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p. 2230

NEUROCOGNITIVE DISORDERS (NCD)

NCD is a syndrome that exhibits multiple cognitive deficits that

compromise normalsocial or occupational function. There are numerous

etiologies such as Alzheimer’s disease (AD), dementia with Lewy

bodies (DLB), and vascular disease, which require a comprehensive

evaluation to define a potential diagnosis.

Case 108-1 (Question 1)

NCD DUE TO ALZHEIMER’S DISEASE

AD is a chronic, progressive, neurodegenerative disorder that results

from neuropathological findings, such as neurofibrillary tangles and βamyloid plaques that interfere with cholinergic transmission, as well as

other neurochemical changes in the brain.

Case 108-1 (Questions 1–3)

AD has multiple risk factors such as age, family history, Down

syndrome, head trauma, hypertension, and mild cognitive impairment,

yet the exact etiology is still unknown.

Case 108-1 (Question 2)

Treatment for AD currently is symptomatic management, not disease

altering, and focuses on neurotransmission (e.g., cholinergic system).

Case 108-1 (Question 4)

Cholinesterase inhibitors may be used as monotherapy or in combination

with an N-methyl-D-aspartate antagonist for patients in the moderate to

severe stage of AD.

Case 108-1 (Questions 4–6)

Monitoring for treatment efficacy should focus on cognition, function,

and possibly behaviors, whereas treatment toxicity should look for

common adverse effects such as gastrointestinal complaints with

cholinesterase inhibitors.

Case 108-1 (Question 5)

NCD DUE TO LEWY BODY DISEASE

Has similar neuropathology noted with α-synuclein aggregates found in

Lewy bodies and neuritis (α-synucleinopathies), which typically present

with parkinsonian findings as well as associated symptoms such as falls

and visual hallucinations.

Case 108-2 (Question 1)

Cholinesterase inhibitors have demonstrated symptomatic benefit in

patients with Lewy body dementias, yet monitoring for worsening of

Case 108-2 (Question 2)

motor symptoms such as tremor is needed.

VASCULAR NCD

Vascular dementia is a broad classification of cognitive disorders caused

by vascular disease, and notable multiple risk factors include advancing

age, diabetes mellitus, small vessel cerebrovascular disease,

hypertension, heart disease, hyperlipidemia, cigarette smoking, and

alcohol use.

Case 108-3 (Questions 1, 2)

Treatment for vascular dementia strives to control the underlying

modifiable risk factors owing to limited efficacy and controversial

evidence with cholinesterase inhibitors.

Case 108-3 (Question 3)

p. 2231

p. 2232

BEHAVIORAL DISTURBANCES IN DEMENTIA

When evaluating a dementia patient with behavior disturbances, the first

step is to ensure that the problem is not caused by an unrecognized

medical problem or adverse effect of a medication.

Case 108-4 (Question 1),

Case 108-5 (Question 1)

Nonpharmacologic strategies are effective for managing many behavior

disturbances and should be attempted before using medications to

manage behavior.

Case 108-4 (Questions 1–4)

Delusions and hallucinations are common behaviors in dementia patients,

yet the use of antipsychotics for these symptoms is not approved by the

US Food and Drug Administration and has been associated with the

increased risk of stroke and mortality in this patient population.

Case 108-4 (Question 2)

Wandering is a safety concern that often does not respond to

pharmacologic intervention; instead, other strategies such as

environmental modifications are used.

Case 108-4 (Question 3)

Antidepressants such as selective serotonin reuptake inhibitors have

shown promise in addressing depressive symptoms, as well as

screaming and irritability.

Case 108-4 (Question 4)

Caregiver support is essential to maintaining a dementia patient safely in

his or her home as long as possible.

Case 108-1 (Questions 3, 5),

Case 108-4 (Question 5)

Neurocognitive disorders span a wide range of conditions that exhibit a global

decline in cognition. Among the disorders included are delirium, dementia, and

several other disorders with various etiologies (e.g., head trauma, HIV, Huntington

disease).

1 Among older adults, the dementias are the most commonly encountered

diseases and are the focus of this chapter.

