic brain injury; NCD due to HIV infection; substance/medication-induced NCD; NCD due to Huntington's disease; NCD due to prion disease; NCD due to another medical condition; NCD due to multiple etiologies; and unspecified NCD. The NCD category encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental. Although cognitive deficits are present in many if not all mental disorders (e.g., schizophrenia, bipolar disorders), only disorders whose core features are cognitive are included in the NCD category. The NCDs are those in which impaired cognition has not been present since birth or very early life, and thus represents a decline from a previously attained level of functioning.
The NCDs are unique among DSM-5 categories in that these are syndromes for which the underlying pathology, and frequently the etiology as well, can potentially be determined. The various underlying disease entities have all been the subject of extensive research, clinical experience, and expert consensus on diagnostic criteria. The DSM-5 criteria for these disorders have been developed in close consultation with the expert groups for each of the disease entities and align as closely as possible with the current consensus criteria for each of them. The potential utility of biomarkers is also discussed in relation to diagnosis. Dementia is subsumed imder the newly named entity major neurocognitive disorder, although the term dementia is not precluded from use in the etiological subtypes in which that term is standard. Furthermore, DSM-5 recognizes a less severe level of cognitive impairment, mild neurocognitive disorder, which can also be a focus of care, and which in DSM-IV was subsumed under "Cognitive Disorder Not Otherwise Specified." Diagnostic criteria are provided for both these syndromic entities, followed by diagnostic criteria for the different etiological subtypes. Several of the NCDs frequently coexist with one another, and their relationships may be multiply characterized under different chapter subheadings, including "Differential Diagnosis" (e.g., NCD due to Alzheimer's disease vs. vascular NCD), "Risk and Prognostic Factors" (e.g., vascular pathology increasing the clinical expression of Alzheimer's disease), and/or "Comorbidity" (e.g., mixed Alzheimer's disease-vascular pathology).
The term dementia is retained in DSM-5 for continuity and may be used in settings where physicians and patients are accustomed to this term. Although dementia is the customary term for disorders like the degenerative dementias that usually affect older adults, the term neurocognitive disorder is widely used and often preferred for conditions affecting younger individuals, such as impairment secondary to traumatic brain injury or HIV infection. Furthermore, the major NCD definition is somewhat broader than the term dementia, in that individuals with substantial decline in a single domain can receive this diagnosis, most notably the DSM-IV category of "Amnestic Disorder," which would now be diagnosed as major NCD due to another medical condition and for which the term dementia would not be used.
The essential feature of delirium is a disturbance of attention or awareness that is accompanied
by a change in baseline cognition that cannot be better explained by a preexisting
or evolving neurocognitive disorder (NCD). The disturbance in attention (Criterion A) is
manifested by reduced ability to direct, focus, sustain, and shift attention. Questions must
be repeated because the individual's attention wanders, or the individual may perseverate
with an answer to a previous question rather than appropriately shift attention. The individual
is easily distracted by irrelevant stimuli. The disturbance in awareness is manifested
by a reduced orientation to the environment or at times even to oneself.
The disturbance develops over a short period of time, usually hours to a few days, and
tends to fluctuate during the course of the day, often with worsening in the evening and
night when external orienting stimuli decrease (Criterion B). There is evidence from the
history, physical examination, or laboratory findings that the disturbance is a physiological
consequence of an underlying medical condition, substance intoxication or withdrawal,
use of a medication, or a toxin exposure, or a combination of these factors
(Criterion E). The etiology should be coded according to the etiologically appropriate subtype
(i.e., substance or medication intoxication, substance withdrawal, another medical
condition, or multiple etiologies). Delirium often occurs in the context of an underlying
NCD. The impaired brain function of individuals with mild and major NCD renders them
more vulnerable to delirium.
There is an accompanying change in at least one other area that may include memory
and learning (particularly recent memory), disorientation (particularly to time and place),
alteration in language, or perceptual distortion or a perceptual-motor disturbance (Criterion
C). The perceptual disturbances accompanying delirium include misinterpretations,
illusions, or hallucinations; these disturbances are typically visual, but may occur in other
modalities as well, and range from simple and uniform to highly complex. Normal attention/
arousal, delirium, and coma lie on a continuum, with coma defined as the lack of any
response to verbal stimuli. The ability to evaluate cognition to diagnose delirium depends
on there being a level of arousal sufficient for response to verbal stimulation; hence, delirium
should not be diagnosed in the context of coma (Criterion D). Many noncoma tose patients
have a reduced level of arousal. Those patients who show only minimal responses to
verbal stimulation are incapable of engaging with attempts at standardized testing or even
interview. This inability to engage should be classified as severe inattention. Low-arousal
states (of acute onset) should be recognized as indicating severe inattention and cognitive
change, and hence delirium. They are clinically indistinguishable from delirium diagnosed
on the basis of inattention or cognitive change elicited through cognitive testing and
interview.
