Chapter 4

Diagnosis of Dementia

Chapter Question:
What tests are available for dementia?
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The diagnosis of dementia largely relies on clinical interviews

with the patient and family members, because there are no lab-
oratory tests or radiologic studies that can affirm or refute a diag-
nosis of dementia. There are brief bedside tests of mental status
that may aid in the initial screening of dementia as well as more
extensive neuropsychologic exams, blood tests, and neurodiag-
nostic tests, such as MRI and electroencephalogram (EEG). Chapter
4 reviews some of the different kinds of tests that may be used
in the diagnosis of AD.

BRIEF BEDSIDE TESTS OF MENTAL STATUS

B can be conducted (3 to 10 minutes) that

RIEF TESTS OF MENTAL STATUS
provide the neurologist with important information that may lead
to further testing or a fine-tuning of diagnostic considerations. These
tests are not considered diagnostic on their own, but when included as
part of a complete examination, they assist in ruling out or “ruling in”
certain causes. Seven of these exams will be briefly discussed in this
chapter.

The Mini-Mental State Examination

One of the oldest and most widely used bedside tests is the Mini-Mental
Copyright 2005. Demos Health.

State Examination (MMSE), which was developed by Dr. Marshall

Folstein in the mid-1970s. This examination has achieved widespread

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 Alzheimer’s Disease

acceptance in both the research and clinical communities. The MMSE

asks questions covering several areas of cognition, with possible scores
ranging from 0 to 30. The first 10 points are earned by answering ques-
tions regarding the date and present location. Three points are earned

One of the oldest and most widely used

bedside tests is the Mini-Mental State
Examination (MMSE).

for immediate memory (repetition of three items; for example, “apple,

table, penny”); 3 points are earned for the recall of these three items.
Five points are earned for serially subtracting 7s from 100 (that is, “93-
86-79-72-65”), or for correctly spelling a five-letter word backwards.
Finally, 9 points are earned for tasks that assess a range of cognitive
function, including naming objects, following a three-part instruction,
writing a sentence, and copying a figure. In general, scores of 27 or high-
er are considered normal; scores between 23 and 26 are borderline; and
scores 22 or below are abnormal. For AD patients, scores from 20 to 26
correlate to mild AD; scores from 10 to 19, and those less than 10, cor-
respond to moderate and severe AD, respectively.
In AD patients, scores on this exam have been used to predict when
certain difficulties might arise over the course of the illness. Figure 4-1
shows the correlation of the loss of ability to perform various activities
of daily living with the MMSE score and the number of years since diag-
nosis. For example, the ability to keep appointments may be lost by one-
fourth of those with an initial MMSE score of 25, but after several years,
when the MMSE score has dropped to 18, as many as three-fourths of
patients have lost this ability. Similarly, the ability to appropriately select
clothes is lost by one-fourth of those with MMSE scores of 20 2 years
after diagnosis; after 7 years and an MMSE score of 8, three-fourths of
patients may have trouble with this task. On average, untreated AD
patients lose 2 to 4 points per year on the MMSE.
Unfortunately, the MMSE has two important limitations. First, it is
sensitive to education. Highly educated people who are mildly dement-

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 CHAPTER 4 • Diagnosis of Dementia

FIGURE 4-1
Correlation of activities of daily living with years since diagnosis and
MMSE scores.

ed may still score within the normal range because the questions are too
easy for them, but, conversely, poorly educated but cognitively normal
people may score in the dementia range because some of the questions
are too difficult. Second, some physicians choose not to use this test
because it takes too long to administer (5 to 10 minutes).

The Clock Drawing Test

The clock drawing test is a simple, easy to administer exam that is used
both as a screening tool and as part of more comprehensive neuropsy-

The clock drawing test is a simple, easy-to-

administer exam, but is not sensitive for
detecting early dementia.