GERIATRIC DEMENTIAS

With the continuing growth in the elderly population, the incidence and prevalence of

neurocognitive disorders continues to rise.

1,2 Alzheimer’s disease (AD) is the most

common cause, and accounts for more than half of all diagnosed cases.

4–6 Vascular

dementia (VaD), dementia with Lewy bodies (DLB), and Parkinson’s disease with

dementia (PDD) are the next most common dementias, with frontotemporal dementia,

pseudodementia, and other forms occurring less often.

5,7 AD is currently the fifth

leading cause of death for people age 65 years and older and the sixth leading cause

of death for all people in the United States.

3,8

Incidence and Prevalence

It is estimated that 5.3 million Americans have AD, including approximately 11% of

people age 65 years and older and 32% of people age 85 years and older. Of these,

more than 3.2 million are women. Prevalence is greater among both African

Americans and Hispanics compared with whites.

3 The annual incidence of AD in the

United States rises from 53 per 1,000 among people age 65 to 74 years to 170 per

1,000 for those age 75 to 84 years, and to 231 per 1,000 for those at least 85 years of

age.

9 Worldwide prevalence has been estimated to be as high as 24.3 million, with

8.4 million new cases annually.

2,10 Projections into the mid-century include a

worldwide prevalence of more than 81 million, with cases in undeveloped countries

occurring at about three times the rate as in developed countries.

10

In the United

States, AD accounts for nearly 70% of cases; VaD accounts for 17.4%, with the

remaining 12.6% attributable to DLB, frontotemporal dementia, and other forms.

6

Life expectancy after a diagnosis of AD is reduced by as much as 69% for those

diagnosed before age 70 years and by 39% for those diagnosed after age 90 years.

11

The cost of dementia is staggering. Annual costs for Medicare recipients with

dementia average $21,585, compared with $8,191 for those without dementia. For

Medicaid recipients with dementia, the annual costs are $11,021, compared with

$574 for those without dementia. The annual direct costs, in 2014 dollars, of treating

a dementia patient are $47,752 annually, compared with $15,115 for an older adult

without dementia. This translates to an estimated annual direct cost for dementia care

of $226 billion for the year 2015.

3

Clinical Diagnosis

Dementia is a neurocognitive disorder that exhibits impaired short- and long-term

memory as its most prominent feature. Multiple cognitive deficits that compromise

normal social or occupational function must be present before dementia can be

diagnosed (Table 108-1).

1 Commonly, forgetfulness is the primary complaint of

patients or the first symptom noted by the family.

12 Family members or others may

note several symptoms that should prompt a medical evaluation (Table 108-2).

12,13

Memory loss often accompanies several diseases or disorders in elderly individuals.

Therefore, a medical history, physical examination, and medication history are

essential in excluding systemic illness or medication toxicity as causes of the memory

loss (Table 108-3).

13–16 Laboratory and other tests to assist in differentiating

dementia from other disorders are listed (Table 108-4). In patients with AD, test

results will generally be normal; evidence of cerebrovascular disease is present in

patients with VaD.

Brain imaging, such as a computed tomography (CT) scan or magnetic resonance

imaging (MRI), can be useful in establishing the presence of a dementia, but neither

is diagnostic. A CT scan is useful when a space-occupying lesion, such as a tumor, is

suspected as a possible cause. An MRI scan is capable of identifying small infarcts,

such as those found in some forms of VaD, and atrophy of subcortical structures such

as the brainstem.

15

Several simple tests, including the Mini-Cognitive Assessment Instrument (MiniCog), the Montreal Cognitive Assessment (MoCA), and the St. Louis University

Mental Status (SLUMS) exam are appropriate for initial screening of people with

suspected cognitive impairment.

17–19 The Folstein Mini-Mental State Exam (MMSE)

also can be used; however, it is less sensitive than others

p. 2232

p. 2233

for dementia and now is proprietary.

