24/12/21 13:25 Evaluation of cognitive impairment and dementia - UpToDate

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Evaluation of cognitive impairment and dementia

Author: Eric B Larson, MD, MPH
Section Editors: Steven T DeKosky, MD, FAAN, FACP, FANA, Kenneth E Schmader, MD
Deputy Editor: Janet L Wilterdink, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2021. | This topic last updated: May 03, 2019.

INTRODUCTION

Dementia is a disorder that is characterized by a decline in cognition involving one or more

cognitive domains (learning and memory, language, executive function, complex attention,
perceptual-motor, social cognition) [1]. The deficits must represent a decline from previous level
of function and be severe enough to interfere with daily function and independence. The most
common form of dementia in older adults is Alzheimer disease (AD), accounting for 60 to 80
percent of cases.

Mild cognitive impairment (MCI) is an intermediate clinical state between normal cognition and
dementia. While specific subtle changes in cognition can occur in normal aging, MCI can also be
a precursor to dementia [1]. At the same time, MCI may also represent a reversible condition in
the setting of depression, as a complication of certain medications, or during the recovery from
an acute illness.

As the population ages, the overall burden of dementia is increasing worldwide. With an aging
population and growing awareness of AD and other late-life dementias, clinicians should be
equipped to test for cognitive impairment and ask about functional decline to avoid failure to
recognize cases of AD and related dementias. Clinicians will need to accurately diagnose and
manage the early cognitive manifestations of AD and other dementias.

This topic will discuss the evaluation of patients with cognitive impairment and dementia.
Recommendations for the evaluation of cognitive impairment and dementia are derived from
our clinical experience as well as from the American Academy of Neurology (AAN) practice
guidelines [2,3].
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The clinical, diagnostic, and pathologic aspects of specific dementia syndromes and the
treatment, risk factors, and prevention of dementia are discussed separately:

● (See "Clinical features and diagnosis of Alzheimer disease".)

● (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

● (See "Clinical features and diagnosis of dementia with Lewy bodies".)

● (See "Frontotemporal dementia: Clinical features and diagnosis".)

● (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment".)

● (See "Treatment of Alzheimer disease".)

● (See "Risk factors for cognitive decline and dementia".)

● (See "Prevention of dementia".)

CAUSES

Most dementia is caused by a neurodegenerative disease; these produce broadly overlapping

clinical syndromes, albeit with some distinctive features. (See 'Dementia syndromes' below.)

The most common neurodegenerative conditions causing dementia are [4-6]:

● Alzheimer disease (AD) (see "Clinical features and diagnosis of Alzheimer disease")

● Dementia with Lewy bodies (DLB) (see "Clinical features and diagnosis of dementia with
Lewy bodies")

● Frontotemporal dementia (FTD) (see "Frontotemporal dementia: Clinical features and

diagnosis")

● Parkinson disease dementia (PDD) (see "Cognitive impairment and dementia in Parkinson
disease")

Less common neurodegenerative disorders such as progressive supranuclear palsy (PSP),

corticobasal degeneration (CBD), multisystem atrophy, and Huntington disease can also be
associated with dementia. (See "Progressive supranuclear palsy (PSP): Clinical features and
diagnosis" and "Corticobasal degeneration" and "Multiple system atrophy: Clinical features and
diagnosis" and "Huntington disease: Clinical features and diagnosis".)

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Non-neurodegenerative dementias may be reversible, or progression slowed or halted, if the

underlying cause can be identified and adequately treated [7]. The most common of these is:

● Vascular dementia (see "Etiology, clinical manifestations, and diagnosis of vascular

dementia")

Most older adult patients with chronic dementia have AD (approximately 60 to 80 percent), and
many of these patients also have concomitant cerebrovascular disease. The prevalence of
vascular dementia and vascular cognitive impairment (VCI) is relatively high in black patients,
hypertensive persons, and patients with diabetes; some of the reversible dementias (eg,
metabolic dementias) tend to occur in younger individuals. DLB may be as prevalent as vascular
dementia in older cohorts of patients [8]. FTD is less common than AD or vascular dementia.

Dementia may have more than one cause, particularly as the condition progresses and
especially in older persons. In addition, medical illnesses and comorbidities exacerbating poor
cognition are common in older adult patients with dementia; examples include chronic diseases
such as congestive heart failure and renal insufficiency, as well as the effects of
antihistaminergic and anticholinergic medications.

● Mixed dementia refers to the coexistence of more than one dementia-producing

pathology, most commonly AD and vascular dementia.

Less common etiologies include alcohol-related dementia, chronic traumatic encephalopathy,

normal pressure hydrocephalus (NPH), chronic subdural hematoma, and other central nervous
system (CNS) illnesses (eg, prion diseases, HIV infection):

● (See "Overview of the chronic neurologic complications of alcohol".)

● (See "Sequelae of mild traumatic brain injury", section on 'Chronic traumatic

encephalopathy'.)

● (See "Creutzfeldt-Jakob disease".)

● (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and

diagnosis".)

● (See "Normal pressure hydrocephalus".)

● (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

● (See "Copper deficiency myeloneuropathy".)

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● (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".)

CLINICAL PRESENTATION

Dementia syndromes — Most patients with dementia do not present with a self-complaint of
memory loss; it is often a spouse or other informant who brings the problem to the clinician's
attention. Self-reported memory loss does not appear to correlate with the subsequent
development of dementia, while informant-reported memory loss is a much better predictor of
the current presence and future development of dementia [9,10]. Nevertheless, family
members are often delayed in recognizing the signs of dementia, many of which are
inaccurately ascribed to aging.

An essential aspect of dementia is that the cognitive impairment represents a change from
baseline. With most of the dementia syndromes, the change is gradual and progresses over
time; however, that aspect may not be appreciated by family members. By the time the patient
has stopped driving or managing finances, subtle but worsening clinical manifestations have
often been present for at least a few years.

Forgetfulness is the most common chief complaint; in addition, patients with dementia also
have difficulty with one or more of the following [11]:

● Retaining new information (eg, trouble remembering events)

● Handling complex tasks (eg, balancing a checkbook)
● Reasoning (eg, unable to cope with unexpected events)
● Spatial ability and orientation (eg, getting lost in familiar places)
● Language (eg, word finding)
● Behavior

Alzheimer disease (AD) and vascular dementia comprise the majority of cases such that in the
absence of other compelling anomalies, these are often diagnosed presumptively (see 'Making
a presumptive diagnosis' below). Their clinical syndromes, however, are somewhat nonspecific:

● Alzheimer disease occurs in older adults, typically older than 65 years and with increasing
incidence and prevalence over the next two decades, with memory impairment as the
most common initial symptom. Other common early features are impaired executive
function and reduced insight. Behavioral and psychologic symptoms, apraxia, and sleep
disturbance become more common as the disease progresses. (See "Clinical features and
diagnosis of Alzheimer disease".)