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 Alzheimer’s Disease

chologic testing. The instructions are to “Draw a clock. Put in all the
numbers. Set the hands at ten past eleven.” This test appears simple but
the results can provide a wealth of information related to memory, strat-
egy, vision, and processing of information. Figure 4-2 is a clock drawing
from an 85-year-old man who was referred for possible Lou Gehrig’s dis-
ease (amyotrophic lateral sclerosis). The man and his family denied any
problems with memory, but admitted that occasionally he seemed “a lit-
tle confused.”
The patient made several errors. He duplicated the number 12, left
out the hands, and wrote “to” in between the 11 and 12 with a little
arrow pointing to it (perhaps trying to represent ten to eleven). As a
result of this and other testing, as well as conversations with the family,
the gentleman was later diagnosed with AD.
Although numerous scoring systems are available for this test, the
AD cooperative scoring system has 5 points: 1 for the circle, 1 for all
numbers being present in the correct order, 1 for the numbers being in
a proper spatial arrangement, 1 for two hands being present, and 1 for
the correct time. The drawing in Figure 4-2 would earn a score of 2 (1
for the circle and 1 for the numbers being in a proper spatial arrange-
ment). A normal score is 4 or 5.
The clock drawing test shares a similar criticism with the MMSE: It
is not very sensitive to mild impairments. Virtually all normal people
will perform well on this test, as will many individuals with mild demen-
tia. When the exam is abnormal, however, it does offer specific clues as
to which system is affected.

FIGURE 4-2
Example of a clock drawing by an 85-year-old man with AD.

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 CHAPTER 4 • Diagnosis of Dementia

Memory Impairment Screen

Because memory is often one of the earliest and most affected aspects of
cognition in AD, it seems reasonable that a screening test focusing on
memory would be developed. Herman Buschke designed a 4-minute
screening test involving the recall of four items. This test also includes
“category cues” to help people remember the items. AD patients are
unable to utilize the clues as well as unimpaired adults, so they score
lower on the test.
The test procedure is relatively straightforward. The patient is hand-
ed a piece of paper with four items printed in large letters and asked to
read them aloud. The examiner states each cue, in turn, and the person
picks the word that goes with it. For example, if the items are “peach,
truck, calculator, shirt,” the category cues might be “fruit, vehicle, elec-
tronic device, clothing.” After a delay of 2 to 3 minutes, during which
time the patient is engaged in some other activity, such as counting or
drawing, he is asked to recall the items. He gets 2 points for each item
he recalls without the cue. He gets 1 point for each item recalled with
the cue. If he does not remember the item even with the cue, he gets 0
points. This makes the best possible score 8, and the worst 0. A score of
4 or less is consistent with dementia.
Overall, the memory impairment screen is a simple test that can
expose the early memory weakness seen in AD, but it may miss the
minority of dementias that present with cognitive problems other than
memory as the most afflicted area because of its strict reliance on
memory.

The memory impairment screen is a simple

test that can expose the early memory
weakness seen in AD.

The Six-Item Screener

Careful analysis of the various items on the MMSE has shown that the
ones most sensitive to early AD are the three-word recall and the date.

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 Alzheimer’s Disease

The six-item screener consists of the three-word recall combined with

asking the month, year, and day of the week in between. The patient
gets 1 point for each correct item, so scores range from 0 to 6. This test
is fast, taking less than a minute to administer. The physician asks the
patient to “Repeat and remember these three words: flag, tree, dime.”
After the person repeats the three words once, the physician asks the
patient to state the day, month, and year. Last, the patient is asked to
repeat the three words. A score of 3 or less indicates a problem.
In studies so far, the six-item screener has been evaluated primarily
in a population dominated by people of lower socioeconomic and edu-
cational status, where it was found to be a good tool for distinguishing
normal individuals from those with dementia. However, has not been
evaluated in a more highly educated sample. By definition, for example,
someone with a mild dementia and MMSE scores of 28 or higher will
automatically pass the six-item screener.