20 These tests rapidly assess multiple

domains, typically including orientation, registration, attention and calculation,

recall, and language. Patients with dementia exhibit deficits in multiple areas. Those

who score below the normal range on the MMSE or other screens, or who exhibit

symptoms characteristic of dementia receive further testing. A somewhat more

detailed screen, the Cognitive Abilities Screening Instrument (CASI), provides

quantitative assessment on attention, concentration, orientation, short-term memory,

long-term memory, language abilities, visual construction, list-generating fluency,

abstraction, and judgment.

21 All screening tests are subject to limitations. Therefore,

additional psychometric testing is often ordered to further establish the presence and

type of dementia.

2,22

Dementias may be classified as cortical or subcortical, according to the areas of

the brain preferentially affected by the disorder. AD, a typical cortical dementia,

disrupts the cerebral cortex. Patients with cortical dementias display impaired

language rather than impaired speech, a learning deficit (amnesia), reduced higher

cortical functions (e.g., inability to perform calculations, poor judgment), and an

unconcerned or disinhibited affect. Subcortical dementias such as PDD primarily

affect the basal ganglia, thalamus, and brainstem. Deficits include abnormal motor

function, disrupted speech patterns rather than language difficulties, forgetfulness

(impaired recall), slowed cognitive function, and an apathetic or depressed affect.

16

Table 108-1

Differentiating Neurocognitive Disorders

Mild (formerly Mild Cognitive Impairment) Major (formerly Dementia)

Neurocognitive Disorder (NCD)

Modest cognitive decline from previous (baseline)

performance in at least one cognitive domain, including:

Learning and memory

Complex attention

Executive function

Language

Perception and motor

Social cognition

The deficits do not impair the capacity to be

independent in everyday activities

The cognitive symptoms do not occur exclusively

during a period of delirium

The cognitive deficits are not better explained by

depression, schizophrenia or other mental disorders

Significant cognitive decline from previous (baseline)

performance in at least one cognitive domain, including:

Learning and memory

Complex attention

Executive function

Language

Perception and motor

Social cognition

The deficits impair the capacity to be independent in

everyday activities

The cognitive symptoms do not occur exclusively

during a period of delirium

The cognitive deficits are not better explained by

depression, schizophrenia or other mental disorders

p. 2233

p. 2234

NCD due to Alzheimer’s Disease

Criteria for either mild or major NCD are met

Insidious onset and gradual progression of impairment

Mild: impairment in one cognitive domain

Major: impairment in at least two cognitive domains

Probable Alzheimer’s disease (either of the following must be present)

Alzheimer’s disease genetic mutation based on family history or genetic testing

All of the following are present:

Decline in memory and learning plus one other cognitive domain

Steady and gradual cognitive decline

No evidence of another condition that is likely to cause cognitive decline

Possible Alzheimer’s disease

Lack of an Alzheimer’s disease genetic mutation

All of the following are present:

Decline in memory and learning

Steady and gradual cognitive decline

No evidence of another condition that is likely to cause cognitive decline

Cognitive decline is not better explained by cerebrovascular disease or another condition associated with

cognitive decline or neurodegeneration

Vascular NCD

Criteria for either mild or major NCD are met

Clinical presentation is consistent with a vascular cause (either of the following is present)

Onset of cognitive impairment follows a cerebrovascular event or multiple events

Prominent decline in complex attention and executive function

History, physical exam and/or neuroimaging indicates cerebrovascular disease as the most likely cause of the

cognitive decline

Probable vascular NCD (at least one of the following is present)

Neuroimaging supports cerebrovascular disease as the cause of the clinical presentation

The neurocognitive deficit follows at least one cerebrovascular event

Presence of both clinical and genetic evidence of cerebrovascular disease

Possible vascular NCD

Clinical criteria are met

Neuroimaging is not available

Temporal relationship between the cerebrovascular event(s) and the onset of neurocognitive decline is not

established

A systemic disorder or other brain disease do not adequately explain the symptoms

NCD with Lewy Bodies

Criteria for either mild or major NCD are met

The onset is insidious, with gradual progression

A combination of the following core and suggestive diagnostic features are present

Core features

Fluctuating cognition accompanied by variable attentiveness and alertness

Recurrent, well-formed and detailed visual hallucinations

Onset of Parkinsonian features that are exhibited after the onset of cognitive decline

