The Natural History of Alzheimer Disease

Abstract

Knowledge of the evolution of cognitive deficits in Alzheimer disease is important for our understanding of disease progression. Previous reports, however, have either lacked detail or have not covered the presymptomatic stages.
To delineate the onset and progression of clinical and neuropsychological abnormalities in familial Alzheimer disease.
Nineteen subjects with familial Alzheimer disease underwent serial clinical and neuropsychological assessments. Eight of these had undergone presymptomatic assessments. The follow-up period was 1 to 10 years (mean, 5 years). The relative timing of the occurrence of 3 markers of disease onset and progression (onset of symptoms, Mini-Mental State Examination score < or = 24, and impaired scores on a range of neuropsychological tests) were compared using the binomial exact test.
Neurological abnormalities were not prominent, although myoclonus appeared early in some. Mini-Mental State Examination score was not sensitive to early disease. Memory and general intelligence deficits appeared at an earlier stage, in some patients when presymptomatic. Perceptual, naming, and especially spelling skills were preserved to a late stage.
Familial Alzheimer disease may have a long prodromal phase of several years with subtle deficits initially of general intelligence and memory, while spelling, naming, and perception are relatively preserved until a late stage.

Full text

ORIGINAL CONTRIBUTION
The Natural History of Alzheimer Disease
A Longitudinal Presymptomatic and Symptomatic Study of a Familial Cohort
Alison K. Godbolt, MRCP; Lisa Cipolotti, PhD; Hilary Watt, MSc; Nick C. Fox, MD, FRCP;
John C. Janssen, MRCP; Martin N. Rossor, MD, FRCP
Background: Knowledge of the evolution of cognitive
deficits in Alzheimer disease is important for our under-
standing of disease progression. Previous reports, how-
ever, have either lacked detail or have not covered the
presymptomatic stages.
Objective: To delineate the onset and progression of
clinical and neuropsychological abnormalities in famil-
ial Alzheimer disease.
Methods: Nineteen subjects with familial Alzheimer
disease underwent serial clinical and neuropsychologi-
cal assessments. Eight of these had undergone presymp-
tomatic assessments. The follow-up period was 1 to 10
years (mean, 5 years). The relative timing of the occur-
rence of 3 markers of disease onset and progression
(onset of symptoms, Mini-Mental State Examination
scoreⱕ 24, and impaired scores on a range of neuropsy-
chological tests) were compared using the binomial
exact test.
Results: Neurological abnormalities were not promi-
nent, although myoclonus appeared early in some. Mini-
Mental State Examination score was not sensitive to early
disease. Memory and general intelligence deficits ap-
peared at an earlier stage, in some patients when pre-
symptomatic. Perceptual, naming, and especially spell-
ing skills were preserved to a late stage.
Conclusion: Familial Alzheimer disease may have a long
prodromal phase of several years with subtle deficits ini-
tially of general intelligence and memory, while spell-
ing, naming, and perception are relatively preserved un-
til a late stage.
Arch Neurol. 2004;61:1743-1748
A
DETAILED UNDERSTAND-
ing of the clinical and neu-
ropsychological features of
Alzheimer disease (AD) is
essential for improving
the accuracy of diagnosis and prognosis
and the assessment of potential disease-
modifying treatments of the future. The
typical early, insidious decline in
episodic memory is well established,
1
but
surprisingly little has been reported of the
subsequent pattern of progression of neu-
ropsychological and clinical features. Most
studies have been cross-sectional, and
those longitudinal studies that have been
performed have focused on rates of pro-
gression rather than on how the pattern
of decline in 1 specific cognitive domain
relates to that in another.
2
One reason for the limited study of this
area is the difficulty in confident diagno-
sis of AD, especially at the early stages in
which deficits in specific cognitive do-
mains are of most interest. The occur-
rence of AD in an early-onset, autosomal
dominantly inherited familial form pro-
vides an opportunity to study patients in
whom early diagnosis can be made con-
fidently and in whom, unlike in elderly
populations, comorbidity is seldom a sig-
nificant consideration.
