DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994); HIV, human immunodeficiency virus.

TABLE 65-2 NINCDS-ARDA Criteria for Diagnosis of Probable Alzheimer’s Disease

Criteria for Diagnosis of Probable Alzheimer’s Disease

Dementia established by clinical examination, documented by a standard test of cognitive function (e.g., Mini-Mental State Examination, Blessed Dementia Scale), and confirmed by neuropsychological tests

Significant deficiencies in two or more areas of cognition: for example, word comprehension and task-completion ability

Progressive deterioration of memory and other cognitive functions

No loss of consciousness

Onset from age 40 to 90, typically after 65

No other diseases or disorders that could account for the loss of memory and cognition

Support for Diagnosis of Probable Alzheimer’s Disease

Progressive deterioration of specific cognitive functions: language (aphasia), motor skills (apraxia), and perception (agnosia)

Impaired activities of daily living and altered patterns of behavior

A family history of similar problems, particularly if confirmed by neurological testing

The following laboratory results:

Normal cerebrospinal fluid (lumbar puncture test)

Normal EEG test of brain activity

Evidence of cerebral atrophy in a series of CT scans

Other Features Consistent with Alzheimer’s Disease

Plateaus in the course of illness progression

CT findings normal for the person’s age

Associated symptoms, including depression, insomnia, incontinence, delusions, hallucinations, weight loss, sexual problems, and significant verbal, emotional, and physical outbursts

Other neurological abnormalities, especially in advanced disease, including increased muscle tone and a shuffling gait

Features That Decrease the Likelihood of Alzheimer’s Disease

Sudden onset

Such early symptoms as seizures, gait problems, and loss of vision and coordination

CT, computed tomographic; EEG, electroencephalographic; NINCDS-ADRDA, National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease Related Disorders Association.

Adapted from McKhann, G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS/ADRDA Work Group under the auspices of Department of Health Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939-944.

EPIDEMIOLOGY

Alzheimer’s disease causes about 70% of cases of dementia.¹ In the Framingham study, Bachman and colleagues reported that the incidence of Alzheimer’s disease increases from 3.5 per 1000 per year between the ages of 65 and 69 to 72.8 per 1000 per year at ages 85 to 89 years.² Bachman and colleagues found that the incidence of Alzheimer’s disease doubled with every 5 years of age. Alzheimer’s disease prevalence is low among persons younger than 65 years, but it increases to 10% to 30% among persons older than 85.³

In 1907, when Alois Alzheimer described the disease named for him, mean life expectancy was 42 years; since then, in developed countries, life expectancy has greatly increased.⁴ For example, in the United States, 50% of persons are expected to live past 75 and 25% past 85. With age being such an important risk factor and so many people living into the high-risk ages, the prevalence of Alzheimer’s disease has greatly increased; it is 4.5 million in the United States, according to the 2000 census.⁵ Because of the staggering cost of caring for patients with Alzheimer’s disease (estimated at $100 billion annually in the United States⁶) and because “baby boomers” are reaching the high-risk period, it can be argued strongly that the world should invest heavily in finding ways to prevent this disease. In fact, Brookmeyer and associates⁷ predicted that if the onset of the disease is delayed by an average of 5 years, the present-day U.S. prevalence of Alzheimer’s disease would remain constant (at 4.5 million) instead of increasing to an anticipated 13 million in 2047.

RISK AND PUTATIVE PROTECTIVE FACTORS FOR ALZHEIMER’S DISEASE

Table 65-3 lists risk factors and Table 65-4 the putative protective factors for Alzheimer’s disease.

TABLE 65-3 Risk Factors for Alzheimer’s Disease

TABLE 65-4 Putative Protective Factors for Alzheimer’s Disease

Genetics

Researchers have discovered three genes that, if they have undergone mutation, cause early-onset Alzheimer’s disease. Although they account for fewer than 1% of cases of Alzheimer’s disease, the knowledge of how these genes probably cause Alzheimer’s disease has been helpful for understanding the pathogenesis of this disease. Table 65-5 lists the genes from the Alzheimer Disease and Frontotemporal Dementia Mutation Database and tabulates for each gene the number of mutations and families reported. By January 2005, investigators had reported a total 404 families with 189 different mutations in these three genes.