Delirium is often associated with a disturbance in the sleep-wake cycle. This disturbance can include daytime sleepiness, nighttime agitation, difficulty falling asleep, excessive sleepiness throughout the day, or wakefulness throughout the night. In some cases, complete reversal of the night-day sleep-wake cycle can occur. Sleep-wake cycle disturbances are very common in delirium and have been proposed as a core criterion for the diagnosis. The individual with delirium may exhibit emotional disturbances, such as anxiety, fear, depression, irritability, anger, euphoria, and apathy. There may be rapid and unpredictable shifts from one emotional state to another. The disturbed emotional state may also be evident in calling out, screaming, cursing, muttering, moaning, or making other sounds. These behaviors are especially prevalent at night and under conditions in which stimulation and environmental cues are lacking.
The prevalence of delirium is highest among hospitalized older individuals and varies
depending on the individuals' characteristics, setting of care, and sensitivity of the detection
method. The prevalence of delirium in the community overall is low (l%-2%) but increases
with age, rising to 14% among individuals older than 85 years. The prevalence is
10%-30% in older individuals presenting to emergency departments, where the delirium
often indicates a medical illness.
The prevalence of delirium when individuals are admitted to the hospital ranges from
14% to 24%, and estimates of the incidence of delirium arising during hospitalization
range from 6% to 56% in general hospital populations. Delirium occurs in 15%-53% of
older individuals postoperatively and in 70%-87% of those in intensive care. Delirium occurs
in up to 60% of individuals in nursing homes or post-acute care settings and in up to
83% of all individuals at the end of life.
Delirium itself is associated with increased functional decline and risk of institutional placement. Hospitalized individuals 65 years or older with delirium have three times the risk of nursing home placement and about three times the functional decline as hospitalized patients without delirium at both discharge and 3 months postdischarge.
Major and mild NCDs exist on a spectrum of cognitive and functional impairment. Major
NCD corresponds to the condition referred to in DSM-IV as dementia, retained as an alternative
in this volume. The core feature of NCDs is acquired cognitive decline in one or
more cognitive domains (Criterion A) based on both 1) a concern about cognition on the
part of the individual, a knowledgeable informant, or the clinician, and 2) performance on
an objective assessment that falls below the expected level or that has been observed to decline
over time. Both a concern and objective evidence are required because they are complementary.
When there is an exclusive focus on objective testing, a disorder may go
undiagnosed in high-functioning individuals whose currently "normal" performance actually
represents a substantial decline in abilities, or an illness may be incorrectly diagnosed
in individuals whose currently "low" performance does not represent a change
from their own baseline or is a result of extraneous factors like test conditions or a passing
illness. Alternatively, excessive focus on subjective symptoms may fail to diagnose illness
in individuals with poor insight, or whose informants deny or fail to notice their symptoms,
or it may be overly sensitive in the so-called worried well.
A cognitive concern differs from a complaint in that it may or may not be voiced spontaneously.
Rather, it may need to be elicited by careful questioning about specific symptoms
that commonly occur in individuals with cognitive deficits (see Table 1 in the
introduction to this chapter). For example, memory concerns include difficulty remembering
a short grocery list or keeping track of the plot of a television program; executive concerns
include difsculty resuming a task when interrupted, organizing tax records, or
planning a holiday meal. At the mild NCD level, the individual is likely to describe these
tasks as being more difficult or as requiring extra time or effort or compensatory strategies.
At the major NCD level, such tasks may only be completed with assistance or may be
abandoned altogether. At the mild NCD level, individuals and their families may not notice
such symptoms or may view them as normal, particularly in the elderly; thus, careful
history taking is of paramount importance. The difficulties must represent changes rather
than lifelong patterns: the individual or informant may clarify this issue, or the clinician
can infer change from prior experience with the patient or from occupational or other
clues. It is also critical to determine that the difficulties are related to cognitive loss rather
than to motor or sensory limitations.
Neuropsychological testing, with performance compared with norms appropriate to
the patient's age, educational attainment, and cultural background, is part of the standard
evaluation of NCDs and is particularly critical in the evaluation of mild NCD. For major
NCD, performance is typically 2 or more standard deviations below appropriate norms
(3rd percentile or below). For mild NCD, performance typically lies in the 1-2 standard deviation
range (between the 3rd and 16th percentiles). However, neuropsychological testing
is not available in all settings, and neuropsychological thresholds are sensitive to the
specific test(s) and norms employed, as well as to test conditions, sensory limitations, and
intercurrent illness. A variety of brief office-based or "bedside" assessments, as described
in Table 1, can also supply objective data in settings where such testing is unavailable or
infeasible. In any case, as with cognitive concerns, objective performance must be interpreted
in light of the individual's prior performance. Optimally, this information would
be available from a prior administration of the same test, but often it must be inferred
based on appropriate norms, along with the individual's educational history, occupation,
and other factors. Norms are more challenging to interpret in individuals with very high
or very low levels of education and in individuals being tested outside their own language
or cultural background.