Previous studies of familial AD (FAD)
have either focused on reporting the ear-
liest features of the disease
3-6
or on pro-
gression in those already moderately af-
fected.
5
The course and pattern of cognitive
decline from the presymptomatic stages to
advanced disease have not been system-
atically reported in detail.
METHODS
Patients with autosomal dominant, early-
onset FAD were recruited into a longitudinal
study from referrals to the Dementia Re-
search Group at The National Hospital for Neu-
rology and Neurosurgery, London, England.
The study received ethical approval from the
institutional review board and informed con-
sent was obtained. All families of patients in-
cluded fulfilled 3 generational criteria for au-
Author Affiliations: Dementia
Research Group, Institute of
Neurology, (Drs Godbolt, Fox,
Janssen, and Rossor and Ms
Watt), and the Department of
Neuropsychology
(Dr Cipolotti), National
Hospital for Neurology and
Neurosurgery (Drs Godbolt,
Fox, Janssen, and Rossor),
London, England.
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tosomal dominant inheritance, and at least1 affected member
of each family had undergone neuropathological examina-
tion. All patients, on completion of this study, fulfilled stan-
dard criteria for probable AD (except for the requirement of
the criteria of the National Institute of Neurological Disorders
and Stroke and the Alzheimer’s Disease and Related Disorders
Associations that symptoms develop at older than 40 years).
For patients who had participated in a longitudinal study of
subjects at risk of FAD prior to developing the disease, pre-
symptomatic data were included.
Each patient had serial clinical and neuropsychological as-
sessments at the National Hospital for Neurology and Neuro-
surgery at approximately annual intervals, until untestable. As-
sessors were blinded to the outcome of assessments other than
their own.
Clinical assessment included history taking, neurological ex-
amination, and Mini-Mental State Examination (MMSE).
7
Onset
of symptoms was established from information given by the pa-
tient and their caregiver when the patient was first symptomatic.
Neuropsychological tests assessed intellectual function-
ing, current (Wechsler Adult Intelligence Scale Revised)
8
and
premorbid (National Adult Reading Test)
9
; verbal and visual
recognition memory (Recognition Memory Test for Words and
Faces)
10
; naming (Graded Naming Test)
11
; spelling (Oral Graded
Difficulty Spelling Test)
12
; calculation (Graded Difficulty Arith-
metic Test)
13
; and visuospatial and perceptual abilities (cube
analysis and silhouettes from the Visual Object and Space Per-
ception Battery).
14
For all cognitive domains except intelligence, raw scores were
converted into percentiles, referring to published normative data.
Scores at or below the fifth percentile were taken to indicate
an impairment. For intelligence, a difference of 10 or greater
between the National Adult Reading Test and the perfor-
mance or verbal IQ was considered an impairment.
The relative timings of the onset of symptoms, impaired
scores on the MMSE (ⱕ24), and impairments in the different
cognitive domains were analyzed in a pairwise fashion, using
the binomial exact test. In some patients, performance was im-
paired but then reverted to normal before declining again. We
determined the time of onset to be when a deficit was first ob-
served but also repeated the analysis taking the time of onset
to be when a deficit first became permanent.
Modified Kaplan-Meier plots were used to illustrate the rela-
tive survival of cognitive domains and unimpaired MMSE scores
across time following the onset of symptoms. The proportion
plotted at time zero represents those patients who were as-
sessed before the onset of symptoms and were unimpaired. Drops
in the proportion represent those patients who first showed a
deficit at the given assessment time. The number of patients
who had had an initial assessment but did not show a deficit
prior to this time was used as the denominator.
RESULTS
Nineteen patients participated (9 male). Seven patients
belonged to amyloid precursor protein (APP) gene mu-
tation pedigrees, with V717G (3 patients), V717I (3 pa-
tients), and V717L (1 patient) mutations. Eleven pa-
tients belonged to presenilin-1 (PSEN1) gene mutation
pedigrees, 8 with point mutations (G378V, M139V,
I143F,orL153V) and 3 with deletions (␦ 4 or 9). One
patient belonged to a pedigree in which we have not
been able to demonstrate a mutation in APP, PSEN1,or
presenilin-2.