TABLE 65-5 Genes Related to Early-Onset Alzheimer’s Disease

Gene	Number of Mutations	Total Number of Families Published
APP	18	48
PSEN1	141	280
PSEN2	10	16

Based on Alzheimer Disease and Frontotemporal Dementia Mutation Database, maintained by Marc Cruts and Roos Rademakers (www.molgen.ua.ac.be/ADMutations/, accessed June 8, 2006).

APP, amyloid precursor protein; PSEN, presenilin.

Many studies (summarized in a meta-analysis by Farrer and colleagues ⁸) have established apolipoprotein E4 (ApoE4) as an important risk factor for Alzheimer’s disease. ApoE is a lipoprotein that carries cholesterol and has three forms: ApoE2, ApoE3, and ApoE4. The allelic prevalence varies in different ethnic groups. Table 65-6 reveals that persons with Alzheimer’s disease have a higher prevalence of ApoE4. Although community-based studies do not show ApoE4 as a risk factor for Alzheimer’s disease in African American patients, a large clinically based series reported that it is.⁹ One of Graff-Radford and colleagues’ findings in that report was that ApoE4 is associated with early-onset risk. In the community-based studies, there were very few early-onset cases.

TABLE 65-6 Apolipoprotein (Apo) Genotypes Related to Alzheimer’s Disease in Different Population Groups, Divided into Cases and Controls

There is strong evidence that there are undiscovered genetic factors related to late-onset Alzheimer’s disease.¹⁰ Although many candidate genes have been proposed, associations have often not been reproduced by different investigators. Therefore, researchers are working on refining their techniques and working out the pitfalls in case-control methods. Difficulties in the studies so far include heterogeneity of populations, the possible complexity of the factors causing the disease, the fact that many of the controls are probably susceptible themselves to the disease (as they age), and the fact that the effect size is too small to detect with the size of the samples used.

Amyloid Hypothesis

When Alzheimer described the disease histologically, he noted the deposition of a substance in the form of plaques that was later identified as the β amyloid protein (Aβ) by Glenner and Wong.¹¹ Subsequently, many lines of evidence have led to the hypothesis that brain deposition of this protein causes Alzheimer’s disease.

Aβ is produced by the sequential proteolytic cleavage of the amyloid precursor protein (APP) (coded for on chromosome 21) by enzymes known as secretases (Fig. 65-1). There are two pathways, one of which leads to the production of the Aβ peptides and the other does not. In the amyloidogenic pathway, the first step involves cleavage of APP at the amino terminus by an aspartyl protease (β-secretase), resulting in the formation of soluble APPβ and a membrane-bound APP carboxy terminal fragment (CTF-β). Cleavage of this CTF-β by γ-secretase results in the formation of Aβ peptides of variable length, including a 40–amino acid Aβ peptide (Aβ40) and a 42–amino acid peptide (Aβ42). The γ-secretase cleavage requires the presence of two membrane proteases, presenilin-1 and presenilin-2; it is thought that these presenilins may, in fact, be part of the γ-secretase complex. Other parts of this complex include nicastrin, a type I membrane protein that was originally purified, and two other membrane proteins, APH-1 and PEN-2. Together with presenilin, these three components appear to constitute a minimal functional γ-secretase complex. It is also possible that these “accessory” proteins are involved in substrate presentation. The non-amyloidogenic pathway is carried out by α-secretase, which cleaves the APP protein in the middle into soluble APPα and CTF-β, which, in turn, is cleaved by γ-secretase into P3 and CTF-γ (see Fig. 65-1).

Figure 65-1 Amyloid precursor protein (APP) processing pathways. CTF, carboxy terminal fragment; sAPP, soluble amyloid precursor protein.

Aβ42 constitutes less than 10% of the total secreted amyloid protein and is more likely to form fibrils than is Aβ40.¹² Aβ42 is found in the brains of all patients with Alzheimer’s disease, and Aβ40 is found in two thirds.¹³ Both accumulate as extracellular plaques consisting of β-pleated sheets, but before plaque formation, a combination of fewer Aβ molecules form oligomers, which may mediate the neurotoxic effects seen in Alzheimer’s disease. Understanding of the generation of Aβ has proceeded at a faster rate than understanding of the pathways that lead to neuronal dysfunction and death. Aβ may be neurotoxic directly, may initiate inflammation, may cause oxidative stress, or may affect calcium homeostasis, or it may lead to a combination of all of these. Table 65-7 lists some of these factors supporting the amyloid hypothesis.