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● Vascular dementia or vascular cognitive impairment (VCI), particularly that associated

with arteriolosclerotic small vessel disease, has a cognitive profile that is characterized by
prominent impairments in executive function and processing speed. A step-wise
progression in association with recognized or unrecognized strokes is characteristic, but a
more gradual progression is also reported, not infrequently with concomitant AD. In many
cases, a clinically diagnosed stroke appears to initiate the onset of what has been called
poststroke dementia. Signs and symptoms related to diagnosed or undiagnosed stroke
may also be present. Brain magnetic resonance imaging (MRI) will show evidence of
vascular disease; however, the extent of changes does not clearly correlate with the
severity of dementia and its poststroke progressive course. (See "Etiology, clinical
manifestations, and diagnosis of vascular dementia".)

Different causes of dementia present with different patterns of cognitive impairment in

association with other neurologic manifestations. These differences are not always easy to
distinguish, particularly in the very early stages of illness. Very late in the disease course, when
patients are very disabled, the syndromes are also not easily distinguishable.

Conditions that include parkinsonism (tremor, bradykinesia, rigidity, and/or postural instability)
along with dementia include:

● Lewy body dementia and Parkinson disease dementia – Lewy body diseases (eg,
Parkinson disease, dementia with Lewy bodies [DLB]) produce a gradual, progressive
decline in cognitive abilities with motor parkinsonism. The presence of rapid eye
movement (REM) sleep behavior disorder, visual hallucinations, fluctuations in level of
alertness, and prominent visuospatial dysfunction favor DLB as the cause of or contributor
to the dementia. Notably, the dementia of Parkinson disease emerges five to eight years
after the onset of the movement disorder, whereas DLB manifests parkinsonism and
cognitive decline contemporaneously. (See "Clinical features and diagnosis of dementia
with Lewy bodies" and "Cognitive impairment and dementia in Parkinson disease".)

● Progressive supranuclear palsy – Progressive supranuclear palsy (PSP) is a rare disease

that includes dementia and parkinsonism. Distinctive early features of this disorder
include vertical supranuclear gaze palsy, especially diminished downgaze, and prominent
postural instability with falls. Behavioral changes including apathy, disinhibition,
dysphoria, and anxiety are common. (See "Progressive supranuclear palsy (PSP): Clinical
features and diagnosis".)

● Multiple system atrophy – An umbrella term for olivopontocerebellar atrophy,

striatonigral degeneration, and Shy-Drager syndrome, multiple system atrophy (MSA)

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commonly presents with parkinsonism. Other features can include dysautonomia,

cerebellar ataxia, and corticospinal tract deficits. (See "Multiple system atrophy: Clinical
features and diagnosis".)

● Corticobasal degeneration (CBD) – Patients with this condition can manifest asymmetric
parkinsonism along with cognitive impairment. More distinctive features can include
ideomotor apraxia, alien limb phenomenon, aphasia, and loss of cortical sensory function.
Absence of tremor is typical for CBD. (See "Corticobasal degeneration".)

Less common clinical syndromes with relatively distinctive clinical features include:

● Normal pressure hydrocephalus (NPH) produces decline in cognition, slowed gait, and
urinary incontinence. The classic gait sign in NPH is an apraxic, wide-based "magnetic"
gait. (See "Normal pressure hydrocephalus" and "Normal pressure hydrocephalus",
section on 'Clinical features'.)

● Creutzfeldt-Jakob disease (CJD) is a rare but rapidly progressive dementia that produces
prominent behavioral and sleep abnormalities early on. Myoclonus and cerebellar deficits
are also common features. (See "Creutzfeldt-Jakob disease", section on 'Clinical features'.)

Other rapidly progressive dementia syndromes are discussed separately. (See

"Creutzfeldt-Jakob disease", section on 'Differential diagnosis'.)

Dementia mimics — The normal cognitive decline associated with aging consists primarily of
mild changes in memory and rate of information processing. Features that distinguish normal
aging from dementia include that deficits are generally not very progressive and usually do not
affect daily function. In a study of 161 community-dwelling, cognitively normal individuals ages
62 to 100 years, learning or acquisition performance declined uniformly with increasing age
[12]. By contrast, delayed recall or forgetting remained relatively stable. Similarly, a second
report found that aging was associated with decline in learning of new information but not in
memory retention [13].

Mild cognitive impairment (MCI) is an intermediate category in which the severity of cognitive
change appears worse than expected for normal aging but does not meet criteria for dementia.
Its presence indicates a greater risk of progression to dementia, but it may also be stable and
not progress or even revert to normal. (See 'Mild cognitive impairment' below and "Mild
cognitive impairment: Epidemiology, pathology, and clinical assessment".)

Cognitive impairment related to dementia must be distinguished from delirium and depression
( table 1) [14].

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● Delirium is usually acute or subacute in onset and is associated with a clouding of the
sensorium; patients have fluctuations in their level of consciousness and have difficulty
maintaining attention and concentration ( table 2). Delirium and dementia can co-occur,
making the distinction difficult and sometimes impossible in acute presentations. (See
"Diagnosis of delirium and confusional states".)

● Patients with depression are often more likely to complain about memory loss than those
with dementia; the latter are frequently brought to clinicians by their families, while
depressed patients often present by themselves. The presentation of depression as
dementia has been called "pseudodementia" or, more recently, "dementia of depression."
Patients with depression may have signs of psychomotor slowing and give poor effort on
testing ("I just can't do this"), while those with dementia often try hard but respond with
incorrect answers. It is important to ask the test administrator to estimate the effort given
by the patient. It is also important to realize that depression and dementia may occur in
the same patient and that patients with dementia present with depression as a presenting
complaint. (See "Diagnosis and management of late-life unipolar depression" and
"Unipolar depression in adults: Clinical features", section on 'Symptoms'.)

EVALUATION

A full dementia evaluation probably cannot be completed in a routine 30-minute visit; adequate
time should be arranged in a follow-up appointment. A family member or close friend familiar
with the patient should accompany them to the visits to present symptoms they have seen and
remember what the patient is told. The initial step at the follow-up visit is an assessment of
cognitive function. This should be followed by a complete physical examination, including
neurologic examination. The subsequent work-up may include laboratory and imaging studies
[15,16]. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and
Fifth Edition (DSM-5) criteria for the diagnosis of dementia (major neurocognitive disorder) are
shown in the table ( table 3).

Screening for dementia — The US Preventive Services Task Force (USPSTF) has concluded that
there is insufficient evidence to recommend for or against routine screening for dementia in
older adults [17,18]. Similarly, the American Academy of Neurology (AAN) and the Canadian
Task Force on Preventive Health Care either do not endorse screening or recommend against it
in asymptomatic adults.

We do not routinely screen asymptomatic older adults for cognitive impairment. However,
observed cognitive difficulty in a patient encounter and family or patient concerns for memory

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and cognition require thorough evaluation.