Mean age at onset of symptoms was 44 years (range,
35-57 years) and at first assessment when symptomatic
was 46 years (range, 35-59 years). At the time of last con-
tact with the research team, 6 patients had died (mean,
8.2 years after onset of symptoms [range, 5.6-12.7 years]),
10 patients were living at home (mean, 7.3 years after
onset [range, 2.7-12.4 years]), and 3 patients were in resi-
dential care (mean, 8.9 years after onset [range, 7.0-
11.2 years]).
NEUROLOGICAL FEATURES
Clinical data were available for 18 subjects. Fifteen de-
veloped abnormalities on neurological examination dur-
ing the study, as follows: myoclonus (11 subjects), a mean
of 4 years (range, 1-11 years) after symptom onset; limb
dyspraxia (8); brisk reflexes (4); late visual disorienta-
tion (3); and nonspecifically slow gait (3). Two subjects
developed seizures during study follow-up, 5 and
6 years after symptom onset, respectively, and seizures
occurred in a further subject after follow-up ceased,
6 months prior to death.
NEUROPSYCHOLOGICAL FEATURES
All 19 patients underwent at least 2 neuropsychological
assessments a minimum of 1 year apart (mean, 5.4 as-
sessments [range, 2-14 assessments]). Mean interval be-
tween assessments was 1 year, with a mean follow-up of
5 years (range, 1-10 years). Sixteen patients were untest-
able at the end of the study. Mean time from onset of
symptoms to final neuropsychological assessment in these
16 patients was 5 years (range, 1-10 years). Three pa-
tients are receiving ongoing follow-up.
Eight patients had presymptomatic neuropsychologi-
cal assessments at least 6 months before reported onset
of symptoms (starting a mean of 2.7 years [range, 0.8-
5.0 years] before onset of symptoms; mean age of 42 years
[range, 31-50 years]). One further subject was first as-
sessed only 2 months before developing symptoms. All
subjects had subsequent symptomatic assessments.
Table 1 presents the proportion of patients who
showed a deficit in each domain at initial and final pre-
symptomatic assessment and initial and final symptom-
atic assessment. At initial presymptomatic assessment,
impairments of cognition were restricted to general intel-
ligence (4/8) and memory (2/8). By the final presymp-
tomatic assessment, 5 of 9 of those assessed showed defi-
cits in general intelligence, 3 of 9 in visual memory, and
2 of 9 in verbal memory, whereas none showed deficits in
MMSE score. At the first symptomatic assessment, only
4 of 11 patients showed deficits in MMSE score. However,
14 of 19 showed deficits in intelligence, 14 of 18 in verbal
memory, and 11 of 18 in visual memory; 5 of 17 were dys-
calculic. Disorders of perception, naming, and spelling were
rare. By the time of the final symptomatic assessment, cog-
nitive deficits were pervasive with relative preservation of
naming and perception (consistent with previous re-
ports
15
). Spelling skills were especially resilient.
Figure 1 illustrates the typical ordering of deficits
occurring in the different domains. Domains placed to-
ward the left of the diagram generally show deficits at
earlier points than domains placed further toward the
right. When there is no dashed circle/oval enclosing a pair
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of domains, the relative order of deficits occurring achieves
statistical significance. The statistical details of this are
shown in
Table 2. Mini-Mental State Examination score,
calculation, visuoperceptual and visuospatial skills, nam-
ing, and spelling all showed deficits significantly later than
symptom onset and in the order shown in Figure 1. When
the data were reanalyzed using the time when deficits first
became permanent (rather than sometimes showing tran-
sient improvement), verbal IQ and visual memory also
showed deficits significantly later than symptom onset,
but there were no other differences.
Figure 2 shows the
modified Kaplan-Meier plots for survival of each do-
main, for visual comparison.
CORRELATION OF
NEUROLOGICAL ABNORMALITIES
AND MEMORY DEFICITS
Five patients were examined when presymptomatic and
when memory scores were normal. Four had subtle abnor-
malities at this early stage: myoclonus (3) and tremor (1).