TABLE 65-7 Factors Supporting the Amyloid Hypothesis as a Cause of Alzheimer’s Disease

Amyloid is found in the brains of all patients with Alzheimer’s disease.

There are three genes that, if they have undergone mutation, cause early-onset Alzheimer’s disease, and all increase Aβ production.⁵⁶

Patients with Down’s syndrome have trisomy 21. The amyloid precursor protein gene is located on chromosome 21. All patients with Down’s syndrome who live past age 40 develop the pathology of Alzheimer’s disease. Also, patients with Down’s syndrome have an increased production of Aβ from birth.⁵⁷^–⁵⁹

Patients with apolipoprotein E4 have increased deposition of Aβ in their brains.⁶⁰

First-degree relatives of patients with Alzheimer’s disease have increased plasma Aβ levels.⁶¹

When the double-transgenic mouse model of TG2576 (the amyloid mouse) is crossed with the P301L (tau mouse), the tau pathology is accelerated in their progeny; this is evidence of an interaction between these two fundamental pathological processes of Alzheimer’s disease.¹⁶

Low levels of CSF Aβ are correlated with Alzheimer’s disease, which suggests that the disease occurs when large amounts of Aβ have been deposited in the brain.

Aβ, β amyloid protein; CSF, cerebrospinal fluid.

Arguments against the Amyloid Hypothesis

The anatomical distribution of the tangle (tau) pathology is correlated better with the clinical picture than is distribution of the Aβ plaques.¹⁴ Because of this, some authors have proposed that tau, rather than Aβ, is the cause of the disease. Furthermore, there are many patients with extensive Aβ plaques who are not demented. Their condition is referred to as pathological aging in the literature.¹⁵ Because tau pathology is accelerated in the double-transgenic mouse¹⁶ by Aβ deposition, it is possible that Aβ deposition may be partially responsible for the tau pathology. Also, in the cases of early-onset Alzheimer’s disease, such as those caused by the APP mutations, there is typical tau pathology. Thus, attributing the disease exclusively to either the Aβ or tau pathology is incorrect; rather, it is much more likely that both pathological processes are involved. In further studies, investigators should work out how they interact, rather than ruling out one. Other important factors found in brains of patients with Alzheimer’s disease, including oxidative stress, inflammation, cell loss, apoptosis, and synapse loss, are probably crucial in the pathogenesis. Many researchers are studying the relationship of these factors to the amyloid and tau pathology.

PATHOLOGY

A definite diagnosis of Alzheimer’s dementia requires histopathological confirmation.

On gross examination (Fig. 65-2), the brain weight varies between 900 and 1200 g. The loss of brain weight is more marked in the early-onset form of Alzheimer’s disease, whereas in the late-onset form, there is substantial overlap with findings in age-matched controls. The temporal and parietal lobes are more affected than the frontal lobes. The occipital lobe may be involved but is relatively spared in the majority of cases. On examination, the diseased brain may appear normal in the early stages, but closer inspection usually reveals temporal lobe atrophy of its medial aspect with thinning of the cortical mantle. Other features include enlargement of the third and lateral ventricles, normal pigmentation of the substantia nigra, and pallor of the locus ceruleus in advanced cases. Alteration of pigmentation in the brainstem raises the possibility of other neurodegenerative disease (for example, Lewy body disease). In Alzheimer’s disease, the olfactory bulb is consistently smaller than expected. On occasion, atrophy may be asymmetrical or focal, and cases of Alzheimer’s disease with focal atrophy may be associated with focal cognitive deficits such as progressive aphasia, Balint’s syndrome, or frontal dementia.

Figure 65-2 Gross appearance of the brain of a patient with Alzheimer’s disease.

(Courtesy of Dennis Dickson, MD.)