Criterion B relates to the individual's level of independence in everyday functioning.
Individuals with major NCD will have impairment of sufficient severity so as to interfere
with independence, such that others will have to take over tasks that the individuals were
previously able to complete on their own. Individuals with mild NCD will have preserved
independence, although there may be subtle interference with function or a report that
tasks require more effort or take more time than previously.
The distinction between major and mild NCD is inherently arbitrary, and the disorders
exist along a continuum. Precise thresholds are therefore difficult to determine. Careful
history taking, observation, and integration with other findings are required, and the implications
of diagnosis should be considered when an individual's clinical manifestations
lie at a boundary.
Typically the associated features that support a diagnosis of major or mild NCD will be specific to the etiological subtype (e.g., neuroleptic sensitivity and visual hallucinations in NCD due to Lewy body disease). Diagnostic features specific to each of the subtypes are found in the relevant sections.
The prevalence of NCD varies widely by age and by etiological subtype. Overall prevalence
estimates are generally only available for older populations. Among individuals
older than 60 years, prevalence increases steeply with age, so prevalence estimates are
more accurate for narrow age bands than for broad categories such as "over 65" (where the
mean age can vary greatly with the life expectancy of the given population). For those etiological
subtypes occurring across the lifespan, prevalence estimates for NCD are likely to
be available, if at all, only as the fraction of individuals who develop NCD among those
with the relevant condition (e.g., traumatic brain injury, HIV infection).
Overall prevalence estimates for dementia (which is largely congruent with major
NCD) are approximately l%-2% at age 65 years and as high as 30% by age 85 years. The
prevalence of mild NCD is very sensitive to the definition of the disorder, particularly in
community settings, where evaluations are less detailed. In addition, in contrast with clinical
settings, where cognitive concern must be high to seek and locate care, there may be a
less clear decline from baseline functioning. Estimates of the prevalence of mild cognitive
impairment (which is substantially congruent with mild NCD) among older individuals
are fairly variable, ranging from 2% to 10% at age 65 and 5% to 25% by age 85.
Individuals' and families' level of awareness and concern about neurocognitive symptoms may vary across ethnic and occupational groups. Neurocognitive symptoms are more likely to be noticed, particularly at the mild level, in individuals who engage in complex occupational, domestic, or recreational activities. In addition, norms for neuropsychological testing tend to be available only for broad populations, and thus they may not be easily applicable to individuals with less than high school education or those being evaluated outside their primary language or culture.
Like age, culture, and occupation, gender issues may affect the level of concern and awareness of cognitive symptoms. In addition, for late-life NCDs, females are likely to be older, to have more medical comorbidity, and to live alone, which can complicate evaluation and treatment. In addition, there are gender differences in the frequency of some of the etiological subtypes.
By definition, major and mild NCDs affect functioning, given the central role of cognition in human life. Thus, the criteria for the disorders, and the threshold for differentiating mild from major NCD, are based in part on functional assessment. Within major NCD there is a broad range of functional impairment, as implemented in the severity specifiers. In addition, the specific functions that are compromised can help identify the cognitive domains affected, particularly when neuropsychological testing is not available or is difficult to interpret.
Beyond the neurocognitive disorder (NCD) syndrome (Criterion A), the core features of major
or mild NCD due to Alzheimer's disease include an insidious onset and gradual progression
of cognitive and behavioral symptoms (Criterion B). The typical presentation is
amnestic (i.e., with impairment in memory and learning). Unusual nonamnestic presentations,
particularly visuospatial and logopenic aphasie variants, also exist. At the mild
NCD phase, Alzheimer's disease manifests typically with impairment in memory and learning,
sometimes accompanied by deficits in executive function. At the major NCD phase,
visuoconstructional/perceptual motor ability and language will also be impaired, particularly
when the NCD is moderate to severe. Social cognition tends to be preserved until
late in the course of the disease.
A level of diagnostic certainty must be specified denoting Alzheimer's disease as the
"probable" or "possible" etiology (Criterion C). Probable Alzheimer's disease is diagnosed in
both major and mild NCD if there is evidence of a causative Alzheimer's disease gene, either
from genetic testing or from an autosomal dominant family history coupled with autopsy
confirmation or a genetic test in an affected family member. For major NCD, a
typical clinical picture, without extended plateaus or evidence of mixed etiology, can also
be diagnosed as due to probable Alzheimer's disease. For mild NCD, given the lesser degree
of certainty that the deficits will progress, these features are only sufficient for a
possible Alzheimer's etiology. If the etiology appears mixed, mild NCD due to multiple etiologies
should be diagnosed. In any case, for both mild and major NCD due to Alzheimer's
disease, the clinical features must not suggest another primary etiology for the NCD
(Criterion D).
