A Guide to the Diagnosis and Assessment of Alzheimer's Disease

Section 2
Diagnosing Alzheimer's disease in primary care

• Describe the assessment process for the diagnosis of patients suspected of AD
• Evaluate the assessment tools available to the primary care physician in the diagnosis of AD

CASE-FINDING FOR COGNITIVE IMPAIRMENT

AD is the most common cause of dementia. In the community, however, up to half of all sufferers may remain undiagnosed. It is often only when the care support is removed, for example, when a caregiver dies or becomes unable to cope because of illness, that the patient suffering from AD is discovered.

It is, therefore, necessary to be vigilant to the presence of cognitive impairment in elderly patients and proactively case-find during routine appointments. If a problem is suspected, a very simple way of opening up the discussion is to ask the patient the following question:

"How is your memory?"

In addition, there are a number of very quick and simple structured tests, such as the Clifton Assessment Procedures for the Elderly (CAPE), that can be used to assess the patient's level of cognitive ability (Appendix 2). These tests can also be used to provide a rapid initial evaluation of patients who approach you directly complaining of memory problems. In other cases it is often a concerned family member or caregiver who seeks medical advice for the patient.

If there is a suspicion of memory or cognitive impairment, a more structured assessment can then be performed. This should include:

• Clinical history (including caregiver assessment and support)
• Physical examination (including laboratory tests)
• Functional assessment
• Cognitive assessment
• Neuroimaging

The clinical assessment can be complicated by a number of factors. These include the age of the patient, level of education, intelligence, cultural background and co-morbid illnesses. Assessment instruments should be validated for specific populations. All these factors should be considered when a clinical assessment is undertaken.

CLINICAL HISTORY

The AD assessment begins with a comprehensive clinical history. The clinical history is an essential part of the assessment process and must involve carers and relatives as well as the patient. It should be focused, planned and use all available information sources.

The clinical history provides the opportunity to establish the patient's baseline functional ability, intelligence and social interaction prior to onset of the problems. It also allows the pattern of deterioration to be assessed. Is the deterioration stepwise or continuous? Was the onset slow and insidious, or abrupt? Are the symptoms worsening, fluctuating or improving?

Patient and caregiver interview

The history must include an interview with the patient and the family, if available. The patient and family should be interviewed both together and separately. Family members are often reluctant to discuss problems in front of the patient for fear of upsetting them. Patients are often not aware of the symptoms or are in a state of denial. A more accurate and reliable picture of the patient's pre-morbid functioning, onset and pattern of deterioration can be obtained in this way. This, however, is not always possible; patients are often distressed and anxious and insist on being accompanied by the family. If a separate interview cannot be arranged during the patient visit, then the family should be interviewed by telephone or a separate appointment organized.

To obtain an accurate picture, a second interview should be performed, especially if the patient appears to be behaving normally. Often patients with AD perform better in the doctor's office. A patient may try particularly hard at the interview to disguise the problems described by the family.

A home visit provides an alternative approach, if deemed appropriate. This can give a first-hand indication of the functional ability of the patient and how the family is coping.

Caregiver input

Caregiver input is an essential part of the clinical history. A number of approaches can be adopted to help the caregiver recognize and monitor the changes in the patient. Two useful methods are caregiver checklists (containing questions and signs to look for) and a caregiver diary (a weekly record that monitors changes in the patient). This diary provides a comparison between the current and pre-morbid functioning, and allows the progression of the disease to be monitored. The caregiver observations provide vital background information that may support the suspicion of AD and will initiate further assessment.

The interview may disclose changes in cognition, ADLs and IADLs, mood, and the presence of delusions and hallucinations.

Common problems presented by the patient or family may include:

• Forgetfulness
• Deterioration in performance at work or in the home
• Difficulties managing finances
• Inability to recognize, or a lack of interest in, family members
• Difficulties driving, shopping, using the telephone
• Getting lost in familiar settings

If there is a suspicion of AD, the following questions should be asked at the initial AD assessment:

• How did it start?
• Did the changes start suddenly or gradually?
• How long has this been going on?
• Is the situation progressing? If so, how rapidly?
• What changes have you noticed?

Behavioral changes are common in AD. Ask the caregiver questions that specifically relate to behavioral changes, such as:

• Have you noticed any personality changes (these may include irritability, lack of enthusiasm, loss of interest in hobbies, unhappiness, unreasonable behavior and being unaffectionate and less kind)?
• Has the patient suffered any, delusions or hallucinations?
• Does the patient become agitated or wander?

Answering questions

The well-informed patient or caregiver who is concerned about the possibility of AD may ask a number of questions based on facts they have gleaned from television, radio or in newspapers.