The cardinal histopathological lesions of Alzheimer’s disease are senile plaques composed of extracellular amyloid deposits (Fig. 65-3) and neurofibrillary tangles composed of intraneuronal tau protein aggregates (Fig. 65-4). The plaques are detected by silver staining (Bielschowsky stain) or by specialized amyloid stains (thioflavin S, Congo red). The β-pleated sheet structure gives rise to the staining characteristics: that is, a birefringent apple-green appearance under polarized light. Some plaques are “diffuse,” and these may be present in nondemented individuals. These plaques do not have dystrophic neurites (nerve endings containing tau protein), unlike the “cored” or neuritic plaques, which have deposition of extracellular amyloid surrounded by tau-containing neurites. Neurofibrillary tangles are filamentous inclusions that are intraneuronal and are composed of hyperphosphorylated aggregates of the microtubule-associated protein tau. Electron microscopy reveals that tau consists of a paired helical filament structure. Initially, tau collects in the nucleus and becomes aggregated into paired helical filaments, after which it may be attached to the protein ubiquitin. These tau tangles affect the microtubules, which, in turn, interfere with neuronal and dendrite/axonal transport. The neurons die and are surrounded by phagocytes removing the debris. Eventually, the tangles become extracellular structures.

Figure 65-3 Dense amyloid core plaque stained with thioflavin S.

Figure 65-4 Neurofibrillary tangle stained with thioflavin S.

(Courtesy of Dennis Dickson, MD.)

Nonamyloid Components of Plaques

The plaques show evidence of inflammation because they are associated with activated microglial cells, components of the complement cascade, α₁-antichymotrypsin, and proinflammatory cytokines. Activated microglial cells are most evident in dense-cored plaques, especially those with Aβ40. In addition to their association with senile plaques, microglial cells are activated throughout the brain in Alzheimer’s disease. Microglial activation is correlated with the degree of neurofibrillary degeneration in the hippocampus, where microglial cells may be responding to neuronal and synaptic degeneration and loss.

Other nonamyloid components localized to senile plaques include components of the extracellular matrix, such as proteoglycans, amyloid P component (a serum-derived protein, present in virtually all types of amyloid deposits, which has been shown to accumulate in cerebral amyloid deposits, possibly because of alterations in the blood-brain barrier), and apolipoprotein E, which is derived from astrocytes.

Other Alzheimer’s disease–associated pathological changes include the following:

1. Amyloid deposition in cerebral blood vessels, known as cerebral amyloid angiopathy.

2. Granulovacuolar degeneration, which is not specific for Alzheimer’s disease; it is also seen in very old persons (>100 years old), in amyotrophic lateral sclerosis dementia–parkinsonism complex of Guam, in Down’s syndrome, and in Pick’s disease. It is characterized by a vesicle with a central basophilic granule that is seen in the hippocampal pyramidal neurons.

3. Hirano bodies, seen in the area CA1 and the subiculum of the hippocampus, consisting of eosinophilic rod-shaped structures lying adjacent to pyramidal neurons.

4. Increased density of fibrous astrocytes in the cortex of patients with Alzheimer’s disease.

5. Neuronal and synaptic loss in the area CA1 layer of the hippocampus, entorhinal cortex, anterior olfactory nucleus, and amygdala.

PATHOLOGICAL DIAGNOSTIC CRITERIA

Histopathological changes seen in patients with Alzheimer’s disease may overlap with changes seen in a nondemented elderly persons and may occur in patients with other neurodegenerative disease also (e.g., vascular dementia, Lewy body dementia). Different criteria are used in pathological assessment of Alzheimer’s disease cases. They include the Khachaturian criteria, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Guidelines for the Diagnosis of Alzheimer’s Disease, and the National Institute on Aging–Ronald and Nancy Reagan Institute criteria.¹⁷^–¹⁹

With the Khachaturian criteria, the age of the patient is compared with the density of the plaque count; this method tends to overestimate the frequency of Alzheimer’s disease. Major limitations of this method include a failure to distinguish between different plaque types and the lack of inclusion of neurofibrillary tangles in the analysis.

The CERAD criteria, which are widely used and reproducible between different laboratories,²⁰ involve the following:

Macroscopic features, such as brain weight, regional atrophy, atrophy of specific regions (hippocampus, entorhinal cortex), the presence of lacunar infarcts, and the color of the substantia nigra and locus ceruleus.