In specialty clinical settings, approximately 80% of individuals with major NCD due to Alzheimer's disease have behavioral and psychological manifestations; these features are also frequent at the mild NCD stage of impairment. These symptoms are as or more distressing than cognitive manifestations and are frequently the reason that health care is sought. At the mild NCD stage or the mildest level of major NCD, depression and/or apathy are often seen. With moderately severe major NCD, psychotic features, irritability, agitation, combativeness, and wandering are common. Late in the illness, gait disturbance, dysphagia, incontinence, myoclonus, and seizures are observed.
The prevalence of overall dementia (major NCD) rises steeply with age. In high-income countries, it ranges from 5% to 10% in the seventh decade to at least 25% thereafter. U.S. census data estimates suggest that approximately 7% of individuals diagnosed with Alzheimer's disease are between ages 65 and 74 years, 53% are between ages 75 and 84 years, and 40% are 85 years and older. The percentage of dementias attributable to Alzheimer's disease ranges from about 60% to over 90%, depending on the setting and diagnostic criteria. Mild NCD due to Alzheimer's disease is likely to represent a substantial fraction of mild cognitive impairment (MCI) as well.
Detection of an NCD may be more difficult in cultural and socioeconomic settings where memory loss is considered normal in old age, where older adults face fewer cognitive demands in everyday life, or where very low educational levels pose greater challenges to objective cognitive assessment.
The prominence of memory loss can cause significant difficulties relatively early in the course. Social cognition (and thus social functioning) and procedural memory (e.g., dancing, playing musical instruments) may be relatively preserved for extended periods.
Major or mild frontotemporal neurocognitive disorder (NCD) comprises a number of syndromic
variants characterized by the progressive development of behavioral and personality
change and/or language impairment. The behavioral variant and three language variants (semantic,
agrammatic/nonfluent, and logopenic) exhibit distinct patterns of brain atrophy and
some distinctive neuropathology. The criteria must be met for either the behavioral or the language
variant to make the diagnosis, but many individuals present with features of both.
Individuals with behavioral-variant major or mild frontotemporal NCD present with
varying degrees of apathy or disinhibition. They may lose interest in socialization, selfcare,
and personal responsibilities, or display socially inappropriate behaviors. Insight is
usually impaired, and this often delays medical consultation. The first referral is often to a
psychiatrist. Individuals may develop changes in social style, and in religious and political
beliefs, with repetitive movements, hoarding, changes in eating behavior, and hyperorality.
In later stages, loss of sphincter control may occur. Cognitive decline is less prominent,
and formal testing may show relatively few deficits in the early stages. Common neurocognitive
symptoms are lack of planning and organization, distractibility, and poor judgment.
Deficits in executive function, such as poor performance on tests of mental
flexibility, abstract reasoning, and response inhibition, are present, but learning and memory
are relatively spared, and perceptual motor abilities are almost always preserved in
the early stages.
Individuals with language-variant major or mild frontotemporal NCD present with primary
progressive aphasia with gradual onset, with three subtypes commonly described:
semantic variant, agrammatic/nonfluent variant, and logopenic variant, and each variant
has distinctive features and corresponding neuropathology.
"Probable" is distinguished from "possible" frontotemporal NCD by the presence of
causative genetic factors (e.g., mutations in the gene coding for microtubule-associated protein
tau) or by the presence of distinctive atrophy or reduced activity in frontotemporal regions
on structural or functional imaging.
Extrapyramidal features may be prominent in some cases, with an overlap with syndromes such as progressive supranuclear palsy and corticobasal degeneration. Features of motor neuron disease may be present in some cases (e.g., muscle atrophy, weakness). A subset of individuals develop visual hallucinations.
Major or mild frontotemporal NCD is a common cause of early-onset NCD in individuals younger than 65 years. Population prevalence estimates are in the range of 2-10 per 100,000. Approximately 20%-25% of cases of frontotemporal NCD occur in individuals older than 65 years. Frontotemporal NCD accounts for about 5% of all cases of dementia in unselected autopsy series. Prevalence estimates of behavioral variant and semantic language variant are higher among males, and prevalence estimates of nonfluent language variant are higher among females.
Because of the relative early age at onset of the disorder, the disorder oftens affects workplace and family life. Because of the involvement of language and/or behavior, function is often more severely impaired relatively early in the course. For individuals with the behavioral variant, prior to diagnostic clarification there may be significant family disruption, legal involvement, and problems in the workplace because of socially inappropriate behaviors. The functional impairment due to behavioral change and language dysfunction, which can include hyperorality, impulsive wandering, and other dishinhibited behaviors, may far exceed that due to the cognitive disturbance and may lead to nursing home placement or institutionalization. These behaviors can be severely disruptive, even in structured care settings, particularly when the individuals are otherwise healthy, nonfrail, and free of other medical comorbidities.