Such areas may include:

• Family links
• Aluminium (this is no longer considered to play a role in AD)
• Stressful life events

AD protective factors:

• Estrogen use (in women)
• Long-term anti-inflammatory use
• Nicotine
• Education
• Vitamins and food supplements
• ApoE2

PHYSICAL EXAMINATION

A complete physical examination should be undertaken using the same principles that are employed in the assessment of any illness. Potentially dangerous and treatable conditions should be considered first: intracranial mass lesions, vascular lesions, and infections. The examination should include blood pressure, pulse, vision and hearing, cardiac and respiratory function, mobility and balance. A thorough examination of sensory and motor systems is necessary, including tone, reflexes, gait and coordination.

LABORATORY TESTS

To supplement the physical examination, certain laboratory tests should be requested to rule out concomitant illnesses and other causes of dementia (Table 11). HIV testing may be indicated in high risk groups.

FUNCTIONAL ASSESSMENT

Decline in ADLs is a distinctive feature of AD and has a major impact on the quality of life of AD patients and their carers. As decline in ADLs is so prominent, it is included in all the AD diagnostic criteria. Assessing ADL function is a major part of clinical assessment and of planning future care for the patient.

• Complete blood count
• Thyroid function
• Vitamin B₁₂ and folate
• Syphilis serology
• BUN and creatinine
• Calcium
• Glucose
• Electrolytes
• Urinalysis
• Liver function tests

• ECG
• Chest X-ray

In the primary care setting, one way to obtain a quick and easy measure of functional disability is to score a structured functional activities questionnaire.

Functional Activities Questionnaire (FAQ)

FAQ is an informant-based questionnaire that provides a rapid appraisal of patient performance in functional ability. It may be necessary to adapt the questions, depending on gender and culture.

The informant is asked to rate the performance of the patient in 10 areas of IADL (Table 12 below).

• Dealing with financial matters, paying bills, writing checks
• Keeping records of taxes, business affairs
• Shopping for everyday necessities: groceries, clothes, etc
• Hobbies or playing games
• Making tea, turning the kettle on and off
• Cooking a balanced meal
• Perception of current events
• Level of attention and understanding: books, television
• Memory: remembering appointments and medications
• Getting about: driving or taking public transport

COGNITIVE ASSESSMENT

The FAQ will establish whether functional impairment is present, raising concern and allowing
further testing to be conducted. Functional disability is usually linked to a decline in cognitive functioning. However, the prime marker for AD is cognitive decline. Determining the status of a patient's cognitive function if AD is suspected is, therefore, a critical element of the clinical assessment.

An objective examination of cognitive function must form part of the initial evaluation. This assessment provides a profile of the cognitive functioning of the patient. Several brief tests are available to assess cognitive function and mental status.

Primary care cognitive assessment

Two assessments that can be deployed easily in the primary care setting are:

• Mini Mental State Examination
• Clock Draw Test

Mini Mental State Examination (MMSE)

The MMSE is a short collection of cognitive tests that examines several areas of cognition (Table 13 below). It is widely used to measure the onset, progression and severity of Alzheimer's disease in the clinical setting.

• Orientation
• Memory
• Attention
• Recall
• Language (reading, writing and drawing)

This test was originally developed for use by 'Western' cultures and therefore needs modifying for use in other societies. For example, the statement 'close your eyes' signifies death in Chinese culture.

The test guidelines are brief and simple to understand; however, the test can still be problematical to perform. The interpretation and scoring of answers is broad and largely subjective. This may lead to variations in the interpretation of results. Attempts have been made to standardize the MMSE by including specific guidelines (Molloy et al 1991, Appendix 3).

Clock Draw Test (CDT)

The CDT examines areas that are not fully evaluated by the MMSE.

These include planning and construction abilities. This test is easy to understand. The patient is asked to draw a clock. They are then asked to interpret the time they have depicted by writing in figures the time shown on the clock (see Appendix 4). Interpretation of the clock varies enormously from patient to patient (Figure 6). The drawings, however, can be evaluated and scored using four easily distinguishable criteria (Table 15).

If the CDT test is performed in isolation, scores ranging between 6 and 7 represent normal cognitive functioning. Scores between 0 and 5 suggest that there is evidence of impairment in the planning and construction areas of cognition.

Performing both the CDT test and the MMSE gives a broader and more informative screening of cognitive functioning. Both tests can be evaluated together using the combined CDT and MMSE scoring system. Scores ranging between 7 and 9 represent normal cognitive function (Table 15).

Brain imaging techniques are a useful adjunct in the diagnosis of AD. These techniques visualize changes in the brain and identify gross neuropathological processes, such as cerebral atrophy. The principle reason for conducting brain imaging is to eliminate other causes of dementia, such as tumors and ischemic lesions. Imaging will not necessarily confirm a diagnosis of AD; for example, cerebral atrophy is observed in many patients with AD; however, it is also present in older individuals with normal cognitive functioning.