The Mini-Cog
The mini-cog combines a clock drawing test and a three-item recall test.
Soo Borson authored this exam, which is easy to administer and score. It is
a pass or fail exam. If the patient recalls all three items, she automatically
passes; if she does not recall any of them, she automatically fails. The clock
drawing test is used as a tie-breaker in case only one or two items are
recalled. If the clock drawing is normal, the patient earns a pass; if not, she
earns a fail. The mini-cog has been tested in multiethnic samples and has
been shown to significantly improve recognition of both MCI and demen-
tia by primary care doctors. Again, it is not clear how well it performs in
the more highly educated population. Because many normal people fail
the three-item recall if they are distracted, a failure on either the mini-cog
or six-item screener due only to recall should be interpreted cautiously.

The Hopkins Verbal Learning Test

The Hopkins Verbal Learning Test (HVLT) takes about 5 minutes to
administer and hence is somewhat longer than the mini-cog and six-

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 CHAPTER 4 • Diagnosis of Dementia

item screener. To administer the test, the physician reads a list of twelve
words, and immediately afterwards the person repeats as many of them
as he can. The procedure is repeated two more times, and the total num-
ber of words recalled over the three trials is added up to get the “total
recall” score. This is the working memory, immediate recall portion of
the test. The physician then reads a list of twenty-four words: the twelve
on the original list mixed with twelve new words. The patient is asked
to give a “yes” or “no” response for each word as to whether it was on
the list. The number of new words the patient claims to remember is
subtracted from the number actually recognized as being on the list for
the “discrimination index.” The total recall score is added to the dis-
crimination index to give the “memory score.” Scores range from 12 to
48 with an average range of 30 to 35.
A memory score of less than 25 indicates impairment. This test is bet-
ter at identifying AD than other dementias because it is restricted to
memory. It has not been examined in a mild dementia sample, however.

Dr. D’s Quick and Easy (Q & E) Dementia Screening Test

The last dementia screening test discussed here is a relatively new, 2.5-
minute exam designed by one of the authors of this book, Paul Dash,
who adopted screening tests used by physicians at the University of
California at San Diego to create “Dr. D’s Q & E.” This test is similar to
one independently developed by Wes Ashford that is used at the
University of Kentucky. The Q & E has four parts, including encoding
(learning three paired items; for example: “red ball, white horse, gold
key”); temporal orientation (the date); verbal fluency (number of ani-
mals named in 1 minute); and recall (pairs). The scoring system for this
test is different from other tests because lower scores are better.
For encoding, if the patient repeats the items twice on the first
attempt, or with one repetition by the physician, he earns 0 points. If the
items must be repeated a second time, he gets 1 point; a third time, 2
points. If he still cannot repeat them all, he is asked to repeat them one
by one, thus earning a score of 3. For the temporal orientation portion,
patients earn 0 points if they are within 1 day of the date, and 1 point if

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 Alzheimer’s Disease

more than a day off. An additional 2 points are given if they state the
wrong month; 3 points if they give the wrong year. For the verbal flu-
ency task, the patient earns 0 points if they name fourteen or more ani-
mals, 1 point for ten to thirteen animals, 2 for six to nine animals, 3 for
three to five animals, and 4 for zero to two animals. One point is earned
if the same animal is repeated two or three times; 2 points are earned if
they repeat four or more animals. Finally, for the recall of the three
paired items, patients earn one point for every pair missed and a half a
point for mixed-up pairs (for example, “red horse”).
The scores from each section are added up to arrive at a final Q & E
score. Scores range from 0 to 21. A normal score is 0 to 2. Three is a bor-
derline score and scores of 4 or greater typically indicate a problem. The
Q & E evaluates more than just memory. Consequently, it may help
detect non-AD dementias. This test can also be used to track changes,
because it has a relatively large score range. Preliminary research indi-
cates that the Q & E is more sensitive than the MMSE, mini-cog, clock
draw, and six-item screener in detecting mild dementia, while still
allowing the vast majority of normal people to score within the normal
range, regardless of educational background.

The Q & E is more sensitive than the MMSE,

mini-cog, clock draw, and six-item screener in
detecting mild dementia.

