 |
|
Patterns of Cognitive Decline in Presymptomatic Alzheimer Disease
A Prospective Community Study
Peijun Chen, MD, MPH, PhD;
Graham Ratcliff, DPhil;
Steven H. Belle, PhD;
Jane A. Cauley, DrPH;
Steven T. DeKosky, MD;
Mary Ganguli, MD, MPH
Arch Gen Psychiatry. 2001;58:853-858.
ABSTRACT
| |
Background Specific patterns of decline over time were evaluated across a spectrum
of cognitive measures in presymptomatic Alzheimer disease (AD) within a community
sample.
Methods A total of 551 individuals completed a battery of standard cognitive
tests 3.5 and 1.5 years before outcome (clinical onset of AD vs continued
nondemented status) within a prospective community-based study of AD. Test
score changes in 68 cases (who subsequently developed symptomatic AD) and
483 controls (who remained nondemented) on each of 15 cognitive measures were
transformed into z scores adjusted for age, sex,
and education. A case-control rate ratio of the proportions of individuals
who showed "cognitive decline" on each test was calculated, representing the
relative magnitude of cognitive decline on each test in presymptomatic AD
compared with normal aging.
Results Declines in Trail-Making Tests A and B and Word List delayed recognition
of originals and third immediate learning trial had the highest rate ratios,
larger than 3.0 (P<.01). These were followed by
Word List delayed recognition of foils and delayed recall, Consortium to Establish
a Registry for Alzheimer's Disease Praxis, Clock Drawing, the Boston Naming
Test, and Orientation, with rate ratios between 1.7 and 3.0 (P<.05).
Conclusions Memory and executive dysfunction showed the greatest decline over time
in individuals who would clinically manifest AD 1.5 years later. These findings
might help us understand the underlying evolution of the early neurodegenerative
process. They highlight the importance of executive dysfunction early in the
disease process and might facilitate early detection of AD.
INTRODUCTION
IN ALZHEIMER disease (AD) and other chronic diseases, it is hard to
ascertain how long the underlying pathological disorder has been present before
clinical manifestations become apparent. Very mild cognitive impairments might
be objectively identifiable in the presymptomatic or preclinical phase of
AD.1, 2, 3, 4, 5, 6
Reliable, objective means of early detection would allow incipient AD to be
identified not only before clinical diagnostic criteria are fulfilled but
even before the first symptoms appear and would play an important role in
potential early intervention.
Several studies7, 8, 9, 10, 11
have made cross-sectional comparisons of one-time cognitive function between
nondemented elderly persons and those with dementia after, and even shortly
before, symptomatic onset and diagnosis. However, dementia is defined as "decline
of memory and other cognitive functions in comparison with the patient's previous
level of function,"12 implying a change between
2 or more assessment points. Evaluation of dynamic change over time, by accounting
for potential confounders, is theoretically and clinically more meaningful
than a single assessment. The progressive deterioration characteristic of
AD might affect different cognitive functions at different periods during
its course,7, 13, 14, 15, 16, 17
as would be expected from the pathological evolution of the disease.18
Few previous studies19, 20, 21
empirically evaluated patterns of cognitive decline in presymptomatic AD.
In a prospective community-based study,22 we
compared changes over time on a spectrum of cognitive measures between 2 groups
of nondemented cohort members: cases who subsequently developed symptomatic
AD and controls who remained nondemented. Use of a longitudinal case-control
design, within a cohort study of AD, minimized temporal and recall bias23 and enabled us to compare cases and controls at a
time when they were all symptom free. Such data might also have relevance
for the evolving concept of mild cognitive impairment.24
SUBJECTS AND METHODS
STUDY DESIGN AND SUBJECTS
The sample was derived from a community-based, multiwave, prospective
study—the Monongahela Valley Independent Elders Survey (MoVIES)—in
southwestern Pennsylvania.22 At study entry
(baseline [wave 1]), the MoVIES cohort included 1422 subjects representing
a 1:13 age-stratified sample randomly selected from voter registration lists.