At the time of first memory impairment, 14 patients
had a neurological examination. Seven had subtle ab-
normalities: myoclonus (5), dyspraxia (1), pout reflex
(1), and broken pursuit eye movements (1).
COMMENT
This study provides detailed longitudinal data across a
prolonged follow-up period of up to 10 years of the neu-
ropsychological and clinical features of FAD. Our sub-
jects carried a range of pathogenic APP and PSEN1 mu-
tations and belonged to well-characterized FAD pedigrees.
The inclusion of presymptomatic assessments and the long
follow-up allowed an evaluation of the deficits across
much of the disease course of FAD.
It is seldom possible to date symptom onset more ac-
curately than half a year, and data should be interpreted
in light of this. Initial symptoms begin very insidiously,
sometimes across a period of several years before the sub-
ject seeks medical attention and meets accepted criteria
for the diagnosis of AD.
1
It is also recognized that histo-
Table 1. Proportion of Patients Assessed Showing Deficits in Each Domain at Initial
and Final Presymptomatic and Initial and Final Symptomatic Assessments*
Initial Presymptomatic
Assessment†
Final Presymptomatic
Assessment‡
Initial Symptomatic
Assessment
Final Symptomatic
Assessment
Total No. of subjects assessed 8 9 19 19
Psychometric domain
MMSE 0/2 0/4 4/11 16/16
Verbal IQ 3/8 4/9 14/19 18/19
Performance IQ 4/8 5/9 13/19 16/19
Verbal memory 1/7 2/9 14/18 19/19
Visual memory 2/8 3/9 11/18 19/19
Naming 0/8 0/9 1/18 3/18
Spelling 0/7 0/7 2/15 6/18
Calculation 0/8 0/8 5/17 12/18
Visuospatial 0/8 0/8 3/17 10/18
Visuoperceptual 0/7 0/7 3/16 6/18
Abbreviation: MMSE, Mini-Mental State Examination.
*Values are expressed as number of subjects of all subjects assessed with that psychometric domain.
†Subjects assessed at least 6 months before the onset of symptoms.
‡Subjects with any presymptomatic assessments.
Verbal Memory
Verbal IQ
Performance IQ
Visual Memory
Onset Calculation PerceptualMMSE Spelling
Spatial
Naming
Figure 1. Typical ordering of deficits occurring in different domains during the progression of Alzheimer disease. Definitions of failure were as follows: onset,
clinical onset of disease as estimated by year of initial symptoms; Mini-Mental State Examination (MMSE), MMSE score of 24 or lower; cognitive domains, fifth
percentile or below for verbal and visual memory, calculation, perception, spatial skills, naming, and spelling and a difference of 10 or greater between
performance IQ and the National Adult Reading Test and verbal IQ and the National Adult Reading Test. Domains placed toward the left of the diagram generally
show deficits at earlier points than domains placed further toward the right. When there is no dashed circle/oval enclosing a pair of domains, the relative order of
deficits occurring achieves statistical significance (P⬍.05).
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pathological change may have begun even earlier, some
years before symptom onset.
16
Abnormalities of the neurological examination were
not prominent, though myoclonus was noted at or be-
fore the time of the first objective impairment of memory
in some. This was usually fine finger myoclonus and may
not have been apparent to a casual observer. Of note, pa-
tients and their spouses did not comment on myoclo-
nus at this early stage.
Our study, in line with previously reported data,
3
in-
dicated early impairment of episodic memory and gen-
eral intelligence in FAD. Formal neuropsychological as-
sessment was essential for the detection of these early
cognitive changes. As expected, the MMSE was less sen-
sitive than these measures, though performed reason-
ably well in detecting impairment before more wide-
spread cognitive deficits were present. In terms of early
diagnosis, however, it was limited, with 50% of patients
still scoring higher than the cutoff score of 24 of 30 nearly
4 years after onset of symptoms.