EXTENSIVE NEUROPSYCHOLOGIC TESTING

Although the dementia screens are useful during office visits, and often
provide sufficient information to the doctor, more extensive testing can
help diagnose AD and other dementias. Typically, these evaluations are
performed by a neuropsychologist. The tests are administered one-on-
one, often over the course of 2 or more days in order to minimize
fatigue. In-depth testing is necessary in a variety of circumstances. Three
common reasons are to rule out illness in the presence of mild or bor-
derline impairment (if the patient’s problems are unusual), and when a

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 CHAPTER 4 • Diagnosis of Dementia

significant psychiatric history complicates the interpretation of bedside

cognitive tests. In any case, tests can be used as a baseline measure so
that follow-up exams also include information about changes or the rate
of decline.
Specialized tests in multiple cognitive areas can confirm or deny that
problems are present and outline their severity if warranted. The neu-
ropsychologist often provides helpful suggestions for utilizing preserved
cognitive strengths in problem solving and exercises for improving areas
of cognitive weakness. Neuropsychologic testing is also potentially help-
ful in certain medical/legal situations; for example, when a person’s
competence to make decisions is at issue.
In AD, there are three tests a patient is likely to encounter that may
be portions of a larger comprehensive neuropsychologic battery. The
first is the Alzheimer’s Disease Association Diagnostic cognition test
(ADAS-cog). It takes about 45 minutes to administer, and surveys all
aspects of cognition in some detail. The second is the Repeatable Battery
for the Assessment of Neuropsychological Status (RBANS). This is a
comprehensive test designed for the elderly that takes about a half an
hour to administer. Preliminary evidence indicates the RBANS is more
sensitive than the MMSE in detecting very mild dementia. Last is the
Addenbrooke’s Cognitive Examination (ACE) test, developed in
England, which also takes about a half-hour to administer. Although
these and other tests are readily available, the majority of individuals
with a typical history and cognitive evaluation consistent with AD will
not require extensive neuropsychologic testing.

STANDARD MEDICAL TESTS FOR DEMENTIA

If the physician discovers significant cognitive problems, either through
simple office visit exams or through more extensive neuropsychologic
testing, the next step is to try to uncover the potential causes. Blood

The next step is to try to uncover the

potential causes.

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 Alzheimer’s Disease

tests, neuroimaging, electroencephalography (EEG), and the sampling of

cerebrospinal fluid (CSF) may all be requested by the doctor.

Blood Tests
The blood tests typically ordered when dementia is suspected include a
set of routine tests and some special ones. The routine tests are a com-
plete blood count (CBC) and a comprehensive chemistry panel. The
CBC includes tests for the number of white blood cells, which can indi-
cate whether an infection or immunodeficiency syndrome is present,
and the hemoglobin and hematocrit, which are measures of the number
and size of red blood cells. Changes in red blood cell size may indicate
whether certain vitamin or mineral deficiencies are present. For exam-
ple, iron deficiency causes the red cells to shrink; whereas vitamin B12
and folate (folic acid) deficiencies cause them to become enlarged. Last,
there is a platelet count. Platelets are involved in blood clotting.
The chemistry panel includes measurement of standard blood chem-
icals, such as glucose, sodium, potassium, and calcium, as well as the
levels of various enzymes and cholesterol. It provides an indication of
functioning for certain vital organs, especially the liver and kidneys. The
brain requires a healthy level of important minerals and proper func-
tioning of the internal organs in order to work properly. People with
untreated liver or kidney failure, or whose blood sugar is too high or too
low, will have problems with cognition. Patients often have normal CBC
and chemistry panels because disruptions in these systems do not usual-
ly accompany AD. In addition to these routine tests, a few special blood
tests are recommended. These include measures of thyroid function,
usually a serum T4 and thyroid-stimulating hormone (TSH) to check
whether the thyroid gland is under- or overactive. Also, vitamin B12 and
folate levels are checked, as well as the erythrocyte sedimentation rate
(ESR). The ESR is increased in certain autoimmune diseases, such as sys-
temic lupus, which can be associated with cognitive problems. It was for-
merly recommended that a Venereal Disease Research Laboratory Slide
Test (VDRL), a test for syphilis, be routinely ordered, but this is now in
the optional category because advanced syphilis affecting the nervous