Entry criteria included age of at least 65 years, not institutionalized at
the time of recruitment, and fluent in English, with a minimum sixth-grade
education. The MoVIES cohort has been followed up prospectively in a series
of data collection "waves" at approximately 2-year intervals. The present
analyses excluded prevalent dementia cases (n = 121), ie, those individuals
with symptomatic onset of dementia before study entry, and 6 demented individuals
with uncertain onset, leaving a total of 1295 nondemented subjects "at risk"
for developing incident dementia during follow-up. At the time of the present
analyses, 153 of these 1295 at-risk subjects had developed incident AD during
5 waves of follow-up. Forty-six subjects who developed non-AD dementias were
excluded from these analyses. Informed consent for all study procedures was
obtained according to methods approved by the institutional review board of
the University of Pittsburgh, Pittsburgh, Pa.
COGNITIVE SCREENING
At each wave, every subject underwent in-home screening with the same
battery of cognitive tests (see the "Outcome and Predictors" subsection).
Descriptions and population norms for the MoVIES cognitive test battery, test
scores in demented and nondemented participants at baseline, and the utility
of these tests for screening have been reported previously.10, 25, 26
At each follow-up wave, based on screening scores, 3 groups were selected
for further clinical evaluation: (1) those who were "cognitively impaired,"
(2) those who had "cognitively declined" since previous waves, and (3) a subgroup
of cognitively unimpaired controls randomly selected at baseline.22 Briefly, the cross-sectional operational criteria
for cognitive impairment were scores at or below the 10th percentile of the
MoVIES sample on the Mini-Mental State Examination (MMSE) or on at least 1
memory test and 1 other cognitive test. During follow-up, the longitudinal
operational criterion for cognitive decline was a decline in scores since
an earlier wave by an amount greater than or equal to the decline experienced
by 95% of the sample or a decline in scores to levels below the impairment
criteria described earlier.
IDENTIFICATION OF SUBJECTS WITH DEMENTIA
In-home clinical evaluations22 were performed,
blind to the screening cognitive data according to the standardized protocols
of the Alzheimer's Disease Research Center at the University of Pittsburgh
and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD),27 which were modified for field use. The MoVIES protocol
included a standardized general medical history and a general physical examination;
detailed neurological and mental status assessments; psychiatric examinations;
laboratory studies for relevant hematologic, chemical, and serologic evaluations;
and neuroimaging when possible and appropriate. Relevant medical records were
obtained and abstracted. Final diagnosis was made by consensus, using the
Alzheimer's Disease Research Center protocol, among all evaluating clinicians
and using all available data. Because the study began in 1987, the diagnosis
of dementia was made according to DSM-III-R criteria28 and according to the Clinical Dementia Rating Scale,29 for which CERAD provides a scoring algorithm based
on functional (rather than cognitive) impairment. Diagnosis of probable and
possible AD was made according to National Institute of Neurological and Communicative
Disorders and Stroke–Alzheimer's Disease and Related Disorders Association
criteria.12 Once the diagnosis of dementia
was made, the date of symptomatic onset was estimated retrospectively using
all available evidence as to the time of emergence of symptoms of cognitive
and functional decline.11
SELECTION OF CASES AND CONTROLS
Selection criteria for cases were (1) development of incident AD during
the 10-year follow-up period, with a mean ± SD date of symptom onset
within 1.5 ± 1.0 years of their most recent cognitive assessment date,
ensuring that cases were in the presymptomatic phase of AD at the time of
cognitive testing, and (2) completion of all cognitive tests 3.5 years (time
1 [T1]) and 1.5 years (time 2 [T2]) before symptom onset, ensuring that the
change in performance of all individuals could be compared on all cognitive
measures. Among the 153 incident cases of AD identified during the study,
120 (78%) completed all neuropsychological tests at their T2 assessments;
of these 120 cases, 68 (57%) also had complete neuropsychological test data
at their T1 assessments. These 68 individuals comprised the case group.