Suggestive features

Criteria for rapid eye movement (REM) sleep behavior disorder are met

Severe sensitivity to neuroleptic agents

Probable NCD with Lewy Bodies (either of the following is present)

At least two core features

One or more core features and one suggestive feature

Possible NCD with Lewy Bodies (either of the following is present)

One core feature

One or more suggestive features

Cognitive decline is not better explained by cerebrovascular disease or another condition associated with

cognitive decline or neurodegeneration

Adapted from references

1,36,75,77,81,83 and Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the

recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic

guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):257–262, 2011 10.1016/j.jalz.2011.03.004; Albert MS,

DeKosky ST, Dickson D, et al: The diagnosis of mild cognitive impairment due to Alzheimer’s disease:

recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic

guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):270–279, 2011 10.1016/j.jalz.2011.03.008; Román

GC, Tatemichi TK, Erkinjuntti T, et al: Vascular dementia: diagnostic criteria for research studies. Report of the

NINDS-AIREN International Workshop. Neurology 43(2):250–260, 1993

Table 108-2

Symptoms Suggesting Dementia

Symptom Evidence

Difficulty learning or retaining

new information

Repeats questions; difficulty remembering recent conversations, events, etc.;

loses items

Unable to handle complex tasks Cannot complete tasks that require multiple steps (e.g., difficulty following a

shopping list)

Impaired reasoning Difficulty solving everyday problems; inappropriate social behavior

Impaired spatial orientation and

abilities

Gets lost in familiar places; difficulty with driving

Language deficits Problems finding appropriate words (e.g., difficulty with naming common

objects)

Behavior changes Changes in personality; suspiciousness

Adapted from Costa P et al. Recognition and initial assessment of Alzheimer’s disease and related dementias.

Clinical Practice Guideline No. 19. Rockville, MD: U.S. Department of Health and Human Services, Public Health

Service, Agency for Health Care Policy and Research. AHCPR Publication No. 97-0702. November 1996.

Table 108-3

Causes of Dementia Symptoms

Central Nervous System

Disorders Systemic Illness Medications

Adjustment disorder (e.g., inability to

adjust to retirement)

Cardiovascular disease

Arrhythmia

Heart failure

Anticholinergic agents

Anticonvulsants

Antidepressants

Antihistamines

Amnestic syndrome (e.g., isolated

memory impairment)

Delirium

Vascular occlusion

Deficiency states

Vitamin B12

Folate

Iron

Anti-infectives

Antineoplastic agents

Antipsychotic agents

Cardiovascular agents

Antiarrhythmics

p. 2234

p. 2235

Depression

Intracranial causes

Brain abscess

Normal pressure

Hydrocephalus

Stroke

Subdural hematoma

Tumor

Infections

Metabolic disorders

Adrenal

Glucose

Renal failure

Thyroid

Antihypertensives

Corticosteroids

H2

-receptor antagonists

Immunosuppressants

Narcotic analgesics

Nonsteroidal anti-inflammatory

agents

Sedative hypnotics and anxiolytics

Skeletal muscle relaxants

Table 108-4

Dementia Screening Tests

Test Rationale for Testing

Complete blood count with sedimentation rate Anemic anoxia, infection, neoplasms

Metabolic screen

Serum electrolytes Hypernatremia, hyponatremia; renal function

Blood urea nitrogen, creatinine Renal function

Bilirubin Hepatic dysfunction (e.g., portalsystemic

encephalopathy, hepatocerebral degeneration)

Thyroid function Hypothyroidism, hyperthyroidism

Iron, vitamin B12

, folate, vitamin D Deficiency states (vitamin B12

, folate neuropathies,

vitamin D deficiency), anemias

Stool occult blood Blood loss, anemia

HIV and RPR Infection

Urinalysis Infection, proteinuria

Chest roentgenogram Neoplasms, infection, airway disease (anoxia)

Electrocardiogram Cardiac disease (stagnant anoxia)

Brain scan Cerebral tumors, cerebrovascular disease

Mentalstatus testing General cognitive screen

Depression testing Depression, pseudodementia

ALZHEIMER’S DISEASE

Etiology

A definitive cause for AD has yet to be determined. Several risk factors, however,

have been identified. Advancing age is the primary risk factor for AD; other risks

include family history, head trauma, metabolic syndrome, diabetes, hypertension and

cardiovascular disease.