History — Family members or someone who knows the patient well must be available to give
an adequate history of cognitive and behavioral changes [5]. A drug history is particularly
important; use of drugs (including nonprescription) that impair cognition (eg, analgesics,
anticholinergics, psychotropic medications, and sedative-hypnotics) should be sought (
table 4) [19,20]. The customary medical, psychiatric, and social histories also provide relevant
information.

Patients and informants are often uncertain about the onset of symptoms since the appearance
of dementia is insidious. Useful questions for the patient and informant are, "When did you first
notice the memory loss?" and "How has the memory loss progressed since then?" By the time
the patient has stopped driving or managing finances, the disease has often been present for a
few years.

An assessment of daily activities also provides evidence of impairment, particularly in the

context of what the patient had done previously, at their baseline. Work and education history
help establish baseline; their current participation in handling finances, community and social
activities, driving, and other household tasks helps assess current performance.

The clinical interview also allows the examiner to establish rapport with the patient. The
comfort level established during the interview may lessen the frequency and severity of any
subsequent test and performance anxiety that may be engendered by explicit testing. Family
members should be present at both examination and follow-up. When explaining findings, it is
important to make eye contact with and speak directly to the patient, and avoid speaking to the
family directly. Asking the family members to "please listen carefully while I talk to [the patient]"
will let them know that the information is for them as well.

Questions guided by the differential diagnosis are also helpful, including loss of vision or motor
function, tremor, poor balance, falls, difficulty walking, urinary incontinence, prominent
personality changes, behavioral disturbances, visual hallucinations, abnormal sleep, and
excessive alcohol use. (See 'Dementia mimics' above and 'Identifying the underlying disease'
below.)

Cognitive testing — Patients with cognitive complaints should undergo a careful mental status
examination. Cognitive and behavioral assessments are designed to distinguish normal and
abnormal performance arising across a range of different conditions. They can be divided into
three levels of rigor: screening tools such as the Mini-Mental State Examination (MMSE), an
extended mental status examination, and formal neuropsychological testing. The scope of the

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evaluation should be guided by the complaints brought forward by the patient or family
member.

The MMSE, Montreal Cognitive Assessment (MoCA), and other brief screening tests for
dementia have a pooled sensitivity of 75 to 92 percent and a specificity of 81 to 91 percent [21].
Typically, these assess a broad range of cognitive domains but do not include an assessment of
mood or thought content. These assessments are discussed in detail separately. (See "Mental
status scales to evaluate cognition".)

More detailed mental status testing is often warranted, for example, when the results from a
screening assessment appear at odds with the history and when observed deficits are uncertain
because of a language barrier, physical handicap, or level of education. An extended bedside
evaluation of mental status is described separately. (See "The mental status examination in
adults".)

Both altered mood and abnormal thought content have a strong impact on cognitive function;
thus, such an assessment should always accompany a brief screening evaluation for dementia.
(See "The mental status examination in adults", section on 'Mood and thought content' and
'Screening for depression' below.)

The diagnosis of dementia cannot be made solely on the basis of a low score on one of these
assessments; these tests help to quantify the types and severity of impairment, but the most
important part of the diagnostic evaluation is a detailed history including the perspective of an
informant (eg, spouse or adult child), interviewed separately from the patient if possible.
Agreement between the history and the mental status examination is strongly suggestive of the
diagnosis of dementia. When the history suggests cognitive impairment but the mental status
examination is normal, possible explanations include mild dementia, high intelligence or
education, depression, or, rarely, misrepresentation on the part of the informants [22].
Conversely, when the mental status examination suggests cognitive impairment but the family
and patient deny any problems, possible explanations include an acute confusional state, very
low intelligence or education, or inadequate recognition by the family [22]. For some, the
diagnosis of dementia is regarded as shameful, and reluctance to recognize or acknowledge the
problem must be addressed.

Neuropsychological assessment (psychometric testing) may be useful in difficult situations;

repeated clinical assessments over time (eg, 9 to 12 months) are often the most helpful tool.

Screening for depression — All patients being evaluated for cognitive impairment or dementia
should be screened for depression. Cognitive impairment may be the chief complaint in a
patient with depression. Depression can also worsen cognitive impairment in patients with
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dementia or mild cognitive impairment (MCI). It is not uncommon for a depressed person to
literally elicit a depressed feeling in the clinician examining that patient.

Several screening tools have been validated in this setting. One, the Patient Health
Questionnaire 2, consists of just two questions ( table 5). This and other screening tools are
described in detail separately. (See "Diagnosis and management of late-life unipolar
depression", section on 'Screening instruments'.)

Physical examination — A thorough general physical examination to rule out an atypical

presentation of a medical illness should be combined with a neurologic examination. The latter
should focus upon focal neurologic deficits that may be consistent with prior strokes,
parkinsonism (eg, cogwheel rigidity and/or tremors), gait abnormalities or slowing, and eye
movements. In comparison, patients with Alzheimer disease (AD) generally have no motor or
sensory deficits at presentation. (See 'Dementia syndromes' above.)

This examination, along with the medical and neurologic history, will allow tailoring of further
testing.

Laboratory testing — We suggest limited laboratory testing in most patients being evaluated
for cognitive impairment and dementia.

● The AAN recommends screening for B12 deficiency (serum vitamin B12 level, complete
blood count) and hypothyroidism (serum thyroid-stimulating hormone [TSH]) in patients
with dementia [2]. Limited data suggest that treating deficiencies may improve cognition.
(See "Neurologic manifestations of hypothyroidism", section on 'Cognitive impairment and
dementia' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency",
section on 'Laboratory testing' and "Treatment of vitamin B12 and folate deficiencies",
section on 'Treatment of vitamin B12 deficiency'.)

● Screening for neurosyphilis is not recommended unless there is a high clinical suspicion
based on sexual history or travel to areas where exposure may be more common;
screening for HIV may also be appropriate in this subgroup of patients. (See
"Neurosyphilis", section on 'Unknown syphilis history' and "HIV-associated neurocognitive
disorders: Epidemiology, clinical manifestations, and diagnosis".)

● We do not order other laboratory tests unless there is a specific suspicion for abnormality.
As an example, some specialized tests can be tailored to patients with a compatible history
(eg, red blood cell folate in a patient with alcoholism, or ionized serum calcium in a patient
with multiple myeloma, prostate cancer, or breast cancer). There are no clear data to

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support or refute ordering "routine" laboratory studies such as electrolytes, glucose, and
renal and liver function tests.

An exception is a patient with a presentation that is possibly acute or subacute in whom

delirium may be the cause of or a contributor to the clinical picture (see 'Dementia mimics'
above). The evaluation of a patient with delirium is discussed separately. (See "Diagnosis
of delirium and confusional states", section on 'Diagnostic tests'.)

The cost effectiveness of obtaining multiple laboratory studies routinely in all patients is
questioned because the yield is low [23]. The prevalence of reversible dementia has fallen since
1972. In a 1994 study, this was less than 1 percent, and in a 2006 community-based series, none
of the 560 patients with dementia screened had a treatable metabolic cause [23,24].