Selection criteria for controls were (1) remaining nondemented during
the 10-year follow-up period, thus ensuring that subjects with incipient dementia
were not inadvertently misclassified as controls, and (2) completing all cognitive
tests at waves 1 through 4, ensuring that case and control performance could
be compared on all tests. Among the 1096 subjects who were not diagnosed as
having dementia during 10 years of follow-up, 483 completed all neuropsychological
tests at waves 1 through 4, thus comprising the control group.
OUTCOME AND PREDICTORS
The outcome variable in the analyses was symptomatic onset of AD in
cases vs maintenance of nondemented status in controls 1.5 years after the
most recent cognitive screening (T2). Predictor variables were changes on
15 cognitive test scores (see the next paragraph) between the 2 assessment
points preceding the outcome. This was further operationalized in cases as
changes in cognitive performance between the assessment points 3.5 years (T1)
and 1.5 years (T2) before symptomatic onset, and in controls as changes in
cognitive performance between wave 2 (T1) and wave 3 (T2) (the midpoint of
10-year follow-up of the overall study). For cases, T1 and T2 could have occurred
at any 2 consecutive waves (Figure 1).
|
|
|
|
Figure 1. Design and timeline of the prospective
cohort study. Case-control comparison superimposed on the course of Alzheimer
disease in presymptomatic cases and a comparable period in nondemented controls.
For explanations of time 1 and time 2, see "Selection of Cases and Controls"
subsection of the "Subjects and Methods" section.
|
|
|
Predictor variables were the following neuropsychological tests: the
CERAD 10-item Word List (first and third immediate learning trials, delayed
recall, delayed recognition of originals, and delayed recognition of foils)27; Story Recall (immediate and delayed)30;
Trail-Making Tests A and B31; Category Fluency32; Initial Letter Fluency33;
the Boston Naming Test (15-item CERAD version)34;
CERAD Praxis35; Clock Drawing36;
and the time/place orientation subtest of the MMSE.37
These tests were part of the MoVIES cognitive screening battery, developed
to assess several cognitive functions known to be affected in dementia25 and incorporating the CERAD neuropsychological panel.27
STATISTICAL METHODS
Statistical software (SAS version 6.12) was used for data analysis.38 All tests were 2-tailed, with statistical significance
set at  = .05. For descriptive statistics, differences between groups
were tested using  2 tests for categorical data and t tests for continuous variables. The scales of individuals' scores
on all cognitive tests were rendered uniform and were adjusted for age, sex,
and education as follows. Controls' raw scores at baseline (wave 1) were transformed
into normally distributed z scores using the formula
(raw score - mean)/SD on each test. By substituting T1 and T2 raw scores
into the same formula, "observed" z scores were calculated
for cases and controls for each test at T1 and T2. A multiple linear regression
model was fit for each test, with controls' baseline z-transformed
scores as the dependent variable and age, sex, and education as the independent
variables, generating coefficients (ß values) for age, sex, and education
for each test. "Predicted" z scores were then calculated
for each subject on each test by entering the individual's age, sex, and education
level, multiplied by the respective coefficients, into the model. Case and
control test scores at T1 and T2 were transformed into age-, sex-, and education-"adjusted" z scores by subtracting predicted z
scores from observed z scores.39, 40
Change in cognitive scores was then measured by subtracting adjusted T2 scores
from adjusted T1 scores on each test for each individual.
Despite efforts to retest subjects at 2-year intervals, the actual mean
± SD interval between T1 and T2 was 783 ± 91 days in cases and
822 ± 123 days in controls. Change in test scores was standardized
to 2-year cognitive change using the formula [(T1 score - T2 score)/(days
between T1 and T2)] x 730.