Major or mild neurocognitive disorder with Lewy bodies (NCDLB), in the case of major neurocognitive disorder (NCD), corresponds to the condition known as dementia with Lewy bodies (DLB). The disorder includes not only progressive cognitive impairment (with early changes in complex attention and executive function rather than learning and memory) but also recurrent complex visual hallucinations; and concurrent symptoms of rapid eye movement (REM) sleep behavior disorder (which can be a very early manifestation); as well as hallucinations in other sensory modalities, depression, and delusions. The symptoms fluctuate in a pattern that can resemble a delirium, but no adequate underlying cause can be found. The variable presentation of NCDLB symptoms reduces the likelihood of all symptoms being observed in a brief clinic visit and necessitates a thorough assessment of caregiver observations. The use of assessment scales specifically designed to assess fluctuation may aid in diagnosis. Another core feature is spontaneous parkinsonism, which must begin after the onset of cognitive decline; by convention, major cognitive deficits are observed at least 1 year before the motor symptoms. The parkinsonism must also be distinguished from neuroleptic-induced extrapyramidal signs. Accurate diagnosis is essential to safe treatment planning, as up to 50% of individuals with NCDLB have severe sensitivity to neuroleptic drugs, and these medications should be used with extreme caution in managing the psychotic manifestations. The diagnosis of mild NCDLB is appropriate for individuals who present with the core or suggestive features at a stage when cognitive or functional impairments are not of sufficient severity to fulfill criteria for major NCD. However, as for all mild NCDs, there will often be insufficient evidence to justify any single etiology, and use of the unspecified diagnosis is most appropriate.
Individuals with NCDLB frequently experience repeated falls and syncope and transient episodes of unexplained loss of consciousness. Autonomic dysfunction, such as orthostatic hypotension and urinary incontinence, may be observed. Auditory and other nonvisual hallucinations are common, as are systematized delusions, delusional misidentification, and depression.
The few population-based prevalence estimates for NCDLB available range from 0.1% to 5% of the general elderly population, and from 1.7% to 30.5% of all dementia cases. In brain bank (autopsy) series, the pathological lesions known as Lewy bodies are present in 20%-35% of cases of dementia. The male-to-female ratio is approximately 1.5:1.
Individuals with NCDLB are more functionally impaired than would be expected for their cognitive deficits when contrasted to individuals with other neurodegenerative diseases, such as Alzheimer's disease. This is largely a result of motor and autonomic impairments, which cause problems with toileting, transferring, and eating. Sleep disorders and prominent psychiatric symptoms may also add to functional difficulties. Consequently, the quality of life of individuals with NCDLB is often significantly worse than that of individuals with Alzheimer's disease.
The diagnosis of major or mild vascular neurocognitive disorder (NCD) requires the establishment
of an NCD (Criterion A) and the determination that cerebrovascular disease is
the dominant if not exclusive pathology that accounts for the cognitive deficits (Criteria B
and C). Vaiscular etiology may range from large vessel stroke to microvascular disease; the
presentation is therefore very heterogeneous, stemming from the types of vascular lesions
and their extent and location. The lesions may be focal, multifocal, or diffuse and occur in
various combinations.
Many individuals with major or mild vascular NCD present with multiple infarctions,
with an acute stepwise or fluctuating decline in cognition, and intervening periods of
stability and even some improvement. Others may have gradual onset with slow progression,
a rapid development of deficits followed by relative stability, or another complex
presentation. Major or mild vascular NCD with a gradual onset and slow progression is
generally due to small vessel disease leading to lesions in the white matter, basal ganglia,
and/or thalamus. The gradual progression in these cases is often punctuated by acute
events that leave subtle neurological deficits. The cognitive deficits in these cases can be attributed
to disruption of cortical-subcortical circuits, and complex attention, particularly
speed of information processing, and executive ability are likely to be affected.
Assessing for the presence of sufficient cerebrovascular disease relies on history, physical
examination, and neuroimaging (Criterion C). Etiological certainty requires the demonstration
of abnormalities on neuroimaging. The lack of neuroimaging can result in
significant diagnostic inaccuracy by overlooking "silent" brain infarction and white matter
lesions. However, if the neurocognitive impairment is temporally associated with one
or more well-documented strokes, a probable diagnosis can be made in the absence of neuroimaging.
Clinical evidence of cerebrovascular disease includes documented history of
stroke, with cognitive decline temporally associated with the event, or physical signs consistent
with stroke (e.g., hemiparesis; pseudobulbar syndrome, visual field defect). Neuroimaging
(magnetic resonance imaging [MRI] or computed tomography [CT]) evidence of
cerebrovascular disease comprises one or more of the following: one or more large vessel
infarcts or hemorrhages, a strategically placed single infarct or hemorrhage (e.g., in angular
gyrus, thalamus, basal forebrain), two or more lacunar infarcts outside the brain stem,
or extensive and confluent white matter lesions. The latter is often termed small vessel disease
or subcortical ischemic changes on clinical neuroimaging evaluations.
For mild vascular NCD, history of a single stroke or extensive white matter disease is generally
sufficient. For major vascular NCD, two or more strokes, a strategically placed stroke,
or a combination of white matter disease and one or more lacunes is generally necessary.
