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Comparison of rate of annual change of mental status score in four independent studies of patients with Alzheimer's disease.

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Comparison of Rate of Annual Change
of Mental Status Score in Four
Independent Studies of Patients with
Alzheimer’s Disease
Robert Katzman, MD,” Theodore Brown, PhD,” Leon J. Thal, MD,’ Paula A. Fuld, P h D , t i
Miriam Aronson, EdD,§QNelson Butters, PhD,t** Melville R. Klauber, PhD,$ Wigbert Wiederholt, MD,*
Mary Pay, RN,$ Xiong Renbing, MA,$ Wee Lock Ooi, D r pH,$$ Richard Hofstetter, PhD,*’II’
and Robert D. Terry, MD”
Longitudinal studies of subjects with autopsy-proven Alzheimer’s disease in one skilled nursing home and of clinically
diagnosed cases (NINCDYADRDA criteria) in three community cohorts are compared with regard to the annual rate
of change in the error score of the Blessed information-memory-concentration test (IMC) in which the maximum
number of errors possible is 33. The four cohorts differed significantly from each other in regard to age, education, sex,
and the degree of dementia as measured by the initial IMC score. Subjects spanned the age range of 52 to 96 years and
had 2 to 20 years of education. The rate of change in error score per year was similar whether the initial error score was
0 to 7 , 8 to 15, or 16 to 23; however, the rate was reduced when the initial error score was 24 or above, due to a ceiling
effect of the test. Among subjects with initial IMC scores less than 24, the annual rate of change varied considerably.
However, the mean annual rate of change, 4.4 errors (SD -1- 3.6, SEM F 0.3) per year, was independent of residence in
a nursing home, location of the study site. and of the patient’s sex or education. Of particular importance was the
finding that the rate of change in mental test score was independent of age. It can be concluded that the rate of
cognitive deterioration in patients with Alzheimer’s disease is quite variable among individuals and is independent of
the patient’s age and whether the patient resides in the community or in a nursing home. More importantly, the rate of
change of the IMC test provides no evidence for a difference between early-onset and late-onset Alzheimer’s disease.
The average rate of change on the IMC and its variance can be used as the basis for designing studies of drugs or
procedures that might alter the course of Alzheimer’s disease.
Katzman R, Brown T , Thal LJ, Fuld P A , Aronson M, Butters N, Klauber MR, Wiederholt W , Pay M,
Renbing X, 0 0 1 WL, Hofstetter R , Terry RD. Comparison of rate of annual change of mental status score
in four independenr studies of patients with Alzheimer’s disease A n n N e u r o l 1988,24 384-489
A cardinal feature of Alzheimer’s disease (AD) is the
progressive decline in cognition, a feature that is clinically obvious and has been incorporated into the currently accepted diagnostic criteria [l]. It is also recognized that the rate of decline is quite variable (e.g.,
[2]),” prompting interest in longitudinal studies designed to measure the rate of change. In this article we
report the annual rate of change in terms of the change
in score of a mental status test, using data from four
longitudinal studies with remarkably different popula-.
tions. In these four studies the overall mean rate ofchange was surprisingly consistent and independent of
subjects’ age, education, and residence. These data
may provide the basis for designing clinical trials of
‘For example, H. H. Merrirr, in the first (1955) edition of his textbook, noted, “The clinical course is progressive terminating inevitably in complete incapacity and death The duration of the disease IS
usually between four and ten years, with extremes varying from less
than one year to more than twenty years ”
Received Dec 15, 1987, and in revised form Mar 21, 1988. Ac-cepted for publication Mar 24. 1988.
Address correspondence to Dr Katzman, Department of Neuroscl
ences, M-024, UCSD School of Medicine, La Jolla. CA ‘12093
From the Departments of “Neurosciences, tpsychiarry, and $Community and Family Medicine, and the IAlzheimds Discase Research Center, University of California, Sail Diego, CA, the ‘Department of Computer Science, Queens College, New York, NY,
‘Neurology and **Psychology Services, Veterans Administration
Medical Center, San Diego, CA, the Departments of ttNeurology
and $$Epidemiology and Social Medicine, and PrjRcsnick Gerontology Center, Albert Einstein College of Medicine, .Yeshiva University, Cronx, NY, and the “‘Department of Political Science, San
Diego State University, San Diego, CA.