Neuroimaging

Indications — Neuroimaging with a head computed tomography (CT) or magnetic resonance

imaging (MRI) scan is unequivocally indicated in patients with acute onset of cognitive
impairment and/or rapid neurologic deterioration. Neuroimaging is also indicated when there
are historical features or findings on physical examination suggestive of a subdural hematoma,
thrombotic stroke, or cerebral hemorrhage [25].

The more routine use of neuroimaging in patients with dementia is controversial. Many
published guidelines on the clinical evaluation of dementia do not recommend imaging studies
routinely, but include clinical prediction rules to identify patients who might have reversible
causes of dementia that can be diagnosed with imaging studies (eg, subdural hematoma,
normal pressure hydrocephalus [NPH], treatable cancer) [2,24,26-32]. The prediction rules vary,
including factors such as younger age (<60 years), focal signs, and short duration of symptoms
(less than two years), among others. However, the sensitivity and specificity of these prediction
rules are low [33].

By contrast, the AAN recommends structural neuroimaging with either a noncontrast head CT
or MRI in the routine initial evaluation of all patients with dementia [2].

Our practice is to order imaging when patients present with unusual or atypical findings or
when imaging findings may be reassuring for patients and families. Such differences in practice
may be attributable to the context in which the patient is seen. Neurologists, who may only see
a person once or for a very limited time period, will usually obtain imaging on a patient referred
from primary care, whereas a primary care clinician who has the advantage of serial
observations over time in patients known to them may order imaging studies more selectively.

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Some families will request imaging studies; we generally honor such requests after explanation
of the limited yield of such studies.

Serial imaging is not informative unless there is an unexpected clinical change, such as abrupt
mental status changes without a readily identified cause, new focal neurologic findings, or
seizure.

Preferred modality — In most cases, MRI is preferred over CT because it is more sensitive for
a broad range of potential pathologies while avoiding exposure to potentially harmful ionizing
radiation. (See "Radiation-related risks of imaging".)

A CT scan is the best option when the patient is too claustrophobic for an MRI, has a pacemaker
or ferromagnetic implants, or is unable to remain still enough to undergo the more time-
consuming MRI. CT scans are generally less costly than MRI and may be preferable in the
acute/emergency care situation when extra-axial or intraparenchymal hemorrhage must be
ruled out quickly and/or when agitation mandates very short scanning times.

Patients who are anxious or restless can be sedated for structural imaging studies, if need be,
since there is little potential for sedatives to interfere with these imaging results.

While intravenous contrast agents highlight acute stroke, expanding neoplasms, certain brain
infections, and localized inflammation, noncontrast brain imaging is sufficient for the routine
evaluation of patients with suspected neurodegenerative dementia. Intravenous contrast poses
risks of allergic reactions and impaired renal function and is generally reserved for patients with
unexplained focal central neurologic findings or in whom there is a suspicion of neoplasm or
central nervous system (CNS) infection.

Findings — Structural imaging findings can assist in the primary diagnosis of dementia or
suggest the presence of comorbidities that may exacerbate dementia symptoms.

Structural imaging findings in specific types of dementia are discussed in more detail
elsewhere. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on
'Indicative biomarkers' and "Clinical features and diagnosis of Alzheimer disease", section on
'Neuroimaging' and "Frontotemporal dementia: Clinical features and diagnosis".)

Some of the more common findings of structural brain imaging that have relevance to
dementia are:

● Cerebral atrophy – Cerebral atrophy is common in patients with neurodegenerative

dementia but also in normal aging. Atrophy may be generalized or regionally localized.

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Cortical atrophy is manifested by widening of sulci, narrowing of gyri, decreased grey

matter thickness, diminished white matter volume, and/or enlargement of the cerebral
ventricles and subarachnoid spaces. Atrophy must be interpreted relative to the patient's
age and other factors. Normal brain aging is associated with some of the same changes,
although typically age-related atrophy is less rapid, and usually less severe, than that of
neurodegenerative disease. It is estimated that the brain loses approximately 0.5 percent
of its volume each year in normal aging, compared with 1 to 2 percent in MCI and 2 to 4
percent in dementia due to AD [34].

Certain regions of the brain show selective vulnerability to different neurodegenerative

disorders. This results in distinctive clinical presentations and characteristic atrophy
patterns visible on brain imaging ( table 6). Asymmetric cortical atrophy is often
observed in neurodegenerative dementias and sometimes manifests as disproportionate
impairments in the functions mediated by the more atrophic regions. A number of other
rare disorders with circumscribed cortical atrophy syndromes have also been described
[35].

Hippocampal atrophy can be one of the earliest and most salient manifestations of AD. It
can be appreciated by visual inspection of volumetric T1 images sliced in coronal planes
perpendicular to the long axis of the hippocampus. Hippocampal atrophy supports the
diagnosis of AD but also occurs in mesial temporal sclerosis, temporal lobe epilepsy, and
certain vascular insults and should not be considered pathognomonic of AD. (See "Clinical
features and diagnosis of Alzheimer disease", section on 'Neuroimaging'.)

● Ventriculomegaly – Ventricular enlargement may occur in association with cortical

atrophy and without evidence of obstruction; this is often referred to as hydrocephalus ex
vacuo. Alternatively, ventricular enlargement may occur in association with NPH. NPH is a
potentially treatable cause of dementia that typically presents as the symptomatic triad of
dementia, incontinence, and gait disturbance. NPH may be due to a variety of causes,
including disturbances of cerebrospinal fluid (CSF) production and circulation [36]. (See
"Normal pressure hydrocephalus", section on 'Pathophysiology'.)

Either CT or MRI can readily document ventricular enlargement, but it is somewhat more
challenging to determine whether the enlargement is explained by or disproportionate to
the degree of cerebral atrophy ( image 1). This assessment is discussed in more detail
separately. (See "Normal pressure hydrocephalus", section on 'Magnetic resonance
imaging'.)

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● Ischemic cerebrovascular disease – Imaging manifestations of cerebrovascular disease

include focal areas of infarction and diffuse white matter ischemic changes, sometimes
called leukoaraiosis.

Cerebrovascular disease can cause cognitive impairment and dementia. The increasing
prevalence of white matter ischemic changes with advancing age has been implicated as
one of the factors responsible for age-related cognitive decline. Most forms of vascular
cognitive impairment (VCI) manifest visible alterations on structural brain imaging studies.
Neuroimaging findings are a required element of some of the commonly used diagnostic
criteria for vascular dementia, including the National Institute of Neurological Disorders
and Stroke and the Association Internationale pour la Recherche et l’Enseignement
Neurosciences (NINDS-AIREN) criteria ( table 7) [37].