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 CHAPTER 4 • Diagnosis of Dementia

system is very rare these days. In certain areas of the United States
where syphilis is highly prevalent, however, this test may still be part of
dementia screening. Similar to the routine tests, the specialized blood
test results are generally normal in AD patients.

Neurodiagnostic Tests
Just as blood tests are necessary to rule out competing diagnoses, so are
tests of brain structure and function. Initially, a physician may order a
computed tomography (CT) scan or magnetic resonance imaging (MRI) of the
brain. Both studies provide pictures of brain anatomy, and help rule out
problems such as brain tumors, strokes, blood clots, or hydrocephalus
(enlargement of the brain’s fluid system). An MRI gives a better overall
picture than a CT and is the preferred test, although it is somewhat more
expensive. Both tests are safe, but some people with a tendency towards
claustrophobia have a difficult time with the MRI. The space in which
the head lies is relatively narrow, and occasionally the patient may
require a mild sedative. In certain circumstances, the ordering physician
may request that the test be performed “with contrast.” In this case, the
patient is injected with a contrast agent that can improve the visualiza-
tion of some lesions, such as tumors. Early AD or MCI patients will usu-
ally have normal neuroimaging studies, although brain atrophy will be
present as the disease progresses (see Chapter 7).
Positron emission tomography (PET) and single photon emission computed
tomography (SPECT) scans are also sometimes used in dementia diagno-
sis. Both tests measure metabolic activity in the brain. Of the two, PET
shows the brain in more detail, although SPECT is less expensive and
more widely available. In AD, both tests show that the temporal and
parietal areas on both sides of the brain are not as active as in healthy
adults. Medicare has indicated that they will now cover PET scans for
dementia diagnosis under certain circumstances.
The last neurodiagnostic test that may be requested is the electroen-
cephalogram (EEG), which is a measure of the electrical activity in the
brain. During the test, small electrodes are placed on the patient’s scalp
in order to detect electrical activity generated by neurons in the cortex.

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 Alzheimer’s Disease

The activity is converted to waveforms, which are interpreted by the neu-

rologist. In the waking state, the normal EEG rhythm consists of oscilla-
tions in the range of 8 to 13 cycles per second (Hz). The EEG is usually
normal in early dementia, but some slowing, typically in the 5 to 7 Hz
range, is often seen as the disease progresses. Unfortunately, this type of
change is common in many disease states, and it generally does not
appear in AD until the dementia is clinically obvious. This prevents the
EEG from aiding in an initial dementia diagnosis.
The EEG can be useful for AD in special circumstances. People with
AD may experience seizures, bursts of electrical activity that disrupt the
normal functioning of the brain. Often, an EEG is required to show that
this activity is present. Typically, seizures can be treated with an
antiepileptic (antiseizure or anticonvulsant) medication.

Lumbar Puncture
A lumbar puncture involves insertion of a needle into the lumbar spinal
canal to withdraw cerebrospinal fluid (CSF). This diagnostic test is not
routinely performed in dementia evaluations. Although quite safe, it is
somewhat uncomfortable, and problems with headaches can occur after
the procedure. The CSF circulates in and around the brain, and its chem-
ical composition is affected by various brain processes. This test is impor-
tant in detecting rather rare causes of dementia by infectious agents,
such as certain fungi, tuberculosis, and syphilis. In the last several years,
however, there has been intense interest in measuring CSF levels of the
amyloid and tau proteins as a means of diagnosing AD.
Surprisingly, in AD, the level of CSF amyloid, specifically the A!42
peptide, is lower than in normal people, even though more of it is pro-
duced in the AD brain (see Chapter 7). The reason given for this is that
it is being “swallowed up” by the amyloid plaques and aggregates in the
brain so that it does not escape into the CSF. On the other hand, the tau
proteins do get into the CSF, so their level is higher in AD patients. The
combination of low amyloid and high tau in the CSF is a sensitive and
specific marker for AD. This test is commercially available and it is also
being used in research.