384 Copyright 0 1988 by t h e American Neurological Association
Table I . Demographic Variables by Location for AN Patients
No. of subjects
Mean years followed
Age (yr)
Median education (yr)
Gender ( % female)
Initial IMC score
Mean 2 S D
77 h
0- 8
13.17 f 8 . 2 2 b
”NH patients were diagnosed o n autopsy; all other patients had probable or possible Alzheimer’s disease.
’p values < 0.001; gender difference value was based on chi-square ( 3 df); age. education, and rate of change were dererniined from the KruskdWallis test.
NH = nursing home; PP
= private practice; BAS = Bronx Aging Study; ADRC = Alzheimer’s Disease Research Center; IMC = Blessed
information-memory-concentratiun test.
drugs or o t h e r treatments intended to slow t h e progression of t h e disease.
Although mental status tests are sometimes considered to be crude indicators of mental status as compared t o m o r e detailed psychological tests, the
Blessed-Roth mental status test has been shown to
remain a reliable measure of cognitive impairment
validated against b o t h the n u m b e r of plaques and the
levels of choline acetyltransferase in t h e postmortem
brain of patients with AD [ 3 , 41. I n fact, this mental
status test is a direct line from the earlier work of
Mayer-Gross w h o spent several decades identifying
the mild symptoms that differentiate generalized disease of t h e brain from both focal and functional disorders [ 5 , 61.
Description of Sites; Subject Selection
At each of the four sites quite different selection biases were
used (Table 1):(1) elderly patients (age range 65 to 98, mean
age 87 years) in a skilled nursing facility in New York City
( N H ) ; (2)patients in a private referral practice (PP) in New
York City; (3) volunteer subjects, initially nondemented,
who participated in an ongoing longitudinal study of normal
aging and development of dementia in the Bronx, New York
(Bronx Aging Study [BAS)); ( 4 ) patients and control subjects who are participating in an ongoing longitudinal study
at the Alzheimer’s Disease Research Center (ADRC) in Sail
Diego, California. In each study the same mental status examination was used and subjects were intensively studied
neurologically and medically at least once each year. There
were similarities as well as marked differences between the
subjects in the various groups. Subjects in the BAS, the PP,
and the ADRC were all living in their communities in contrast to the NH subjects, who lived in a skilled nursing
home. The overall age range in the four studies was 52 to 96.
Subjects in both the N H and BAS were elderly; the latter
study required that participants be bemeen ages 75 and 84
on entry, whereas the other two groups had many younger
subjects. In both the NH and BAS studies, the participants
were predominantly Jewish, although there was a significant
Italian and Irish Catholic minority i n the BAS; in contrast,
the majority of the ADRC subjects were Protestant.
The subjects included in this report from the four sites
were those who had two or more scores recorded on the
mental status test and a diagnosis of probable or possible A D
in the three community studies or an autopsy diagnosis of
A D in the nursing home study. At the N H , autopsies were
obtained on 141 patients, 76 of whom had AD. Thirty-eight
are included in the present analysis. Many had been so impaired during life that they could not answer any items on
the mental status test, even their own name; others died
before a second test could be administered. In the PP group
(the practice of L. T.), the 40 subjects included were all of
the patients (from among 234 dementia patients) who met
diagnostic criteria for probable or possible A D and had two
or more mental status tests at least 15 months apart. In the
BAS study, 434 ambulatory nondemented volunteers were
followed in a longitudinal study of aging; over a 3.5-year
period 56 subjects developed dementia, 32 with AD, 15
with multi-infarct dementidmixed Alzheimer’s and cerebrovascular disease, and 9 with other diagnoses. Mental
status scores on the subjects who developed AD are included in this analysis. In the ADRC, 51 subjects who met
the criteria of probable or possible A D also had mental
status tests on at least two successive testings.
Approval of each study by the appropriate human studies
review board was obtained from each of the three institutions.
Clinical diagnoses of probable A D and possible A D were
made on the basis of the National Institute of Communicative Disorders and Stroke/Alzheimer’s Disease and Related
Disorders Association [ l ) criteria. In the BAS and ADRC,
diagnoses were made independently by two neurologists (including R. K. or L. T.) and in the PP by one of us (L. T.).