Histological sampling/staining of six anatomical regions (middle frontal gyrus, superior and middle temporal gyri, anterior cingulate gyrus, inferior parietal lobule, hippocampus and entorhinal cortex, and the midbrain, including the substantia nigra). These are stained with one or more of the following: hematoxylin/eosin, thioflavin S, a silver stain (modified Bielschowsky), and/or Congo red. The CERAD classification involves three steps: (1) A semiquantitative measurement of neuritic plaque density is made and then compared with a reference, and the score is categorized as none, sparse, moderate, or frequent. (2) Maximal plaque densities in the frontal, temporal, and parietal neocortex are then compared with references for the patient’s age, which yields an age-related plaque score. (3) This score is then used in conjunction with the patient’s history (absence/presence of dementia) to allow categorization of the patient as normal or as having possible, probable, or definite Alzheimer’s disease. As with the Khachaturian method, the classification in the CERAD criteria does not use neurofibrillary tangle density.

The National Institute on Aging–Ronald and Nancy Reagan Institute criteria ¹⁹ constitute the most recent attempt to solve the disadvantages of the first two classifications. They include an age-related plaque score and a staging of neurofibrillary tangle pathology (Braak’s staging system); combination of the two yields an estimate of the likelihood that a patient has Alzheimer’s disease, which is classified as high, intermediate, or low probability.

DIAGNOSIS

The diagnosis of Alzheimer’s disease in the clinic comprises a complete history, a complete physical examination, laboratory studies, special tests, and a neuropsychological evaluation. There is a continuum from normal aging to dementia, including an entity called mild cognitive impairment. Published criteria for this entity are listed in Table 65-8.

TABLE 65-8 Criteria for Mild Cognitive Impairment

Memory complaint, preferably corroborated by informant

Impaired memory function for age and education

Preserved general cognitive function

Intact activities of daily living

Not demented

Adapted from Petersen RC, Smith GE, Waring SC, et al: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303-308.

History

With regard to patients with dementia, physicians should obtain the history from both the patient and an informant. In fact, patients with memory difficulty may be unaware and even deny they have a memory problem (this is a form of anosognosia). While documenting the history, physicians should keep the differential diagnosis in mind (see Table 65-9).

TABLE 65-9 Causes of Dementia

Vascular Causes

Single strategic stroke

Subarachnoid hemorrhage

Superficial siderosis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Subdural hematoma

Infectious Causes

Acute and chronic fungal and bacterial meningitis

Sequelae of herpes encephalitis

Other viral encephalitis

HIV dementia

Neurosyphilis

Transmissible prion disease

Subacute sclerosing panencephalitis (SSPE)

Progressive multifocal leukoencephalopathy (PML)

Toxic, Metabolic, and Deficiency States

Medications (see Table 65-10)

Glue sniffing

Heavy metal ingestion (e.g., mercury)

Hypothyroidism

Vitamins B₁₂, B₁, B₃, and B₆ deficiency

Organ failure (heart, lung, kidney, and liver)

Substance abuse

Psychiatric Causes

Mood disorder (depression, bipolar disorder)

Psychosis

Neurological Diseases

Leukodystrophies (e.g., metachromatic leukodystrophy and adrenoleukodystrophy)

Hashimoto’s encephalopathy

Nonvasculitic autoimmune inflammatory meningoencephalitis

HIV, human immunodeficiency virus.

Determine the Presenting Symptoms

The informant should be asked with an open-ended question what abnormalities he or she noticed first and later, with specific questions to evaluate specific cognitive areas, such as memory.

Time Course of the Disease

The informant should be asked when he or she first noticed a problem and whether the onset was slowly progressive, stepwise, or acute.

Cognitive Domains

Psychiatric Factors

Depression

The clinician should ask whether the patient has lost interest in, or enjoyment of, activities; has become withdrawn; has gained or lost weight; is not taking part in usual activities; and whether he or she is sad or tearful, experiencing a feeling of hopelessness.

Anxiety

The clinician should ask whether the patient is upset when separated from the caregiver and whether the patient is nervous, short of breath, sighing, or tense.

Psychosis

The clinician should determine whether the patient experiences visual or auditory hallucinations or exhibits delusions. Patients often believe that a loved one is stealing from them, or they may suspect that burglars are trying to steal their property.