Although CT can readily identify frank infarction and moderate to severe subcortical
ischemic changes, MRI is more sensitive to chronic cerebrovascular changes. Common
MRI findings associated with vascular dementia include cortical and subcortical infarctions
and periventricular white matter lesions. Since the incidence of ischemic changes is
increased with aging in the absence of dementia as well as in diseases such as AD, these
findings do not necessarily indicate a vascular etiology for the patient's dementia. (See
"Etiology, clinical manifestations, and diagnosis of vascular dementia", section on
'Neuroimaging' and "Etiology, clinical manifestations, and diagnosis of vascular dementia",
section on 'Diagnosis'.)

● Microhemorrhages – Cerebral microhemorrhages can be observed with vascular

anomalies, cerebral amyloid angiopathy (CAA; occurs in the vast majority of AD patients),
or hypertensive microangiopathy.

Microhemorrhages are best detected by gradient echo MRI pulse sequences and with
higher-sensitivity susceptibility-weighted imaging (SWI) ( image 2). In population-based
studies, cerebral microhemorrhages are detected in approximately 15 to 25 percent of
older individuals and become more common with advancing age [38,39].

Microhemorrhages associated with CAA are primarily in the cerebral cortex, whereas
those associated with hypertension typically occur in the basal ganglia, thalamus, or pons
[40]. CAA can occur in subjects without dementia but has an increased prevalence in
patients with AD [41]. (See "Cerebral amyloid angiopathy", section on 'Pathogenesis'.)

MAKING A PRESUMPTIVE DIAGNOSIS

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Criteria for dementia — Although a number of definitions exist for dementia, the Diagnostic
and Statistical Manual of Mental Disorders (DSM) definition provides a reasonable framework
for the concept of dementia in clinical practice. According to DSM-5, the criteria for dementia
(called major neurocognitive disorder) include the following [1]:

● Evidence from the history and clinical assessment that indicates significant cognitive
impairment in at least one of the following cognitive domains:

• Learning and memory

• Language
• Executive function
• Complex attention
• Perceptual-motor function
• Social cognition

● The impairment must be acquired and represent a significant decline from a previous level
of functioning

● The cognitive deficits must interfere with independence in everyday activities

● The disturbances are not occurring exclusively during the course of delirium

● The disturbances are not better accounted for by another mental disorder (eg, major
depressive disorder, schizophrenia)

The DSM-5 definition differs substantively from prior versions in that the cognitive domains
have been renamed and expanded to include social cognition and complex attention. While
previous DSM definitions of dementia listed memory as an essential feature for the diagnosis,
the centrality of memory dysfunction has been deemphasized in DSM-5, with all six cognitive
domains given equal weight in the criteria ( table 3). The change from DSM-IV to DSM-5
presumably reflects the problem that some individuals with dementia due to causes other than
Alzheimer disease (AD) did not meet definitional criteria because memory function was intact or
at least relatively intact compared with norms. That being said, for the most common forms of
dementia, memory and language dysfunction are generally always present.

Prior versions of the DSM definition have had good to very good reliability for the diagnosis of
dementia [2]. The performance of the DSM-5 criteria in relation to prior versions is not yet
known, but it is likely that the changes will have some impact on research and possibly clinical
practice in the future.

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The pretest probability of dementia and of various causes of dementia depends upon patient
characteristics such as age and race. Given that 5 percent of individuals over age 65 years and
35 to 50 percent of persons over age 85 years have dementia, the pretest probability of
dementia in an older person with verified memory loss is estimated to be at least 60 percent. By
contrast, subjective memory complaints are common and not predictive of dementia in
isolation.

Mild cognitive impairment — The diagnosis of mild cognitive impairment (MCI) is similar. MCI
is generally defined by the presence of memory difficulty greater than expected for age, and
objective memory impairment, but preserved ability to function in daily life. The same
exclusions (delirium, psychiatric disease) apply. A formal neuropsychiatric assessment might be
needed in order to make this diagnosis, given that the cognitive deficits are mild. After ruling
out medications or over-the-counter drugs that interfere with memory and ascertaining that
comorbid conditions (depression, congestive heart failure, etc) are not causing the amnestic
syndrome, there is often no imperative to make a formal diagnosis in most cases, as there are
no specific treatments. The diagnosis and management of MCI are discussed separately. (See
"Mild cognitive impairment: Epidemiology, pathology, and clinical assessment" and "Mild
cognitive impairment: Prognosis and treatment".)

Identifying the underlying disease — The bedside evaluation combined with historical
information from a reliable informant and, in selected patients, neuroimaging provides the
information needed to ascertain the likely cause of dementia in most patients [14]. As a
practical (albeit simplistic approach), a presumptive diagnosis of AD is made in most cases on
the basis of a typical clinical syndrome, with vascular dementia considered as an alternative or
contributor in the setting of known cerebrovascular or cardiovascular disease and/or risk
factors and/or suggestive neuroimaging findings (see 'Dementia syndromes' above). Clinical
pathologic studies suggest that this presumptive diagnosis will be incorrect in a significant
minority of patients; however, the absence of specific treatments for neurodegenerative
disorders means that such errors do not affect patient care.

When features atypical for AD predominate, particularly early in the disease course, other
diagnoses are often considered. As examples:

● Parkinsonism suggests dementia with Lewy bodies (DLB), Parkinson disease dementia
(PDD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and
multiple system atrophy (MSA). These conditions are reviewed briefly above and in more
detail in individual topic reviews. (See 'Dementia syndromes' above.)

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● Visual hallucinations and rapid eye movement (REM) sleep behavior disorder can be a
prominent early feature of DLB. (See "Clinical features and diagnosis of dementia with
Lewy bodies".)

● Behavioral abnormalities (including inappropriate behaviors and personality change)

suggest behavioral variant frontotemporal dementia (FTD). (See "Frontotemporal
dementia: Clinical features and diagnosis", section on 'Behavioral variant FTD'.)

● Aphasia out of proportion to memory impairment suggests primary progressive aphasia.

(See "Frontotemporal dementia: Clinical features and diagnosis", section on 'Primary
progressive aphasia'.)

● Gait impairment and urinary incontinence with dementia is the classic triad of normal
pressure hydrocephalus (NPH). In NPH, gait disturbance and urinary incontinence occur
early in the course of disease in patients who have less severe cognitive impairment; this
contrasts with other forms of dementia in which gait disturbance and incontinence are
common only in later stages. (See "Normal pressure hydrocephalus".)

● Rapidly progressive dementia and dementia in younger-age patients typically require

additional evaluation and are discussed in detail separately. (See "Early-onset dementia in
adults" and "Creutzfeldt-Jakob disease", section on 'Evaluation'.)

SPECIALIZED TESTING IN SELECTED PATIENTS

Patients with an atypical syndrome (eg, younger patients [<60 years] or those with rapidly
progressive dementia) may benefit from a more extensive evaluation that may include lumbar
puncture (LP), electroencephalography (EEG), and/or serologic tests ( table 8) [25,42]. These
evaluations are discussed separately. (See "Early-onset dementia in adults".)