In the NH sample, autopsy diagnosis was made by one of
Katzman et al: Rate of Mental Status Change in AD
Table 2. Rate of Change aJ a Function of Initial I M C Score and Site
All Sites
0- 7
2 lY(13)
5 12 ( 5 )
4 60 (10)
-0 38 (10)
2 87
7 15 ( 4 ) )
4.72 ( 2 6 )
5.03 ( 6 )
4 29
0 45
3 24 ( 8 )
3 38 (12)
4 10 ( 2 4 )
1.05 (7)
4 46
4 16
0 53
0 60
0 29
4 77
2 85
3 84
74 (23)
3 87 (11)
2.09 ( 2 )
"No. of patients tested in parentheses.
"Calculateci for each initial IMC score interval without regard to site.
IMC = Blessed information-memory-concentrationtest, N H = nursing home; PP
Alzheimer's Disease Research Center
us tR. D. T.) based on both gross and microscopic examination of the brain using H&E, cresyl violet, and thioflavine
stains, as well as counts of plaques and tangles. The diagnoses
are consistent with the Alzheimer task force criteria [7).
MENTAL STATUS TEST. At each site the Fuld 181adaptation
of the information-memory-concentration test (IMC) of
Blessed and colleagues [ 3 ] was administered annually in a
standardized manner. The IMC consists of 26 items, the
simplest being the person's own name, the most difficult a
five-part name and address to be recalled after intervening
test items. The test is scored for the number of errors made,
the maximum possible being 33. In each series subjects
underwent an annual evaluation which included a number of
other neuropsychological measures, but these differed from
site to site. Thus, neuropsychological test batteries used in
the BAS were designed to test for the first changes observable i n community-based independently functioning elderly,
whereas in the NH the tests were designed for impaired
individuals in a skilled nursing facility. However, in all four
series the IMC was employed, permitting comparison of the
four cohorts. In the N H and BAS studies, the test was administered by a single group of psychological assistants,
under supervision of one of us (P. A. F.), who also trained
the psychometrists. nurse practitioners, and neurologists who
administered the test at the other two sites (PP and ADRC).
Rate of Change
individual subjects included in these series were followed for
a minimum of I year to a maximum of 6 years. For a given
individual, the annual rate of change across the entire period
(measured in days when possible) of evaluation has been
calculated, based on the first and last observations. N o attempt was made to use all the data available for each patient
to estimate the rate of change by least squares regression or
by any other method.
Standard descriptive statistics as well as nonparametric statistics, including chi-square, Kruskal-Wallis one-way analysis of
variance, and Kendall's rank correlation coefficients have
been used. Nonparametric statistics were selected, because
of the heterogeneity of interval lengths over which patients
386 Annals of Neurology
Vol 24
No 3
private practice; BAS
Dronx Aging Study; A D K C =
were followed and because o t the corresponding heterogeneity of standard errors of rates of change.
The number of subjects at each of the four sites, duration of follow-up (in total person years), demographic
characteristics, and initial mental status score are
shown in Table 1. The differences between sites in
relation to age, education, sex, and initial IMC score
are highly significant (at the p < 0.001 level) as would
be expected in view of the diverse nature of patient
selection. The sex ratio among the groups differed
significantly. The sites with older patients ( N H and
BAS) had significantly more women. This excess of
women probably reflects both the greater longevity of
women and an excess of women with this disease, an
observation previously reported [9- 111.
The rate of change as a function of initial IMC score
is shown for the entire cohort of 161 in Table 2. In
analyzing the annual rate of change of the JMC score,
there appeared to be differences between sites in that a
lower rate of change was noted for subjects in the NIH
(2.87 2 0.70) and ADRC (2.85 i 0.45) as compared
to the PP (4.60 -t 0.47) and BAS (4.77 5 0.6s). Bol-h
NH and ADRC subjects had an initial high IMC
score. This suggested that there was a ceiling effe'ct
with the IMC test. Indeed, on inspection of individual
data, a ceiling effect was apparent, that is, the rate of
change fell off dramatically as initial IMC scores above
24 were reached.