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 CHAPTER 4 • Diagnosis of Dementia

There has been some debate regarding how valuable the evaluation
of the CSF actually is in dementia diagnosis. An experienced neurologist
diagnosing AD is right about 85 to 90 percent of the time, as judged by
autopsy studies. The CSF test also detects the AD pattern about 90 per-
cent of the time. Presently, the CSF test is not often used in clinical prac-
tice, because it is expensive, involves a lumbar puncture, and may have
uncomfortable side effects.
In 2001, the American Academy of Neurology published an official
Practice Parameters consensus paper on dementia diagnosis. They con-
cluded that “there are no CSF or other biomarkers recommended for
routine use in determining the diagnosis of AD at this time.” The main
objection of the AAN to these various tests is that they are not superior
to diagnostic accuracy based solely on clinical judgment. In the future,
careful studies that validate new procedures and prove the diagnostic
value of specific biological or neurodiagnostic tests, will serve to enhance
the evaluation of symptoms that may indicate Alzheimer’s disease.

TWO TESTS THAT MAY PROVE USEFUL

IN AD DIAGNOSIS OR TREATMENT

The neural thread protein (NTP) has been found in the same areas and in
similar densities as neurofibrillary tangles in the AD brain (see Chapter
7). The CSF and urine levels of NTP are also elevated in AD patients. The
exact relationship of this protein to AD is not known, but it is under
intense investigation. A urine test for NTP is commercially available that
detects changes in the amount of NTP in some early AD patients,
although this test has not been evaluated with MCI patients.
A second promising test, a blood test, is already widely available.
Evidence has shown that an elevated level of homocysteine, an amino
acid, is a risk factor for AD as well as for cardiovascular disease and
stroke. Homocysteine occurs naturally in the body, but at high levels it
can cause problems. Homocysteine levels can be affected by dietary lev-
els of vitamins B6, B12, and folate. Consequently, there are studies inves-
tigating whether dietary supplements can lower the risk of AD and vas-
cular disease. Measuring homocysteine levels is not very helpful in diag-

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 Alzheimer’s Disease

nosis, however, because normal people can have elevated levels. The B-
vitamin supplements that lower homocysteine levels can be considered
if homocysteine is elevated.

GENETIC BLOOD TESTS FOR AD

There are blood tests available for genetic mutations responsible for
extremely rare cases of AD, and also for a gene that is a risk factor for
AD, the ApoE4 allele. These are discussed in more detail in Chapter 12.
However, the bottom line is that, at this time, genetic blood tests can be
justified only in exceptional circumstances and should not be part of the
routine diagnostic evaluation for AD.

SMELL TESTS AND ALZHEIMER’S

Because the entorhinal cortex is frequently involved early in AD (see
Chapter 3), and because this area of the brain is important for recogniz-
ing smells, a high proportion of people with AD have deficits in this abil-
ity. Several studies also indicate that an impaired sense of smell is a risk
factor for MCI patients to progress to AD. It has therefore been proposed
by some that a standardized test of smell be used as a screening measure.
However, because many other common conditions besides dementia can
cause smell impairment, such as nasal congestion and prior respiratory
infections, and because some studies indicate that reduced smell abilities
are present in up to a quarter of the normal elderly population, more
study of this proposal is needed before it can be recommended. Therefore
the interpretation of the results obtained from various “smell test kits”
recently being marketed to the general public for self-diagnostic purpos-
es, must be done with extreme caution. Indeed, with all of the test men-
tioned in this chapter, interpretation by a physician is necessary.

With all of the test mentioned in this chapter,

interpretation by a physician is necessary.

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