Personality Change and Disinhibition

The clinician should ask the informant whether the patient’s personality has changed and, if so, what has the informant noticed. The informant should discuss whether the patient shows anger or acts in a socially inappropriate way and whether the patient uses coarse language or exhibits inappropriate behavior in public.

Agitation and Aggression

The clinician should ask whether the patient is stubborn and whether he or she refuses help from others.

Sleep

This history is best obtained from a bed partner. The clinician should ask whether the patient has difficulty going to sleep, waking up, and going back to sleep; whether the patient is sleeping in the daytime; whether the patient snores or experiences apneic episodes; whether the patient has dream enactment behavior (acts out dreams at night); and whether the patient sleeps during the day and remains awake at night.

Activities of Daily Living

These activities can be divided into personal and instrumental. Examples of personal activities are the patient’s ability to perform bathroom chores and to dress. Examples of instrumental activities are using the telephone, writing a check, and preparing a meal.

Motor Activities

The clinician should determine whether the patient has trouble walking, writing, cutting food, or swallowing; whether the patient has fallen; and whether the patient has a tremor.

Hearing and Vision

The clinician should ask whether the patient has deficits in these areas.

Family History

The clinician should document a careful history regarding dementia in first-degree relatives (parents, siblings, and children) and any other relatives (grandparents, aunts, uncles, and cousins). If there is a history of dementia, the clinician should try to establish age at onset, symptoms, and specific etiology (e.g., through an autopsy report).

Medical Conditions That May Contribute to Dementia

The clinician should inquire about whether the patient has cardiovascular disease; hypertension; hypercholesterolemia; vitamin B₁₂ deficiency; diabetes; thyroid disease; incontinence; and substance abuse, including alcohol, tobacco, and recreational drugs.

Other Neurological Disease That May Contribute to Dementia

A history of stroke, head injury, seizures, multiple sclerosis, or cardiac arrest should be documented.

Medication

The patient and the informant should provide a list of all prescription and nonprescription medications and food supplements. Ideally, they should bring the containers of all the medications and supplements the patient takes. Table 65-10 contains a list of medications that may adversely affect cognition.

TABLE 65-10 Drugs with Cognitive Side Effects

Antibiotics	Metronidazole
Anticholinergic agents	Antihistamines (diphenhydramine) Atropine Benztropine Oxybutynin Tolterodine

Anticonvulsants

Psychotropic agents

Heterocyclic (imipramine, nortriptyline)

Monoamine oxidase inhibitors

Selective serotonin reuptake inhibitors (citalopram)

Other (bupropion, trazodone)

Antimanic agents

Lithium

Typical antipsychotics

Haloperidol, phenothiazines

Atypical antipsychotics

Quetiapine, olanzapine, risperidone

Amphetamines

Dextroamphetamine, methylphenidate

Analgesics

Cardiac agents

Hypnotics

Nonbenzodiazepines (zolpidem)

Chloral hydrate

Antineoplastic agents 5-Fluorouracil Antiparkinson agents

Miscellaneous agents

Examination

The patient should be given a standardized short mental status test such as the Kokmen Short Test of Mental Status ²¹ (Table 65-11) or the Mini-Mental State Examination. The patient’s anterograde memory should be tested with questions about current events or famous persons, such as the current president’s and spouse’s names and previous presidents’ and their spouses’ names. (The clinician should be sure that the patient has been exposed to this information.) Cardiovascular risk factors such as hypertension, arterial bruits, arrhythmias, and heart murmurs should be documented. A full neurological examination should be completed. The clinician should pay attention to focal deficits such as visual field cuts, pareses, sensory loss, and ataxia. The patient should be evaluated for extrapyramidal problems such as hypokinesia, rigidity, masklike facies, micrographia, and glabellar reflex. The clinician should examine the patient’s gait, looking at step size, speed of walking, arm swing, ability to turn, and how far apart the legs are. The presence of palmomental and snout reflexes is not particularly helpful because these are common in normal individuals. The grasp reflex occurs late in the course of the disease.