3,23-27 Genetics plays a significant role in the development of

Alzheimer’s disease. The high familial occurrence of AD has been linked to

autosomal-dominant traits on chromosomes 21, 14, and 1.

28,29 A gene that encodes for

amyloid precursor protein (APP), a normal protein, is located on chromosome 21. A

defect on chromosome 14 has been identified as the locus for the presenilin-1 gene,

which codes for an inherited form of AD. The presenilin-2 gene, located on

chromosome 1, also codes for an inherited form. Despite a strong genetic link in

some pedigrees, the great majority of AD cases are sporadic.

29,30 The more common

sporadic form appears to be linked to a susceptibility gene, apolipoprotein E, which

occurs in three isoforms.

29 APP, a normal protein found throughout the body, maps on

chromosome 21 and plays a pivotal role in AD neuropathology. Because of

overproduction or transcription errors, an abnormal subunit (i.e., β-amyloid) is

produced.

29 Mutations on chromosomes 14 (presenilin-1 gene) and 1 (presenilin-2

gene) and the presence of apolipoprotein E4 allele code for alterations in the

processing of APP. The abnormal cleavage of APP produces a 42–amino acid form

of β-amyloid (Aβ) that demonstrates a higher toxicity than other amyloid forms.

29

Apolipoprotein E (ApoE), a protein that is involved in cholesterol and

phospholipid metabolism, plays a role in the development of sporadic, late-onset

AD. The ApoE gene possesses three alleles: E2, E3, and E4. The E3 allele is most

common, the E2 allele appears to be protective against AD, and the E4 allele

increases the risk for AD.

29 The presence of ApoE-4, the protein coded for by the E4

allele, appears to increase the deposition of Aβ and promote its change to a more

pathological configuration.

29 The presence of one or two copies of ApoE4 increases

the risk of developing AD twofold or fivefold, respectively.

30 Aβ, which differs from

amyloid protein found in other regions of the body, appears to contribute to neuronal

death through a combination of apoptosis, a direct toxic effect, and an increased risk

for damage owing to oxidative and metabolic stresses.

29,31

Neuropathology

Although brain atrophy is the most obvious finding among patients with Alzheimertype dementia, it is not diagnostic for AD or other dementias because some degree of

atrophy accompanies normal aging. Atrophic changes induced by AD are found

primarily in the temporal, parietal, and frontal areas of the brain; the occipital region,

primary motor cortex, and somatosensory areas are generally unaffected (Fig. 108-

1).

5,31

Neuronal changes in the cerebral cortex associated with AD include

neurofibrillary tangles, neuritic plaques, amyloid angiopathy, and granulovacuolar

degeneration. These changes lead to loss of neurons and synapses (Fig. 108-2).

28

Neurofibrillary tangles (NFTs) are found primarily in the pyramidal regions of the

neocortex, hippocampus, and amygdala, but they are also noted in areas of the

brainstem and locus coeruleus.

5,31 NFTs are composed of paired helical filaments,

combinations of fibrils with a characteristic width and contour, containing a tau

protein with an abnormal pattern of phosphate deposition. They are highly

immunoreactive and are most likely to form in large pyramidal neurons.

p. 2235

p. 2236

Figure 108-1 Alzheimer disease: magnetic resonance imaging scan. Ventricles are enlarged, and there is

generalized atrophy, with greater atrophy present near the temporal areas.

Figure 108-2 Numerous plaques (large, round bodies) and tangles (tear-shaped bodies) are found throughout the

cortex in Alzheimer-type dementia.

Neuritic plaques are spherical bodies of tissue composed of granular deposits and

remnants of neuronal processes.