The disorder must not be better explained by another disorder. For example, prominent
memory deficit early in the course might suggest Alzheimer's disease, early and
prominent parkinsonian features would suggest Parkinson's disease, and a close association
between onset and depression would suggest depression.
A neurological assessment often reveals history of stroke and/or transient ischemic episodes, and signs indicative of brain infarctions. Also commonly associated are personality and mood changes, abulia, depression, and emotional lability. The development of lateonset depressive symptoms accompanied by psychomotor slowing and executive dysfunction is a common presentation among older adults with progressive small vessel ischemic disease ("vascular depression").
Major or mild vascular NCD is the second most common cause of NCD after Alzheimer's disease. In the United States, population prevalence estimates for vascular dementia range from 0.2% in the 65-70 years age group to 16% in individuals 80 years and older. Within 3 months following stroke, 20%-30% of individuals are diagnosed with dementia. In neuropathology series, the prevalence of vascular dementia increases from 13% at age 70 years to 44.6% at age 90 years or older, in comparison with Alzheimer's disease (23.6%-51%) and combined vascular dementia and Alzheimer's disease (2%-46.4%). Higher prevalence has been reported in African Americans compared with Caucasians, and in East Asian countries (e.g., Japan, Chii;ia). Prevalence is higher in males than in females.
Major or mild vascular NCD is commonly associated with physical deficits that cause additional disability
Major or mild NCD due to traumatic brain injury (TBI) is caused by an impact to the head,
or other mechanisms of rapid movement or displacement of the brain within the skull, as
can happen with blast injuries. Traumatic brain injury is defined as brain trauma with specific
characteristics that include at least one of the following: loss of consciousness, posttraumatic
amnesia, disorientation and confusion, or, in more severe cases, neurological
signs (e.g., positive neuroimaging, a new onset of seizures or a marked worsening of a preexisting
seizure disorder, visual field cuts, anosmia, hemiparesis) (Criterion B). To be attributable
to TBI, the NCD must present either immediately after the brain injury occurs or
immediately after the individual recovers consciousness after the injury and persist past
the acute post-injury period (Criterion C).
The cognitive presentation is variable. Difficulties in the domains of complex attention,
executive ability^, learning, and memory are common as well as slowing in speed of information
processing and disturbances in social cognition. In more severe TBI in which there
is brain contusion, intracranial hemorrhage, or penetrating injury, there may be additional
neurocognitive deficits, such as aphasia, neglect, and constructional dyspraxia.
Major or mild NCD due to TBI may be accompanied by disturbances in emotional function (e.g., irritability, easy frustration, tension and anxiety, affective lability); personality changes (e.g., disinhibition, apathy, suspiciousness, aggression); physical disturbances (e.g., headache, fatigue, sleep disorders, vertigo or dizziness, tinnitus or hyperacusis, photosensitivity, anosmia, reduced tolerance to psychotropic medications); and, particularly in more severe TBI, neurological symptoms and signs (e.g., seizures, hemiparesis, visual disturbances, cranial nerve deficits) and evidence of orthopedic injuries.
In the United States, 1.7 million TBIs occur annually, resulting in 1.4 million emergency department visits, 275,000 hospitalizations, and 52,000 deaths. About 2% of the population lives with TBI-associated disability. Males account for 59% of TBIs in the United States. The most common etiologies of TBI in the United States are falls, vehicular accidents, and being struck on the head. Collisions and blows to the head that occur in the course of contact sports are increasingly recognized as sources of mild TBI, with a concern that repeated mild TBI may have cumulatively persisting sequelae.
With mild NCD due to TBI, individuals may report reduced cognitive efficiency, difficulty concentrating, and lessened ability to perform usual activities. With major NCD due to TBI, an individual may have difficulty in independent living and self-care. Prominent neuromotor features, such as severe incoordination, ataxia, and motor slowing, may be present in major NCD due to TBI and may add to functional difficulties. Individuals with TBI histories report more depressive symptoms, and these can amplify cognitive complaints and worsen functional outcome. Additionally, loss of emotional control, including aggressive or inappropriate affect and apathy, may be present after more severe TBI with greater neurocognitive impairment. These features may compound difficulties with independent living and self-care.
Substance/medication-induced major or mild NCD is characterized by neurocognitive
impairments that persist beyond the usual duration of intoxication and acute withdrawal
(Criterion B). Initially, these manifestations can reflect slow recovery of brain functions
from a period of prolonged substance use, and improvements in neurocognitive as well as
brain imaging indicators may be seen over many months. If the disorder continues for an
extended period, persistent should be specified. The given substance and its use must be
known to be capable of causing the observed impairments (Criterion C). While nonspecific
decrements in a range of cognitive abilities can occur with nearly any substance of abuse
and a variety of medications, some patterns occur more frequently with selected drug
classes. For example, NCD due to sedative, hypnotic, or anxiolytic drugs (e.g., benzodiazepines,
barbiturates) may show greater disturbances in memory than in other cognitive
functions. NCD induced by alcohol frequently manifests with a combination of impairments
in executive-function and memory and learning domains. The temporal course of
the substance-induced NCD must be consistent with that of use of the given substance
(Criterion D). In alcohol-induced amnestic confabulatory (Korsakoff's) NCD, the features
include prominent amnesia (severe difficulty learning new information with rapid forgetting)
and a tendency to confabulate. These manifestations may co-occur with signs of thiamine
encephalopathy (Wernicke's encephalopathy) with associated features such as
nystagmus and ataxia. Ophthalmoplegia of Wernicke's encephalopathy is typically characterized
by a lateral gaze paralysis.