Neuropsychological testing — Neuropsychological testing usually involves extensive

evaluation of multiple cognitive domains (eg, attention, orientation, executive function, verbal
memory, spatial memory, language, calculations, mental flexibility, and conceptualization).
Most patients do not require a full neuropsychological examination as part of an evaluation for
dementia; however, testing is useful when bedside cognitive testing is equivocal. (See 'Cognitive
testing' above.)

Most observational studies have demonstrated a relatively high sensitivity (80 to 98 percent)
and specificity (44 to 98 percent) for detection of dementia [3,43-49]. In a 2001 practice
parameter, the American Academy of Neurology (AAN) concluded that neuropsychological

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batteries are useful in identifying patients with dementia, particularly when administered to
those at higher risk by virtue of memory impairment [3]. Aggregate total score accurately
differentiated normal individuals from those with mild cognitive impairment (MCI) and
Alzheimer disease (AD) [50]. However, it is important to recognize that scores can also be
influenced by education and age and apply only to individuals whose primary language is
English [51].

In addition to its role in helping to discriminate between normal aging and dementia,
neuropsychological testing can identify patterns of deficits that suggest a particular cause of
dementia (eg, AD versus dementia with Lewy bodies [DLB]) [52]. However, no single item on the
panel has high discriminatory ability, and the pattern of performance on various domains must
be interpreted in conjunction with the history, neuroimaging studies, and other testing to arrive
at a presumptive etiologic diagnosis [53].

Follow-up testing or just serial observations generally provide more helpful information than a
single study, particularly when results are equivocal, in that evidence of decline can predict
future decline [54]. Perhaps the most important thing to remember is that AD is a progressive
disorder, as are most other causes of dementia, so unless a diagnosis is needed urgently (not
likely) observations over time have high diagnostic utility. (See "Mild cognitive impairment:
Epidemiology, pathology, and clinical assessment", section on 'Neuropsychological testing'.)

Genetic testing — Genetic testing for the apolipoprotein E epsilon 4 allele (which increases the
risk of developing AD) is not currently recommended [55], nor is genetic testing for other
potential causes of dementia (eg, specific mutations) unless there is a specific characteristic
family history obtained [2]. (See "Clinical features and diagnosis of Alzheimer disease", section
on 'Genetic testing' and "Frontotemporal dementia: Clinical features and diagnosis", section on
'Genetic testing'.)

The use of genetic testing for AD in patients with dementia is controversial because of the
potential for both false positives and false negatives. As an example, not all patients who are
homozygotes for the apolipoprotein E epsilon 4 allele will develop AD [56]. In addition, the lack
of specific treatments for these disorders makes this type of testing less imperative.

Advanced neuroimaging — The use of positron emission tomography (PET) imaging using
beta amyloid and other tracers, single-photon emission computed tomography (SPECT), and
other functional neuroimaging techniques to assist in the differential diagnosis of
neurodegenerative dementia is an area of ongoing evolution. They are utilized most frequently
by specialists assessing complex or unclear cases, and in research. (See "Frontotemporal
dementia: Clinical features and diagnosis" and "Clinical features and diagnosis of Alzheimer

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disease", section on 'Neuroimaging' and "Clinical features and diagnosis of dementia with Lewy
bodies".)

Lumbar puncture — The role of LP and cerebrospinal fluid (CSF) analysis in the evaluation of
dementia is primarily to identify infectious, inflammatory, or neoplastic processes. These are
unusual causes of dementia and also have unusual presentations. Thus, LP is typically
performed only in the setting of a rapidly progressive dementia, or in a younger patient, or as a
follow-up to another abnormality identified on clinical history (eg, HIV), examination, laboratory
testing (eg, abnormal syphilis serology), or neuroimaging (eg, meningeal enhancement). (See
"Early-onset dementia in adults", section on 'Lumbar puncture and other laboratories' and
"Neurosyphilis", section on 'Spinal fluid examination' and "HIV-associated neurocognitive
disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'CSF findings' and
"Creutzfeldt-Jakob disease", section on 'Differential diagnosis'.)

CSF biomarkers currently have a limited role in the diagnosis of neurodegenerative conditions
such as AD and DLB and are discussed separately. (See "Clinical features and diagnosis of
Alzheimer disease", section on 'Role of biomarkers' and "Clinical features and diagnosis of
dementia with Lewy bodies", section on 'Investigational biomarkers'.)

Brain biopsy — Brain biopsy has a very limited role in the diagnosis of dementia; the diagnostic
yield is low, and the test is invasive with a significant risk of serious complications. Typically, it is
reserved for younger patients and those with atypical clinical presentations in which a treatable
cause of dementia (eg, inflammatory disorders such as vasculitis or multiple sclerosis) is
considered plausible. In one series of 90 consecutive biopsies undertaken for the investigation
of dementia, 57 percent were diagnostic, although biopsy-obtained information led to specific
treatment interventions in only 11 percent [57].

Increasingly, LP for specific biomarkers and PET scans for specific proteins have made
consideration of cortical biopsy even less necessary and narrowed biopsy indications even
further.

SPECIAL POPULATIONS

Younger patients — The evaluation of younger patients with dementia is presented separately.
(See "Early-onset dementia in adults".)

Rapidly progressive dementia — The differential diagnosis and evaluation of rapidly

progressive dementia syndromes is discussed separately. (See "Creutzfeldt-Jakob disease",
section on 'Differential diagnosis'.)
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SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Cognitive impairment
and dementia".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)"
and "Patient education: Mild cognitive impairment (The Basics)" and "Patient education:
Evaluating memory and thinking problems (The Basics)")

● Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease)
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● We do not routinely screen asymptomatic older adults for cognitive impairment. However,
cognitive difficulty observed in a patient encounter, and family or patient concerns for
memory and cognition, require thorough evaluation. (See 'Screening for dementia' above.)

● The initial step in the evaluation of a patient with suspected dementia should focus upon
the history. Family members or other informants who know the patient well are invaluable
resources for providing an adequate history of cognitive and behavioral changes. A drug

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history is particularly important, as many medications may impact cognition in older

patients. (See 'History' above.)

● Adequate time should be arranged for a full assessment of cognitive function, followed by
a complete physical examination, including neurologic examination. A brief screening
assessment such as the Mini-Mental State Examination (MMSE) or Montreal Cognitive
Assessment (MoCA) is useful and may be sufficient cognitive assessment in some patients.
(See 'Cognitive testing' above and 'Physical examination' above.)

● Screening for depression in patients with dementia is recommended because depression

is a common treatable comorbidity that may also masquerade as dementia. (See
'Screening for depression' above.)

● Screening for B12 deficiency and hypothyroidism is recommended for patients being
evaluated for dementia. Other laboratory testing is performed selectively. Genetic testing
for the apolipoprotein E epsilon 4 allele is not currently recommended, nor is genetic
testing for other potential causes of dementia. (See 'Laboratory testing' above and
'Genetic testing' above.)