5 The typical neuritic plaques of AD are spherical

structures that exhibit a three-tiered structure: a central amyloid core, a middle region

of swollen axons and dendrites, and an outer zone containing degenerating neuritic

processes.

28 Plaques contain APP, which can be cleaved by a defective metabolic

process to form Aβ.

29

In addition to Aβ, plaques also contain protein, ApoE, and

acute-phase inflammatory proteins such as α1

-chymotrypsin and α2

-macroglobulin.

28

The deposition of amyloid in neuritic plaques correlates with the severity of AD, and

the density of cortical plaques is associated with decreased choline acetyltransferase

and the severity of cognitive impairment.

5 Aβ has been identified in plaques

associated with Down syndrome and in both familial and sporadic forms of dementia

of the Alzheimer type.

29 The pathological process of AD development may begin as

early as 20 to 30 years before any disease symptoms appear.

5,29,32

Granulovacuolar degeneration is the other major histologic finding in AD. It

consists of clusters of intracytoplasmic vacuoles that contain tiny granules. The

vacuoles appear to be specifically located in the pyramidal neurons of the

hippocampus.

5,16,28 The loss of cortical neurons that originate in the nucleus basalis

and project into the cerebral cortex is the most significant histopathological

consequence of AD.

31 Cell loss, granulovacuolar degeneration, and neurons with

NFTs are concentrated in this area.

16,28

Accompanying these changes are decreased concentrations of several

neurotransmitters and enzymes. Choline acetyltransferase levels are reduced 60% to

90% in the cortical and hippocampal regions.

28 Acetylcholine and

acetylcholinesterase (AChE) are also decreased, whereas muscarinic receptors in the

cortex and hippocampus remain at normal levels or are moderately decreased.

Nicotinic receptor proteins are also reduced in patients with Alzheimer-type

dementia when compared with age-matched controls. Decreased choline

acetyltransferase activity has been correlated with plaque density and disease

severity. Cortical synapse loss, especially in the midfrontal region, is associated

with disease severity.

5,29-31

Changes affecting AChE have significant implications for the management of AD

symptoms. Many isoforms of AChE have been identified; they possess identical

amino acid sequences, but display different posttranslational modifications,

predominate at diverse anatomical and microanatomical locations, and function in

different ways. The predominant form of AChE in the cortical and hippocampal

regions of humans is G4, a tetrameric form that is membrane bound. The monomeric

form, G1, is found in a much lower concentration. There is a selective loss of the G4

form in patients with AD, allowing the G1 form to assume greater importance.

33

Although cholinergic activity is most significantly affected by Alzheimer-type

dementia, other neurochemical systems are also altered. Norepinephrine, serotonin,

and γ-aminobutyric acid receptors are affected.

28,29

Clinical Presentation and Diagnosis

CASE 108-1

QUESTION 1: T.D. is a 72 year old man who is accompanied by his wife for a memory assessment. During

the interview, the patient notes that memory issues started about 6 to 12 months ago but recently worsened

after he was hospitalized for a fall. The wife notes that he retired at age 70 because he was slowing down and

admits that he may have been having some memory issues back then due to his inability to manage the finances

even though he was an accountant. Since the fall, which occurred when he was doing work on the house and

fell off the ladder and broke his leg, the wife admits he is not quite the same.

T.D.’s medical history is significant for osteoarthritis benign prostatic hyperplasia (BPH) and hypertension.

He is currently taking tamsulosin 0.4 mg in the evening for BPH and amlodipine 10 mg daily for HTN, His

family history is negative for stroke and positive for heart disease and his father died of a myocardial infarction

at age 84. The wife admits that his mother had AD and was diagnosed in her early 70s as well. She died at the

age of 76 due to complications with her AD in a nursing home and her husband witnessed her dramatic decline

from the AD, which worries him.

Physical examination reveals a pleasant, well-groomed man who is in good health oriented to person and

place but not time. His blood pressure (BP) is 120/66 mm Hg supine and 132/72 mm Hg standing, with pulse

rates of 56 beats/minute and 62 beats/minute, respectively.