O n the basis of this finding we recalculated our data
and statistics for the 142 subjects whose initial IMC
scores were below 24. It became apparent that the
annual rate of change of the IMC was approximately
the same at different sites, and the Kruskal-Wallis test
showed that there was no significant difference ip =
0.43) between sites (Table 3 ). The mean rate of change
for the cohort of 142 subjects was 4.4 errors (SD ?
3.6, SEM t 0.3) per year.
Within this cohort of 142 there is still a wide range
September 1088
Table 3. Demographic Variables by Location for Patients with Initial IMC Score n f h s s Than 24 ErrorJ
2 6.8
2 8.4
t- 6.8
2 7.4
5 3.4
2 4.2
2 3.2
t 2.7
5 3.9
2 3.0
1.O- 15.0
5 3.6
- 5.0-15.0
G e n d e r (F female)
Age (yr)
Education (yr)
Rate of change
( I M C score)
t 4.0
"NH patients were diagnosed on autopsy; all other patients had probable or possible Alzheimer's disease.
bp < 0.001.
'Differences in IMC rate of change between sites are not significant ( p
Blessed information-memory-concentration test; NH
Alzheimer's Disease Research Center.
0.43, Kruskal-Wallis test).
nursing home; PP
in age (52-96 years), in education level (2-20 years),
and in initial IMC score (0-23). We carried out Kendall rank correlations (Table 4 ) to determine the relationship between these variables. There was no
significant relationship of rate of change to age ( p =
0.31) or initial IMC score ( p = 0.21), and a weak,
borderline relationship ( p = 0.06) to education.
Moreover, the correlation between initial IMC score
and either age o r education is trivial in magnitude.
It seems most likely that the very low annual rate of
change in the IMC in severely demented subjects with
an IMC score of 24 or higher is due to a ceiling effect.
It is interesting that functional rating scales, such as
that of Blessed and coworkers [3], also show a ceiling
effect [12]. It is also possible that the natural history of
AD is such that the rate of progression of cognitive
deterioration slows as dementia advances, but we are
not aware of any evidence in this regard. However,
subjects with clinically recognizable dementia in the
early to moderately severe stages, with scores of 0 to
23 errors on the IMC, are surprisingly well monitored
by this test with the mean annual rate of change being
independent of the initial test score over this range.
With the assumption of limited linearity, an average
time of A D progression can be estimated, provided
one recognizes the wide individual variation. If the
assumption were made that normality is equivalent to
an error score of 0, then on the basis of the present
private practice; BAS
Bronx Aging Study; ADRC
Table 4. Kendall Rank Correlation Coefficientsfor Owall
Annual Rate of Change i n IMC, the Initial I M C Score, Age,
and Education"
Initial IMC
Overall rate
Initial IMC
= 0.21
n = 142
= 0.31
n = 142
p < 0.001
n = 142
Education (yr)
n = 132b
p < 0.005
n = 132
p < 0.001
"All patients with initial IMC score less than 24 errors.
'Educational status was not available for 10 nursing home patients.
Blessed information-memory-concentration test.
results an average time period of 5.2 years could be
specified from the onset of overt cognitive change to
the moderately severe dementia represented by a
score of 24 errors. Additionally, for the PP patients
who presented for medical attention with an initial
mean IMC score of 13.4 with a rate of change of 4.6
points per year, one can infer that disease was present
for approximately 3 years before the subject sought
neurological consultation.
The similarity of the rate of change of the IMC in
subjects with initial scores less than 24 in the NH
Katzman e t al: Rate of Mental Status Change in AD
group compared t o the rate of subjects of similar age
anJ ethnicity in the HAS group suggests that the rate
of cognitive progression is not increaseti tiy the nursing home environment. T h e similarity of the rates of
change of the three N e w York studies with those of
the Sail Diego study suggests that climate and ethnic
origin (within Caucasian populations) do not affect the
rate of change. T h e rates were similar in the predominantly female N H and BAS populations when compared with the more balanced sex distribution seen in
the PP and AIIRC patient populations (see Table 1),
indicating that the rates of change were independent of
gender. Thus, the rate of progression of cognitive impairment in A D probably reflects the biology of the
disease rather than environmental o r other influences.