Brain imaging procedures can be divided into two groups:

• Static or structural procedures visualize tissue structure and neuroanatomy: Computed (axial) Tomography (CT) and Magnetic Resonance Imaging (MRI).
• Dynamic or functional procedures reveal patterns of metabolic activity and blood flow: Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT)

Static or structural imaging

Computed (axial) Tomography (CT)

Although first introduced in 1974, it is only recently that the full potential of the CT scan has begun to be realized. The procedure reveals a structural image of the brain. It is patient-friendly and the experience is less harrowing than some other techniques, for example, MRI (Table 16). This is an important advantage in the assessment of patients with suspected AD who are easily confused and upset. CT scans take 20­30 minutes to perform.

• Normal examination for the patient's age
• Generalized cerebral atrophy
• Small vessel changes, areas of leucoencephalopathy
• No signs of subdural hematoma (if head trauma suspected)
• Absence of specific areas of cerebral infarctions or evidence of stroke

• Less expensive
• Patient-friendly
• Widely available
• Less structural change revealed

• Relatively expensive
• More harrowing for the patient
• Less widely available
• Reveals greater structural change

CT interpretation

A CT scan is considered adequate in most cases to discount space-occupying lesions and is probably as effective as MRI for this purpose. CT can identify moderate to large areas of infarction and can detect significant subdural hematoma.

A standard axial CT angle may reveal:

• Extent of cortical atrophy
• Presence of focal atrophy
• Extent of white-matter change
• Brain infarction
• Tumors
• Subdural hemorrhage

Neuropathological studies show that the highest density of the characteristic neurofibrillary tangles in AD patients are in the hippocampus and other structures that make up the medial temporal lobe. As the loss of neurons in the hippocampus ensues, the volume of this part of the medial temporal lobe is greatly reduced.

In addition, the rate of cerebral, and in particular medial temporal lobe atrophy, in patients with AD, is associated with the rate of decline in cognitive function. Although it can be difficult to differentiate AD from changes associated with normal aging in the initial CT scan, a follow-up scan may, however, reveal an accelerated rate of atrophy in this area that is characteristic for AD.

Although the presence of brain atrophy does not confirm AD, similarly its absence does not discount the disease.

CT remains as effective as MRI in subjectively measuring regional atrophy. The fact that it is relatively inexpensive, accessible and well tolerated by patients makes it an invaluable tool to help support a diagnosis of AD.

BIOLOGICAL MARKERS

The existence of a genetic biological marker for AD has long been sought. If discovered, it would allow genotyping for the disease and the identification of individuals at increased risk of developing the disease.

The discovery of a specific genetic marker proved elusive until 1993, when an association between the gene coding for apolipoprotein E (ApoE) and the risk of AD was established. This gene is the most important genetic determinant of risk of sporadic and late-onset familial AD.

ApoE is involved in lipid transport and is encoded by a gene found on the long arm of chromosome 19. It has three major isoforms (E4, E3 and E2) which are expressed by multiple allelic variants. This gives rise to three common homozygous genotypes, E4/4, E3/3, and E2/2, and three common heterozygous genotypes, E4/3, E4/2 and E3/2. Each genotype encodes a specific apolipoprotein that differs slightly in amino acid sequence, each possessing distinctive biochemical properties.

It has been suggested that the ApoE isoforms differentially affect the disposition of amyloid (senile) plaques and NFT formation. The E4 allele appears to increase the risk of AD. This, however, is not demonstrated across all ethnic groups.

Despite ApoE4 being a marker for AD, it is likely that other factors are involved in the pathogenesis of the disease. In addition, the ApoE2 allele has been associated with a decreased risk of AD. Further research is needed to confirm this finding and clarify these associations.

Although the ApoE4 allele represents a major risk factor, its link with the time of onset of AD is less well defined. This can be demonstrated within families, where individuals may possess a different number of copies of the allele, or none at all. Some ApoE4-positive individuals do not go on to develop the disease, while others without the allele do. With this in mind, ApoE genotyping cannot be used to predict the risk of AD in symptom-free individuals. ApoE genotyping may be clinically useful as an adjunct to other diagnostic procedures in patients with dementia symptoms and where the diagnosis of AD is unclear. If a test for ApoE is to be requested, ensure that the patient and family are fully aware of issues that may arise. Referral to a professional genetic clinic may be appropriate.

The diagnostic process:

• Clinical history
• Physical examination
• Laboratory tests
• Functional assessment
• Cognitive assessment
• Neuroimaging

Clinical history and physical examination form the basis of the assessment of AD

The Functional Activity Questionnaire (FAQ) provides a rapid appraisal of patient performance and functional ability

MMSE and CDT provide a quick and simple screen of cognitive function

Staging assessments establish the extent of disease progression and determine the disease course

A CT scan without contrast is recommended in most cases

ApoE should be considered as an adjunct in cases where the AD diagnosis is unclear, and not as a test in asymptomatic individuals