The Folstein MMSE score was 22/30, with errors in orientation, attention, calculation (inability to spell

“world” backward), recall, and language (difficulty with word finding). The rest of the physical examination was

within normal limits.

What additional evaluation steps should be considered for T.D.?

p. 2236

p. 2237

Before any conclusions can be reached, potentially reversible causes for T.D.’s

impaired cognition must be evaluated. Although he displays several trigger symptoms

associated with dementia (Table 108-2), including difficulty with managing finances

(change especially noted in light that he was an accountant) and word finding issues

coupled with memory impairment impacting day to day function.

Several systemic diseases and other disorders can cause cognitive impairment, as

shown in Table 108-3. T.D. should undergo a battery of laboratory tests to rule out

anemia, cardiac and renal disease, thyroid abnormalities, and tumors. In addition, he

should receive thorough neuropsychological testing, including depression screening

and more in-depth assessment of his cognitive function. The testing should be

conducted by clinicians who are skilled in cognitive assessment, as educational and

cultural factors can influence an individual’s performance on these tests.

34

CASE 108-1, QUESTION 2: T.D. is referred by his physician for additional testing. Laboratory tests

performed include renal and liver chemistries, thyroid function tests, vitamin B12

and folate levels, syphilis and

HIV tests, complete blood cell count with sedimentation rate, and urinalysis. All results were normal with the

exception of a low B12 level (147 ng/L). Chest radiograph and electrocardiogram were normal. Neurologic

examination revealed no deficits. Depression testing revealed a mildly anxious individual who was not depressed

just worried about his future.

What is the most probable diagnosis for T.D.?

T.D.’s score of 22/30 on the Folstein MMSE is consistent with mild cognitive

impairment or early dementia as evidenced by errors in orientation, calculation,

recall, and language.

20 Secondary medical causes of cognitive impairment can be

eliminated by T.D.’s generally normal physical examination and laboratory test

results. MRI or CT scanning may be useful in many cases to help eliminate brain

pathology, such as stroke.

34 A positron emission tomography (PET) scan or a single

photon emission computed tomography (SPECT) scan may be useful to help locate

specific areas of pathology and assist with a differential diagnosis, but are not

required.

35 Secondary psychiatric causes for T.D.’s decline can also be discounted.

Although he is sad and anxious, the absence of alterations in appetite or sleep

patterns, absence of suicidal thoughts, and the results of psychologic testing indicate

T.D. is not depressed. He is fully conscious, alert, and oriented to place and person.

He exhibits no psychotic behavior and no evidence of delirium.

T.D.’s slowly progressive decline and its impact on his social and occupational

function (forgetting appointments, failing to pay bills), normal physical examination

and laboratory findings, and family history meet the Diagnostic and Statistical

Manual of Mental Disorders, Fifth Edition (DSM-V) criteria for dementia (Table

108-1). His history and course to date satisfy the criteria for AD and do not indicate

a likely alternative explanation for his condition. Thus, T.D. can be classified as

probable AD.

36

CASE 108-1, QUESTION 3: T.D. ’s children are very concerned about the family history for dementia.

They ask whether there are any tests they should receive at this time to determine their risk. What should they

be told?

Although there is a strong genetic association with AD, such instances account for

a small minority of cases.

29 There is no apparent family history of Down syndrome.

Mutations in the presenilin-1 and presenilin-2 genes are associated with only a small

fraction of AD cases.

29 Although several potential biomarkers have been identified,

they have not been sufficiently validated to be considered reliable predictors for the

development of AD.

3,36,35

Prognosis

CASE 108-1, QUESTION 4: What is the likely prognosis for T.D.?

AD follows a predictable course that may progress over the course of 10 years or

more.

2,10 Two common rating scales for dementia are the Global Deterioration Scale

and the Clinical Dementia Rating Scale. According to the Global Deterioration Scale

(Table 108-5), T.D.’s impaired social functioning, anxiety, and objective cognitive

decline as well as his continued ability to concentrate and perform some complex

skills, combined with his preserved affect and social interaction, are consistent with

the features of stage three dementia of the Alzheimer type. This stage of AD is

generally associated with a period of mild cognitive decline.