● Neuroimaging with a noncontrast magnetic resonance imaging (MRI) or head computed

tomography (CT) should be considered in the initial evaluation of all patients with
dementia. The purposes of structural imaging are to detect treatable causes of dementia
and to differentiate among various dementia subtypes. (See 'Neuroimaging' above.)

● History and examination along with limited laboratory testing and a neuroimaging study
are usually sufficient to make a diagnosis of dementia and in most cases to identify a
presumptive cause. As most causes of dementia are progressive, a follow-up visit after
several months can often confirm the original diagnosis, can offer ongoing treatment and
monitoring, and, in some cases, may cause a clinician to reconsider the original diagnosis
if the progression does not occur or is atypical. (See 'Criteria for dementia' above and
'Dementia syndromes' above.)

● Other tests (neuropsychological assessment, advanced neuroimaging techniques, lumbar

puncture [LP], and, rarely, brain biopsy) are performed in selected patients (such as those
who are younger or have a rapidly progressive course) and when the presentation is
otherwise atypical. (See "Early-onset dementia in adults" and 'Specialized testing in
selected patients' above and "Creutzfeldt-Jakob disease", section on 'Differential
diagnosis'.)

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ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Marie-Florence Shadlen, MD, who
contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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battery. Neurology 2005; 65:102.

51. Beeri MS, Schmeidler J, Sano M, et al. Age, gender, and education norms on the CERAD
neuropsychological battery in the oldest old. Neurology 2006; 67:1006.
52. Gurnani AS, Gavett BE. The Differential Effects of Alzheimer's Disease and Lewy Body
Pathology on Cognitive Performance: a Meta-analysis. Neuropsychol Rev 2017; 27:1.
53. Hutchinson AD, Mathias JL. Neuropsychological deficits in frontotemporal dementia and
Alzheimer's disease: a meta-analytic review. J Neurol Neurosurg Psychiatry 2007; 78:917.
54. Holtzer R, Verghese J, Wang C, et al. Within-person across-neuropsychological test
variability and incident dementia. JAMA 2008; 300:823.

55. Statement on use of apolipoprotein E testing for Alzheimer disease. American College of
Medical Genetics/American Society of Human Genetics Working Group on ApoE and

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Alzheimer disease. JAMA 1995; 274:1627.

56. Henderson AS, Easteal S, Jorm AF, et al. Apolipoprotein E allele epsilon 4, dementia, and
cognitive decline in a population sample. Lancet 1995; 346:1387.
57. Warren JD, Schott JM, Fox NC, et al. Brain biopsy in dementia. Brain 2005; 128:2016.
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GRAPHICS

Differential diagnosis of memory loss

Symptom Usual cause Examples

Gradual onset of short-term memory Dementia Alzheimer disease, Parkinson dementia,
loss and functional impairment in more Lewy body dementia, frontotemporal
than one domain: dementia, alcohol-related dementia,
Creutzfeld-Jacob disease
I. Executive function (finances,
shopping, cooking, laundry,
transportation)

II. Basic activities of daily living

(feeding, dressing, bathing, toileting,
transfers)

Stepwise, sudden deterioration in Cerebrovascular Vascular dementia, multi-infarct

cognition; episodes of confusion, disease dementia, Binswanger dementia
aphasia, slurred speech, focal weakness (subcortical dementia)

Acute cognitive impairment with clouded Delirium Hypo- or hyperglycemia, hypo- or

sensorium; difficulty with attention; may hypernatremia, hypoxemia, anemia,
have hypersomnolence intermittent cerebral ischemia,
thyrotoxicosis, myxedema, alcohol
withdrawal, sepsis, drugs (especially
cholinergics, benzodiazepines, etc)

Complains of memory loss, decreased Depression Minor depression, dysthymic disorder,

concentration, impaired judgment, feels major depression, pathologic grief
worse in morning and hopeless reaction

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Clinical features of delirium versus dementia

Delirium Dementia
Onset More abrupt decline in cognitive Typically insidious, progressive
function over hours to days, with decline in cognition over months
waxing and waning course to years

Attention and orientation Impaired Generally preserved; can be

altered in later stages

Level of consciousness Fluctuating, sometimes reduced Normal

Speech and language Incoherent, disorganized speech Variable impairments in word

retrieval, naming, fluency, and
comprehension

Memory for recent and past Variable, fluctuating impairments Often impaired for recent events;
events memory for remote events
becomes impaired in later stages

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DSM-IV and DSM-5 criteria for dementia

DSM-5 criteria for major neurocognitive

DSM-IV criteria for dementia disorder
(previously dementia)
A1. Memory impairment A. Evidence of significant cognitive decline from a
previous level of performance in one or more
A2. At least one of the following: cognitive domains*:
- Aphasia - Learning and memory
- Apraxia - Language

- Agnosia - Executive function

- Disturbance in executive functioning - Complex attention

- Perceptual-motor

- Social cognition

B. The cognitive deficits in A1 and A2 each cause B. The cognitive deficits interfere with
significant impairment in social or occupational independence in everyday activities. At a minimum,
functioning and represent a significant decline from assistance should be required with complex
a previous level of functioning. instrumental activities of daily living, such as paying
bills or managing medications.

C. The cognitive deficits do not occur exclusively C. The cognitive deficits do not occur exclusively in
during the course of delirium. the context of a delirium.

D. The cognitive deficits are not better explained by

another mental disorder (eg, major depressive
disorder, schizophrenia).

For diagnostic criteria of dementia subtypes such as Alzheimer disease or frontotemporal dementia,
please refer to UpToDate topics on the clinical manifestations and diagnosis of individual dementia
subtypes.

DSM: Diagnostic and Statistical Manual of Mental Disorders.

* Evidence of decline is based on concern of the individual, a knowledgeable informant, or the clinician
that there has been a significant decline in cognitive function and a substantial impairment in cognitive
performance, preferably documented by standardized neuropsychological testing or, in its absence,
another quantified clinical assessment.

References:

1. American Psychiatric Association Diagnostic and Statistical Manual, 4th ed, APA Press, Washington, DC 1994.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American
Psychiatric Association, Arlington, VA 2013.