Previous cross-sectional studies have reached contra-
dictory conclusions about the timing of occurrence of
naming deficits. Ardila et al
6
report naming difficulties
in their poorly educated subjects without dementia who
carried a mutation. However, Warrington et al
15
re-
ported relatively preserved naming in FAD compared with
sporadic AD. Our data show that naming is frequently
preserved many years after initial symptoms and also
document that perception is a relatively resistant cogni-
tive skill in FAD. The very late preservation of spelling
is remarkable, presenting an island of preserved cogni-
tive function when subjects were moderately or se-
verely affected.
Familial AD is often said to follow a more aggressive
disease course than sporadic AD. This is not supported
by our data; 6 cases (5 alive at last contact) are so far
known to have lived for more than 10 years. Survival com-
pares favorably with that in later-onset sporadic AD.
17
CONCLUSIONS
The length of the disease course was very similar to that
reported in sporadic AD. Myoclonus in FAD may begin
early, at or before the time of first objective memory im-
pairment, though it was not prominent. Familial AD may
have a long prodrome during which cognitive deficits are
subtle and may be initially limited to general intelli-
gence and memory. Spelling was the most resilient cog-
nitive domain, and naming and perception were also pre-
served to a late stage.
Accepted for Publication: March 19, 2004.
Correspondence: M. N. Rossor, MD, FRCP, Dementia
Research Group, Institute of Neurology, Queen Square,
Table 2. Order of Development of Deficits in Different Psychometric Domains and Time of Disease Onset: Pairwise Comparisons*
Onset RMT-W
10
RMT-F
10
Verbal IQ Performance IQ
8
MMSE Calculation
13
Visuo-
spatial
14
Visuo-
perception
14
Naming
11
Spelling
12
Onset
RMT-W
10
P = .29;
6, 2
RMT-F
10
P = .18;
7, 2
P = .69;
4, 2
Verbal IQ
8
P = .51;
6, 3
P⬎.99;
3, 4
P = .34;
3, 7
Performance IQ
8
P = .55;
7, 4
P⬎.99;
5, 4
P = .77;
5, 7
P⬎.99;
4, 3
MMSE Onset;
P = .008;
8, 0
P = .22;
5, 1
P = .45;
5, 2
P = .45;
5, 2
P⬎.99;
4, 3
Calculation
13
Onset;
P⬍.001;
12, 0
RMT-W;
P = .003;
12, 1
RMT-F;
P = .02;
9, 1
Verbal IQ;
P = .006;
11, 1
Performance IQ;
P = .006;
11, 1
P = .07;
9, 2
Visuospatia
8
Onset;
P⬍.001;
14, 0
RMT-W;
P⬍.001;
14, 0
RMT-F;
P⬍.001;
12, 0
Verbal IQ;
P = .001;
14, 1
Performance IQ;
P = .003;
12, 1
MMSE;
P = .001;
11, 0
P = .29;
6, 2
Visuoperception
14
Onset;
P⬍.001;
15, 0
RMT-W;
P⬍.001;
15, 0
RMT-F;
P = .001;
14, 0
Verbal IQ;
P = .001;
14, 0
Performance IQ;
P = .001;
12, 0
MMSE;
P = .001;
12, 0
P = .07;
7, 1
P = .34;
7, 3
Naming
11
Onset;
P⬍.001;
16, 0
RMT-W;
P⬍.001;
16, 0
RMT-F;
P⬍.001;
15, 0
Verbal IQ;
P⬍.001;
15, 0
Performance IQ;
P⬍.001;
13, 0
MMSE;
P⬍.001;
13, 0
P = .11;
8, 2
P = .07;
7, 1
P⬎.99;
2, 2
Spelling
12
Onset;
P⬍.001;
14, 0
RMT-W;
P = .002;
13, 1
RMT-F;
P⬍.001;
12, 0
Verbal IQ;
P = .002;
13, 1
Performance IQ;
P = .003;
12, 1
MMSE;
P = .001;
11, 0
Calculation;
P = .02; 9, 1
P = .29;
6, 2
P⬎.99;
3, 3
P⬎.99;
1, 2
Abbreviations: MMSE, Mini-Mental State Examination; RMT -F, Recognition Memory T est–Faces; RMT -W, Recognition Memory Test–W ords.