38 The more general

Clinical Dementia Rating Scale also places T.D. in the category of mild dementia.

39

Clinical diagnoses of AD using clinically appropriate criteria and assessment

methods for probable AD have a sensitivity of up to 90% when compared with

autopsy-confirmed cases.

1,34,37

Because of technologic advances, it is possible to diagnose dementia earlier and

to keep patients alive into the final stages of the disease.

40 The early diagnosis of AD

in T.D. will allow his condition to be followed closely. To ensure the most favorable

outcome, T.D. should receive a thorough assessment beyond his dementia. This

should include evaluation of his daily function (i.e., ability for self-care), comorbid

medical conditions, medications, living arrangements, safety, and potential for abuse

and neglect. Attention also should be given to T.D.’s caregivers and support

system.

41,42 He should be reassessed every 6 months to both document disease

progression and ensure that he is receiving the most appropriate care. At some point,

care at home may become unrealistic. At that time, T.D. should be moved into a

sheltered environment (e.g., residential-care facility or nursing home) before

suffering an injury caused by his poor judgment (e.g., failing to dress properly for the

weather, falling). In the later stages, interventions ranging from tube feedings to life

support may prolong life, yet prove to be controversial.

43 Death in the late stage of

AD is commonly associated with the development of infections such as pneumonia,

urinary tract infections, or decubitus ulcers.

Table 108-5

Stages of Dementia of the Alzheimer Type

Stage of Cognitive Decline Features

No cognitive decline Normal cognitive state

Very mild cognitive decline Forgetfulness, subjective complaints only; no objective decline

Mild cognitive decline Objective decline through psychiatric testing; work and social impairment; mild

anxiety and denial

Moderate cognitive decline Concentration, complex skills decline; flat affect and withdrawal

Moderately severe cognitive

decline

Early dementia; difficulty in interactions; unable to recall or recognize people

or places

Severe cognitive decline Requires assistance with bathing, toileting; behavioralsymptoms present

(agitation, delusions, aggressive behavior)

Very severe cognitive decline Loss of psychomotor skills and verbal abilities; incontinence; total dependence

Adapted from Reisberg B et al. The global deterioration scale for assessment of primary degenerative dementia.

Am J Psychiatry. 1982;139:1136.

p. 2237

p. 2238

Treatment

Maintaining independence as long as possible is an important goal in treating a

patient with dementia. Keeping patients in familiar surroundings allows them to

function without the added burden of having to attempt to adapt to a strange

environment. Concurrent diseases and many medications can reduce function and

increase cognitive impairment in patients with dementia.

CASE 108-1, QUESTION 5: What is an appropriate initial treatment strategy for T.D.?

T.D.’s family needs to be educated about what to expect as his dementia

progresses. They should be referred to the Alzheimer’s Association (www.alz.org)

and to the Family Caregiver Alliance (www.caregiver.org). Both organizations

provide a wealth of information and community resources, including caregiver

support groups. They also should be encouraged to enroll in the MedicAlert +

Alzheimer’s Association Safe Return program, which provides 24-hour nationwide

emergency response for people with dementia who wander or suffer a medical

emergency. T.D.’s family should include him in any advance planning, seek legal

advice regarding advance directives and durable power of attorney for health care

and finance, and conduct estate planning to avoid having to perform these tasks when

T.D. is no longer competent to participate.

41

Currently, there are two classes of medications that are used in the treatment of

Alzheimer’s disease, cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate

(NMDA) receptor antagonist.

44 They are pharmacologically distinct and can be

prescribed concurrently in patients in the moderate to severe stages of the illness.

ChEIs act on inhibiting acetylcholinesterase, an enzyme directly involved in the

destruction of acetylcholine leading to increasing its concentration in the nucleus

basalis of Meynert in the brain and hence ameliorating the cognitive and functional

aspects of AD. Cholinesterase inhibitors have been shown to improve cognition and

function, and delay symptom progression in people with dementia, however benefits

are limited Cholinergic-related effects, particularly in the gastrointestinal (GI) tract,

are the most common adverse effects cause by all of the agents.

45

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