In addition to or independent of the more common neurocognitive symptoms related
to methamphetamine use (e.g., difficulties with learning and memory; executive function),
methamphetamine use can also be associated with evidence of vascular injury (e.g.,
focal weakness, unilateral incoordination, asymmetrical reflexes). The most common neurocognitive
profile approximates that seen in vascular NCD.
Intermediate-duration NCD induced by drugs with central nervous system depressant effects may manifest with added symptoms of increased irritability, anxiety, sleep disturbance, and dysphoria. Intermediate-duration NCD induced by stimulant drugs may manifest with rebound depression, hypersomnia, and apathy. In severe forms of substance/medicationinduced major NCD (e.g., associated with long-term alcohol use), there may be prominent neuromotor features, such as incoordination, ataxia, and motor slowing. There may also be loss of emotional control, including aggressive or inappropriate affect, or apathy.
The prevalence of these conditions is not known. Prevalence figures for substance abuse are
available, and substance/medication-induced major or mild NCDs are more likely in those
who are older, have longer use, and have other risk factors such as nutritional deficits.
For alcohol abuse, the rate of mild NCD of intermediate duration is approximately 30%-
40% in the first 2 months of abstinence. Mild NCD may persist, particularly in those who do
not achieve stable abstinence until after age 50 years. Major NCD is rare and may result from
concomitant nutritional deficits, as in alcohol-induced amnestic confabulatory NCD.
For individuals quitting cocaine, methamphetamine, opioids, phencyclidine, and sedative,
hypnotics, or anxiolytics, substance/medication-induced mild NCD of intermediate
duration may occur in one-third or more, and there is some evidence that these substances
may also be associated with persistent mild NCD. Major NCD associated with these substances
is rare, if it occurs at all. In the case of methamphetamine, cerebrovascular disease
can also occur, resulting in diffuse or focal brain injury that can be of mild or major neurocognitive
levels. Solvent exposure has been linked to both major and mild NCD of both
intermediate and persistent duration.
The presence of NCD induced by cannabis and various hallucinogens is controversial.
With cannabis, intoxication is accompanied by various neurocognitive disturbances, but
these tend to clear with abstinence.
The functional consequences of substance/medication-induced mild NCD are sometimes augmented by reduced cognitive efficiency and difficulty concentrating beyond that seen in many other NCDs. In addition, at both major and mild levels, substance/medicationinduced NCDs may have associated motor syndromes that increase the level of functional impairment.
HIV disease is caused by infection with human immunodeficiency virus type-1 (HIV-1), which is acquired through exposure to bodily fluids of an infected person through injection drug use, unprotected sexual contact, or accidental or iatrogenic exposure (e.g., contaminated blood supply, needle puncture injury to medical personnel). HIV infects several types of cells, most particularly immune cells. Over time, the infection can cause severe depletion of "T-helper" (CD4) lymphocytes, resulting in severe immunocompromise, often leading to opportunistic infections and neoplasms. This advanced form of HIV infection is termed acquired immune deficiency syndrome (AIDS). Diagnosis of HIV is confirmed by established laboratory methods such as enzyme-linked immunosorbent assay for HIV antibody with Western blot confirmation and/or polymerase chain reaction-based assays for HIV. Some individuals with HIV infection develop an NCD, which generally shows a "subcortical pattern" with prominently impaired executive function, slowing of processing speed, problems with more demanding attentional tasks, and difficulty in learning new information, but fewer problems with recall of learned information. In major NCD, slowing may be prominent. Language difficulties, such as aphasia, are uncommon, although reductions in fluency may be observed. HIV pathogenic processes can affect any part of the brain; therefore, other patterns are possible.
Major or mild NCD due to HIV infection is usually more prevalent in individuals with prior episodes of severe immunosuppression, high viral loads in the cerebrospinal fluid, and indicators of advanced HIV disease such as anemia and hypoalbuminemia. Individuals with advanced NCD may experience prominent neuromotor features such as severe incoordination, ataxia, and motor slowing. There may be loss of emotional control, including aggressive or inappropriate affect or apathy.
Depending on stage of HIV disease, approximately one-third to over one-half of HIVinfected individuals have at least mild neurocognitive disturbance, but some of these disturbances may not meet the full criteria for mild NCD. An estimated 25% of individuals with HIV will have signs and symptoms that meet criteria for mild NCD, and in fewer than 5% would criteria for major NCD be met.