*Values are expressed as the P value (from the binomial exact test) followed by the number of patients where the domain named in the row heading shows a deficit
first followed by the number of patients where the domain named in the column heading shows a deficit first. Where the P value reached statistical significance (P⬍.05),
the name of the domain with the earlier deficit also appears in the relevant cell. Patients where both domains show a deficit together or not at all or where missing values
meant the order could not be determine were excluded. Onset is defined as the clinical onset of disease as estimated by year of initial symptoms.
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London WC1N 3BG, England (m.rossor@dementia.ion
.ucl.ac.uk).
Author Contributions: Study concept and design:
Cipolotti, Fox, Janssen, and Rossor. Acquisition of
data: Godbolt, Cipolotti, Fox, and Janssen. Analysis and
interpretation of data: Godbolt, Cipolotti, Watt, Fox, and
Rossor. Drafting of the manuscript: Godbolt, Cipolotti,
Watt, Fox, and Janssen. Critical revision of the manu-
script for important intellectual content: Godbolt,
Cipolotti, Watt, Fox, Janssen, and Rossor. Statistical
analysis: Watt. Obtained funding: Cipolotti and Rossor.
Administrative, technical, and material support: Janssen.
Study supervision: Cipolotti, Fox, and Rossor.
Funding/Support: This study was supported by pro-
gram grant G9626876 from the Medical Research Coun-
cil, London, England.
Additional Information: Dr Fox holds a Medical Re-
search Council senior clinical fellowship.
Acknowledgment: We thank the patients and their fami-
lies, assistants of the Neuropsychology Department of
the National Hospital for Neurology and Neurosurgery,
London, England, and Angus Kennedy, MD, who per-
formed some of the early assessments.
REFERENCES
1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group un-
der the auspices of Department of Health and Human Services Task Force on
Alzheimer’s Disease. Neurology. 1984;34:939-944.
2. Hui JS, Wilson RS, Bennett DA, Bienias JL, Gilley DW, Evans DA. Rate of cogni-
tive decline and mortality in Alzheimer’s disease. Neurology. 2003;61:1356-1361.
3. Fox NC, Warrington EK, Seiffer AS, Agnew SK, Rossor MN. Presymptomatic cog-
nitive deficits in individuals at risk of familial Alzheimer’s disease: a longitudinal
prospective study. Brain. 1998;121:1631-1639.
4. Diaz-Olavarrieta C, Ostrosky-Solis F, Garcia DLC, Rodriguez Y, Alonso E. Neu-
ropsychological changes in subjects at risk of inheriting Alzheimer’s disease.
Neuroreport. 1997;8:2449-2453.
5. Rosselli MC, Ardila AC, Moreno SC, et al. Cognitive decline in patients with fa-
milial Alzheimer’s disease associated with E280a presenilin-1 mutation: a lon-
gitudinal study. J Clin Exp Neuropsychol. 2000;22:483-495.
6. Ardila A, Lopera F, Rosselli M, et al. Neuropsychological profile of a large kin-
dred with familial Alzheimer’s disease caused by the e280a single presenilin-1
mutation. Arch Clin Neuropsychol. 2000;15:515-528.