TABLE 65-11 Kokmen Short Test of Mental Status

Subtests	Testing	Maximum Score
Orientation	Name, address, current location (building), city, state, date (day), month, year	8
Attention	Digit span (present at 1 per second; record longest correct span)	7
	2-9-6-8-3
	5-7-1-9-4-6
	2-1-5-9-3-6-2
Learning & Immediate Recall	Learn four unrelated words: apple, Mr. Johnson, charity, tunnel	4
Learning & Immediate Recall	Record the number of trials for acquisition (maximum of 4 trials)	4
Calculation	5 × 13 =	4
	65 − 7 =
	58/2 =
	29 + 11 =
Abstraction/similarities	Similarities: orange/banana, dog/horse, table/bookcase	3
Information	President; first president; number of weeks per year; define an island	4
Construction	Copy the Necker cube	4
Construction	Draw a clock face showing 11:10	4
Recall	The four words apple, Mr. Johnson, charity, tunnel	4
Total score^*	The four words apple, Mr. Johnson, charity, tunnel	38

* Total score = sum of the subtest scores − (number of trials for acquisition − 1). For example, if a patient learned all 4 words on the first trial, nothing is subtracted from the sum of the subtest scores. If a patient required 4 trials to learn the 4 words, then 3 was subtracted from the sum of the subtest score.

From Kokmen E, Naessens JM, Offord KP: A short test of mental status: description and preliminary results. Mayo Clin Proc 1987; 62:281-288.

Special Tests

The following tests are indicated in the routine workup of a patient with dementia: laboratory studies, including complete blood cell count and measurements of thyroid-stimulating hormone; measurement of vitamin B₁₂ levels and rapid plasma reagin; and neuroimaging (computed tomography or magnetic resonance imaging). Other tests may be ordered as the clinical situation dictates. It is not necessary to perform a lumbar puncture in the routine assessment of a patient with Alzheimer’s disease,^22,²³ but it is indicated when the following diagnoses are suspected: central nervous system infection, prion disease, hydrocephalus in the presence of normal cerebrospinal fluid pressure, and nonvasculitic autoimmune inflammatory meningoencephalitis. Lumbar puncture should also be considered when the manifestation is atypical: for example, a rapid course or an early onset of disease. Cerebrospinal fluid can be analyzed for markers of prion disease (14-3-3 protein) and Alzheimer’s disease (tau protein and Aβ42 level). Neuropsychological test results characterize the pattern of cognitive strengths and weaknesses and, in this way, are helpful in diagnosis. Also, in mild cases, they may be helpful in determining whether there is a deficit. Furthermore, these tests may be used in monitoring patients over time.

Markers for Alzheimer’s Disease

“The Consensus Report of the Working Group on: ‘Molecular and Biochemical Markers of Alzheimer’s Disease’”²⁴ proposed that a diagnostic marker for Alzheimer’s disease should have as many of the following features as possible:

Ability to detect a fundamental feature of Alzheimer’s neuropathology.

Validated in neuropathologically confirmed cases.

Precise (able to detect Alzheimer’s disease early in its course and distinguish it from other dementias).

To date, the best markers are a combination of the cerebrospinal fluid tau and Aβ42 proteins. In an excellent review, Blennow and Hampel ²⁵ noted that the sensitivity and specificity for cerebrospinal fluid tau protein are 81% and 90%, respectively, and for cerebrospinal fluid Aβ42 protein, they are 86% and 90%, respectively. Because the clinical diagnosis without these markers is close to these measurements, most physicians do not use these markers routinely.

Neuroimaging: Distinguishing Cognitively Normal Individuals from Patients with Alzheimer’s Disease

Different imaging modalities can be used to distinguish cognitively normal persons from patients with Alzheimer’s disease.

Using structural magnetic resonance imaging, investigators have reported that with regard to visual inspection of anteromedial temporal lobe atrophy, the sensitivity is 83% to 85% and the specificity is 96% to 98% in distinguishing clinically diagnosed Alzheimer’s disease cases from controls.²⁶ It is possible to outline the areas of interest in Alzheimer’s disease, such as the hippocampus, and to use this information for diagnosis and longitudinal change over time. An example is shown in Figure 65-5. Temporal and parietal hypometabolism characterize the typical positron emission tomography (PET) findings in Alzheimer’s disease. Published estimates of PET sensitivity and specificity, in which pathologically verified cases of Alzheimer’s disease were distinguished from controls by functional imaging, have ranged from 63% to 82%.²⁷ It is now possible to image Alzheimer’s disease plaques and tangles directly with carbon 11 or fluorine 18 isotopes. Using the Pittsburgh B compound (Fig. 65-6), researchers imaged amyloid plaques and were able to distinguish patients with Alzheimer’s disease from controls in most cases.²⁸

Figure 65-5 Hippocampal atrophy in a case of Alzheimer’s disease.