Functional consequences of major or mild NCD due to HIV infection are variable across individuals. Thus, impaired executive abilities and slowed information processing may substantially interfere with the complex disease management decisions required for adherence to the combined antiretroviral therapy regimen. The likelihood of comorbid disease may further create functional challenges.
The classification of major or mild neurocognitive disorder (NCD) due to prion disease includes NCDs due to a group of subacute spongiform encephalopathies (including Creutzfeldt- Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Straussler- Scheinker syndrome, and fatal insomnia) caused by transmissible agents known as prions. The most common type is sporadic Creutzfeldt-Jakob disease, typically referred to as Creutzfeldt-Jakob disease (CJD). Variant CJD is much rarer and is associated with transmission of bovine spongiform encephalopathy, also called "mad cow disease." Typically, individuals with CJD present with neurocognitive deficits, ataxia, and abnormal movements such as myoclonus, chorea, or dystonia; a startle reflex is also common. Typically, the history reveals rapid progression to major NCD over as little as 6 months, and thus the disorder is typically seen only at the major level. However, many individuals with the disorder may have atypical presentations, and the disease can be confirmed only by biopsy or at autopsy. Individuals with variant CJD may present with a greater preponderance of psychiatric symptoms, characterized a by low mood, withdrawal, and anxiety. Prion disease is typically not diagnosed without at least one of the characteristic biomarker features: recognized lesions on magnetic resonance imaging with DWI (diffusion-weighted imaging) or FLAIR (fluid-attenuated inversion recovery), tau or 14-3-3 protein in cerebrospinal fluid, characteristic triphasic waves on electroencephalogram, or, for rare familial forms, family history or genetic testing.
The annual incidence of sporadic CJD is approximately one or two cases per million people. Prevalence is unknown but very low given the short survival.
The essential feature of major or mild neurocognitive disorder (NCD) due to Parkinson's disease is cognitive decline following the onset of Parkinson's disease. The disturbance must occur in the setting of established Parkinson's disease (Criterion B), and deficits must have developed gradually (Criterion C). The NCD is viewed as probably due to Parkinson's disease when there is no evidence of another disorder that might be contributing to the cognitive decline and when the Parkinson's disease clearly precedes onset of the NCD. The NCD is considered possibly due to Parkinson's disease either when there is no evidence of another disorder that might be contributing to the cognitive decline or when the Parkinson's disease precedes onset of the NCD, but not both.
Frequently present features include apathy, depressed mood, anxious mood, hallucinations, delusions, personality changes, rapid eye movement sleep behavior disorder, and excessive daytime sleepiness.
The prevalence of Parkinson's disease in the United States steadily increases with age from approximately 0.5% between ages 65 and 69 to 3% at age 85 years and older. Parkinson's disease is more common in males than in females. Among individuals with Parkinson's disease, as many as 75% will develop a major NCD sometime in the course of their disease. The prevalence of mild NCD in Parkinson's disease has been estimated at 27%.
Progressive cognitive impairment is a core feature of Huntington's disease, with early changes in executive function (i.e., processing speed, organization, and planning) rather than learning and memory. Cognitive and associated behavioral changes often precede the emergence of the typical motor abnormalities of bradykinesia (i.e., slowing of voluntary movement) and chorea (i.e., involuntary jerking movements). A diagnosis of definite Huntington's disease is given in the presence of unequivocal, extrapyramidal motor abnormalities in an individual with either a family history of Huntington's disease or genetic testing showing a CAG trinucleotide repeat expansion in the HIT gene, located on chromosome 4.
Depression, irritability, anxiety, obsessive-compulsive symptoms, and apathy are frequently, and psychosis more rarely, associated with Huntington's disease and often precede the onset of motor symptoms.
Neurocognitive deficits are an eventual outcome of Huntington's disease; the worldwide prevalence is estimated to be 2.7 per 100,000. The prevalence of Huntington's disease in North America, Europe, and Australia is 5.7 per 100,000, with a much lower prevalence of 0.40 per 100,000 in Asia.
In the prodromal phase of illness and at early diagnosis, occupational decline is most common, with most individuals reporting some loss of ability to engage in their typical work. The emotional, behavioral, and cognitive aspects of Huntington's disease, such as disinhibition and personality changes, are highly associated with functional decline. Cognitive deficits that contribute most to functional decline may include speed of processing, initiation, and attention rather than memory impairment. Given that Huntington's disease onset occurs in productive years of life, it may have a very disruptive effect on performance in the work setting as well as social and family life. As the disease progresses, disability from problems such as impaired gait, dysarthria, and impulsive or irritable behaviors may substantially add to the level of impairment and daily care needs, over and above the care needs attributable to the cognitive decline. Severe choreic movements may substantially interfere with provision of care such as bathing, dressing, and toileting.