7. Folstein M, Folstein S, McHughs P. The “Mini Mental State”: a practical method
.6
1
.8
.4
.2
0
No. at Risk
MMSE
7
Performance IQ
8
Verbal IQ
8
0
9
9
9
2
9
4
8
6
3
8
1
1
9
3
10
5
5
7
2
9
0
10
0
5521455200
4421334200
Duration of Symptoms of Alzheimer Disease, y
Proportion of Patients
Remaining Unimpaired
A
MMSE
Performance IQ
Verbal IQ
.6
1
.8
.4
.2
0
No. at Risk
MMSE
7
RMT-F
10
RMT-W
10
0
9
9
9
2
9
4
8
6
3
8
1
1
9
3
10
5
5
7
2
9
0
10
0
6511553100
4411533100
Duration of Symptoms of Alzheimer Disease, y
Proportion of Patients
Remaining Unimpaired
B
MMSE
RMT-F
RMT-W
.6
1
.8
.4
.2
0
No. at Risk
MMSE
7
Cube Analysis
14
Silhouettes
14
0
9
9
9
2
9
4
8
6
3
8
1
1
9
3
10
5
5
7
2
9
0
10
0
994411 10 7 4 2 0
11 10 5 411 10 8 4 2 1
Duration of Symptoms of Alzheimer Disease, y
Proportion of Patients
Remaining Unimpaired
C
MMSE
Cube Analysis
14
Silhouettes
14
.6
1
.8
.4
.2
0
No. at Risk
MMSE
7
Oral Graded Difficulty
Spelling Test
12
GNT
11
0
9
9
9
2
9
4
8
6
3
8
1
1
9
3
10
5
5
7
2
9
0
10
0
12 11 5 411 12 7 4 2 0
12 11 5 310 12 8 4 2 1
Graded Difficulty
Arithmetic Test
13
91074310 9 6 3 1 0
Duration of Symptoms of Alzheimer Disease, y
Proportion of Patients
Remaining Unimpaired
D
MMSE
Spelling
GNT
Arithmetic
Figure 2. Modified Kaplan-Meier plots for survival of each domain, for visual comparison. The plots show a decreasing proportion of patients who are intact in the
specified domain by length of time from onset of symptoms. A, Intellectual decline and Mini-Mental State Examination (MMSE) score. B, Memory and MMSE
score. C, Visuospatial, visuoperceptual skills, and MMSE score. D, Naming, calculation, spelling, and MMSE score. GNT indicates Graded Naming Test;
RMT-F, Recognition Memory Test–Faces; RMT-W, Recognition Memory Test–Words.
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for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;
12:189-198.
8. Wechsler D. Manual for the Wechsler Adult Intelligence Scale-Revised. New York,
NY: Psychological Corp; 1981.
9. Nelson HE, Willison J. The National Adult Reading Test (NART) Manual. 2nd ed.
Windsor, England: NFER-Nelson; 1991.
10. Warrington EK. Manual for the Recognition Memory Test for Words and Faces.
Windsor, England: NFER-Nelson; 1984.
11. McKenna P, Warrington EK. The Graded Naming Test. Windsor, England: NFER-
Nelson; 1983.
12. Baxter DM, Warrington EK. Measuring dysgraphia: a graded-difficulty spelling
test. Behav Neurol. 1994;7:107-116.
13. Jackson M, Warrington EK. Arithmetic skills in patients with unilateral cerebral
lesions. Cortex. 1986;22:611-620.
14. Warrington EK, James M. The Visual Object and Space Perception Battery. Bury
St Edmunds, England: Thames Valley Test Co; 1991.
15. Warrington EK, Agnew SK, Kennedy AM, Rossor MN. Neuropsychological pro-
files of familial Alzheimer’s disease associated with mutations in the presenilin 1
and amyloid precursor protein genes. J Neurol. 2001;248:45-50.
16. Morris JC, Storandt M, McKeel DW, et al. Cerebral amyloid deposition and dif-
fuse plaques in “normal” aging: evidence for presymptomatic and very mild Alz-
heimer’s disease. Neurology. 1996;46:707-719.
17. Brookmeyer R, Corrada MM, Curriero FC, Kawas C. Survival following a diag-
nosis of Alzheimer disease. Arch Neurol. 2002;59:1764-1767.
Call for Papers
A
RCHIVES Express
The A
RCHIVES launched a new ARCHIVES Express section
in the September 2000 issue. This section will enable the
editors to publish highly selected papers within approxi-
mately 2 months of acceptance. We will consider only
the most significant research, the top 1% of accepted pa-
pers, on new important insights into the pathogenesis
of disease, brain function, and therapy. We encourage
authors to send their most exceptional clinical or basic
research, designating in the cover letter a request for ex-
pedited A
RCHIVES Express review. We look foward to pub-
lishing your important new research in this accelerated
manner.
Roger N. Rosenberg, MD
Editor
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