(From Sencakova D, Graff-Radford NR, Willis FB, et al: Hippocampal atrophy correlates with clinical features of Alzheimer disease in African Americans. Arch Neurol 2001; 58:1593-1597.)

Figure 65-6 Positron emission tomographic images of a brain from a patient with Alzheimer’s disease. AD, alzheimer’s disease; MR, magnetic resonance.

(Courtesy of William Klunk, Chet Mathis, Steven DeKosky, and the University of Pittsburgh Imaging Group.)

MANAGEMENT

Pharmacological Treatment

Current pharmacological treatment involves use of a cholinesterase inhibitor, which increases brain acetylcholine concentrations. In 2003, the U.S. Food and Drug Administration approved the use of memantine, a glutamate receptor antagonist, for treatment of moderate to severe Alzheimer’s disease. These two classes of agents represent the mainstay of current treatment and are listed in Table 65-12. Memantine may be used with any of the cholinesterase inhibitors or on its own; if the patient cannot tolerate cholinesterase inhibitors it may be used alone.

TABLE 65-12 Medications for Alzheimer’s Disease

Therapies in Development

One of the targets identified is the Aβ protein. Academic institutions and pharmaceutical companies are investigating a number of strategies. These include drugs that inhibit the enzymes that form Aβ: that is, γ-secretase and β-secretase inhibitors. Experimentally, immunizing transgenic mice may prevent and remove amyloid from their brains; therefore, active and passive immunization are being investigated. One group has shown that heavy metal modulators, such as clioquinol, remove amyloid from the brain; this medication and newer generations of it are being investigated. Another strategy is to prevent amyloid from forming fibrils, and at present, such a medication has entered trials. Knowledge that some nonsteroidal anti-inflammatory agents decrease amyloid in the brains of transgenic mice has led to investigations of these agents. Some researchers are using antioxidant strategies.

Safety Issues

Driving

Patients with memory impairment are at increased risk for automobile accidents and therefore should be made aware of this.²⁹ The American Academy of Neurology guidelines on driving and Alzheimer’s disease indicate that persons with a Clinical Dementia Rating Scale (CDR) score of 0.5 are at increased risk for accidents, but the risk is no greater than that for other groups at high risk, such as men aged 18 to 25 years or those with blood alcohol levels exceeding 0.08%. Patients can be offered a road test to evaluate their driving ability. Patients with a score of 1 or greater (equivalent to a Mini-Mental State Examination score of less than 25) are at great risk and should be advised not to drive.

The health provider should assess the patient’s living situation to make sure the patient is safe. Advice should be tailored for each situation. Factors to consider include severity of the problem, amount of family support available, patients’ behav iors, finances, and community options. Weapons should be removed or disabled. At the beginning, patients often live with a spouse or independently with regular monitoring by family members. Later, options include in-home respite care, day care, and assisted living facilities. In the later stages, the patient may need to be placed in a nursing home. Determining factors in making the decision to place a patient in a nursing home include severity of the disease, behavioral symptoms, incontinence, caregiver stress or ill health, and the family’s financial situation.

Durable Power of Attorney

The health provider should ensure that the patient has designated a person with durable power of attorney for health decisions.

Finances

The family should create a situation so that the patient is less subject to financial errors, such as paying bills more than once or forgetting to pay them. Family members can oversee bill payment, or payment can be automated through a bank. Families should prevent exploitation of patients (which is all too common) and monitor investment decisions, another area of vulnerability.

Infection (especially urinary infection), medication (particularly anticholinergics, analgesics, sedatives, and antipsychotics) (see Table 65-10), dehydration, electrolyte imbalance, constipation, pain, system dysfunction (biliary, cardiac, pulmonary, renal, and endocrine), and neurological dysfunction (cerebrovascular disease, seizure, and subdural hemorrhage) can affect the degree of agitation.