T h e data on the cohort of 142 subjects indicate that
the rate of progression is independent of age over the
age range of 5.2 t o 96. Teng anJ colleagues [ I j ] similarly found that the rate of decline o n the Mini-mental
State Examination (MMSE) was the same for the earlyonset group (aged 5.3 t o 6 4 ) and the late-onset group
This finding of age independence with
(aged 65 t o 96).
respect to the natural progression of the dxsorder supports the hypothesis that A D is a unitary disease process that includes both presenile and senilt, individuals
regardless ol age of onset. However, we did not look
at the very young cases (chose with onset in their 4 0 s )
who clinically appezi; to have very aggressive courses;
nor woulcl our data necessarily apply t o fiamilial AD.
Despite the constancy of mean rates, there was wide
individual variation in the rate of progression. Some
patients had markedly rapid progression, the maximum being 15 points over 1 year. O n e patient actually
showed an improvement of 5 points (from 2 1 errors t o
16 errors) in her score on an annual follow-up, d u e
perhaps t o the cognitive effect of a hii;h dose of
clonidine on which she hail been placed for treatment
of hypertension prior t o the initial testing, a dose that
was halved before the second test; in this subject, four
of the five items showing improvement were time
orientation items. Fuld [S] found that after 3 weeks
the test-retest reliability of the IMC was 0.96, but that
occasional patients would have scores that varied by as
much as 3 points o n retest. In our study, however, the
patient on cloniciine was the only o n e among the 142
who showed an improvement in score exceeding o n e
error. Wc> d o not have any basis for estimating the
problem of drug-induced alterations in rate of progression data among patients who did show deterioration
of performance.
Although a variety of aspects o f A D have been reported to change over time ( e g . , [ 14]), there have
been surprisingly few studies of the rate o f change of
mental status scores in AD. Pfeffer and coworkers
{l5] reporreti the rate of decline in the MMSE in 10
Annals of Neurology
Vol 24
No 3
“clefinitely impaired” elderly T h e rate reported by
these investigator\, 2 6 per year, 15 less than thr rate of
decline in o u r subjects if the MMSI, score is (onverted
to an IMC score using the algorithm of 7 ha1 161
However, whether there w a s a ceiling effect o n the
MMSE in these 10 subjec t h was not discusset1 by the
authors Teng and associates 1 3 .I r e p o r t d the rdtr of
decline of subtest scores on the MMSE ba\ecl upon
the duration of illness Berg and colleagues I1 1, uvng
the Short Portable Mental StatuS (~uestionndire[ 1x1,
found that scores at entry could n o t preclict progression i n a group of mildly dementecl subjccts followecl
for 10 months. Huff and coworkr r\ [ ( I ] ,using ‘i format
of the Blessed Dementia Scale that included the IIM(
as a subscale, reported a more rapid decline in wblrx t\
with onset at age 65 o r grearer than in prewiik-onset
subjects, although the authors noted that tlic differ
ence between the groups just re,iche(i ~r,itisric~l
signihcance at the 0 0 5 level, i n thesc s u h p t s the
interval between testing was 3 month\ Thdl m d a+
tiitterence in rate o f
sociates [19] failed to hntf
progression with age i n the PP subset of the cotiort
reported here
T h e data we have obtnined have providec1 usc:fuI
information regdrding the folloa ing issues ( 1 ) A r c A curring argument has been that A D differs in its clinical presentation in younger and olcier patients in w v era1 ways, including the rate of decline wc habe
shown that the rate of change of mental status s(ore on
the Blessed IMC test in pdtients with Alzheimer’s disease is independent of the patient’s age ( 2 ) A matter
of recurrent concern is the question of whether pitients with dementia deteriorate more rapidiy in a
nursing home We have shown that the rate of change
of mental status score is independent of whether the
patient is in a nursing home o r i n the conimuiiity (3)
Finally, we have shown that the rate of changc of the
IMC series is similar in the N e w Yorh and S,iri 1)iego
groups with different ethnic conipo\ition
September 19x8
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Consult Clin Psycho1 1987;55:96-100
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19. Thal LJ, Grundman M. Duration of Alzheimer’s disease predicts
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