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Drugs believed to cause or prolong delirium or confusional states*

Analgesics Corticosteroids
NSAIDs Dopamine agonists
Opioids (especially meperidine) Amantadine

Antibiotics and antivirals Bromocriptine

Acyclovir Levodopa

Aminoglycosides Pergolide

Amphotericin B Pramipexole

Antimalarials Ropinirole

Cephalosporins Gastrointestinal agents

Cycloserine
Antiemetics
Fluoroquinolones
Antispasmodics
Isoniazid
Histamine 2 receptor blockers
Interferon
Loperamide
Linezolid
Herbal preparations
Macrolides
Atropa belladonna extract
Metronidazole
Henbane
Nalidixic acid
Mandrake
Penicillins
Jimson weed
Rifampin
St. John's wort
Sulfonamides
Valerian
Anticholinergics
Hypoglycemics
Atropine
Hypnotics and sedatives
Benztropine
Barbiturates
Diphenhydramine
Benzodiazepines
Scopolamine

Trihexyphenidyl Muscle relaxants

Baclofen
Antiseizure medications
Cyclobenzaprine
Carbamazepine

Levetiracetam Other CNS-active agents

Disulfiram
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Phenytoin
Cholinesterase inhibitors (eg, donepezil)
Valproate
Interleukin 2
Vigabatrin
Lithium

Antidepressants Phenothiazines

Mirtazapine

Selective serotonin reuptake inhibitors

Tricyclic antidepressants

Cardiovascular and hypertension drugs

Antiarrhythmics

Beta blockers

Clonidine

Digoxin

Diuretics

Methyldopa

NSAIDs: nonsteroidal antiinflammatory drugs; CNS: central nervous system.

* Not exhaustive, all medications should be considered.

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Short Patient Health Questionnaire (PHQ-2)

Name: Date:

Over the past 2 weeks, how Not at all Several days More than Nearly every
often have you been bothered half the days day
by any of the following
problems?

Little interest or pleasure in 0 1 2 3

doing things?

Feeling down, depressed, or 0 1 2 3

hopeless?

Total point ____ ____ + ____ + ____ + ____

score:

Score interpretation[1] :

PHQ-2 score Probability of major depressive Probability of any depressive

disorder (%) disorder (%)

1 15.4 36.9

2 21.1 48.3

3 38.4 75.0

4 45.5 81.2

5 56.4 84.6

6 78.6 92.9

Reference:
1. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care
2003; 41:1284.
PHQ-2 reproduced with the permission of Pfizer Inc.

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Regional atrophy patterns in neurodegenerative dementias

Dementia syndrome Atrophy pattern

Alzheimer dementia Temporal (including hippocampal), parietal,
prefrontal atrophy, sparing sensorimotor strip and
occiput

Behavioral variant frontotemporal dementia Prefrontal, anterior temporal

Huntington disease Head of the caudate

Nonfluent variant primary progressive aphasia Dominant perisylvian

Posterior cortical atrophy Bilateral superior parietal-occipital junction

Progressive supranuclear palsy Diminished midbrain anteroposterior diameter

Semantic variant primary progressive aphasia Dominant anterior temporal

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MRI ventriculomegaly atrophy versus NPH

(A) Axial T2-weighted image at level of lateral ventricles in a patient with

Alzheimer disease demonstrates increased size of the ventricular system in
proportion to sulcal dilatation, consistent with brain parenchymal volume
loss.

(B) Axial T2-weighted image at level of lateral ventricles in a patient with NPH
shows ventricular dilatation out of proportion to the sulci.

MRI: magnetic resonance imaging; NPH: normal pressure hydrocephalus.

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NINDS-AIREN criteria for probable vascular dementia

The criteria for the clinical diagnosis of probable vascular dementia include all of the
following:

Dementia

Defined by cognitive decline from a previously higher level of functioning and manifested by
impairment of memory and of two or more cognitive domains (orientation, attention, language,
visuospatial functions, executive functions, motor control, and praxis), preferably established by clinical
examination and documented by neuropsychological testing; deficits should be severe enough to
interfere with activities of daily living not due to physical effects of stroke alone.

Exclusion criteria: Cases with disturbance of consciousness, delirium, psychosis, severe aphasia, or
major sensorimotor impairment precluding neuropsychological testing. Also excluded are systemic
disorders or other brain diseases (such as AD) that in and of themselves could account for deficits in
memory and cognition.

Cerebrovascular disease

Defined by the presence of focal signs on neurologic examination, such as hemiparesis, lower facial
weakness, Babinski sign, sensory deficit, hemianopia, and dysarthria consistent with stroke (with or
without history of stroke), and evidence of relevant CVD by brain imaging (CT or MRI) including multiple
large vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, or
PCA or ACA territories), as well as multiple basal ganglia and white matter lacunes, or extensive
periventricular white matter lesions, or combinations thereof.

A relationship between the above two disorders

Manifested or inferred by the presence of one or more of the following:

(a) Onset of dementia within three months following a recognized stroke;

(b) Abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits.

NINDS-AIREN: National Institute of Neurological Disorders and Stroke and the Association Internationale
pour la Recherche et l’Enseignement Neurosciences; AD: Alzheimer disease; CVD: cerebrovascular
disease; CT: computed tomography; MRI: magnetic resonance imaging; PCA: posterior cerebral artery;
ACA: anterior cerebral artery.

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Multiple cerebral microhemorrhages in a patient

with amyloid angiopathy and Alzheimer disease

Gradient echo magnetic resonance imaging (MRI) showing multiple

areas of punctate susceptibility artifact consistent with cerebral
microhemorrhages (arrows) due to amyloid angiopathy in a patient
with Alzheimer's disease.

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Rapidly progressive dementia: Potential diagnostic testing

In all patients:
Brain MRI, including FLAIR and DWI, with and without gadolinium enhancement

Serum electrolytes, liver, renal, and thyroid function tests

Vitamin B12, homocysteine

Urinalysis, culture

In most patients:
Lumbar puncture, cell count and differential, protein, glucose, syphilis serology

EEG

In selected patients (based on abnormalities in above tests or suggestive clinical

features):
CSF

Cryptococcal antigen

Bacterial fungal AFB stains and cultures

Cytology

Viral PCRs and cultures

Lyme serology

14-3-3 protein

Paraneoplastic antibodies

Blood

Rheumatologic screen (ESR, ANA, CRP)

Antithyroglobulin, anti-thyroperoxidase antibodies

HIV

Lyme

Paraneoplastic antibodies

Copper, ceruloplasmin

Whipple PCR

Urine copper, heavy metal screen

Further imaging (angiography, PET, SPECT)

Brain biopsy

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MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted
imaging; EEG: electroencephalography; CSF: cerebrospinal fluid; AFB: acid-fast bacilli; PCR: polymerase
chain reaction; ESR: erythrocyte sedimentation rate; ANA: antinuclear antibodies; CRP: C-reactive protein;
HIV: human immunodeficiency virus; PET: positron emission tomography; SPECT: single-photon emission
computed tomography.

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Contributor Disclosures
Eric B Larson, MD, MPH No relevant financial relationship(s) with ineligible companies to
disclose. Steven T DeKosky, MD, FAAN, FACP, FANA Consultant/Advisory Boards: Biogen [Alzheimer
disease]; Cognition Therapeutics [Alzheimer disease]; Vaccinex [Alzheimer disease]; Acumen
[Neuroscience]; Prevail [Dementia]. All of the relevant financial relationships listed have been
mitigated. Kenneth E Schmader, MD No relevant financial relationship(s) with ineligible companies to
disclose. Janet L Wilterdink, MD No relevant financial relationship(s) with ineligible companies to
disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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