For inferential statistics, 2 strategies were used. First, the direction
and amount of change on each test between T1 and T2 was tested for significance
using paired t tests within case and control groups
separately. On each cognitive test, the mean change observed in cases was
then compared with the expected mean change, ie, that observed in controls,
using t tests between groups. Second, each individual
was categorized as "cognitively declined" or "cognitively nondeclined" on
each test. Cognitive decline was uniformly defined across all tests as a cognitive
decline (z score) of at least 1 SD greater than the
mean decline in controls.7 A rate ratio was
then estimated as the case-control ratio of the proportion who declined on
each test, representing the relative magnitude of cognitive decline on each
test. The contingency table method (2 test) was used to test
for significance of differences in proportions between cases and controls.
RESULTS
DESCRIPTIVE CHARACTERISTICS OF THE STUDY POPULATION
Compared with controls, cases were significantly older and a significantly
higher proportion of them had low education levels (Table 1); there was no significant sex difference. Scores on the
MMSE declined significantly more during the 2 years from T1 to T2 in cases
(from 26.68 to 25.94) than in controls (from 27.76 to 27.61).
|
|
|
|
Table 1. Characteristics of Cases and Controls: Demographics and Change
in MMSE Score*
|
|
|
MEAN COGNITIVE CHANGE AMONG AND BETWEEN CASES AND CONTROLS
Among controls, there were no significant cognitive changes between
T1 and T2 on 10 of the 15 cognitive tests; mean age-, sex-, and education-adjusted z score was approximately 0, between -0.1 and +0.1
(P>.05, within-group paired t
tests). Significant improvement over time was seen on the 5 remaining cognitive
tests: Word List first and third immediate learning trials, delayed recall,
and delayed recognition of originals (P<.01 for
all) and Trail-Making Test A (P<.05), with mean z scores between 0.1 and 0.22.
Among cases, performance on Trail-Making Test B on average declined
the most, with mean change in z score being 0.88,
followed by CERAD Praxis, Trail-Making Test A, MMSE Orientation, Word List
third learning trial (P<.01 for all), Word List
delayed recall, Clock Drawing, and Category Fluency (P<.05
for all), with the mean decline in z score being
greater than 0.2.
Significant differences in mean T1-T2 decline between cases and controls
were seen in Trail-Making Test B and A, CERAD Praxis, Word List third learning
trial, Word List delayed recall, Word List delayed recognition of originals,
Word List first learning trial, MMSE Orientation, and Category Fluency (P<.05, t tests) (Table 2).
|
|
|
|
Table 2. Two-Year Mean Cognitive Changes in Cases and Controls From
3.5 Years (T1) to 1.5 Years (T2) Before Outcome*
|
|
|
COGNITIVE DECLINE IN CASES AND CONTROLS
The highest case-control rate ratios, greater than 3.0 (P<.01), were observed for cognitive decline in Trail-Making Tests
B and A and Word List delayed recognition of originals and third learning
trial, followed by Word List delayed recognition of foils and delayed recall,
CERAD Praxis, Clock Drawing, the Boston Naming Test, and Orientation, with
rate ratios of 1.7 to 3.0 (P<.05). Declines on
the remaining tests had the lowest rate ratios, ie, less than 1.7 (P>.05) (Figure 2).
COMMENT
Our prospective community study afforded several advantages over clinical
studies that typically examine patients who are already symptomatic and have
been diagnosed as having AD. First, by following a nondemented cohort for
10 years, during which some but not all cohort members developed AD at different
times, we were able to focus on a defined time window several years before
onset of symptoms and thus examine all cases at the same stage of presymptomatic
disease. Second, our longitudinal assessment of cognitive change over time
enabled us to study the cognitive decline pathognomonic of AD, minimizing
the potential confounders encountered in the study of one-time cognitive performance.
Third, we accounted for the cognitive changes of normal aging as exemplified
by nondemented controls. Fourth, we normalized test scores and adjusted them
for age, sex, and education, enabling direct comparison of changes on different
cognitive tests along the same scale. Fifth, our cases and controls were identified
during prospective follow-up of a randomly selected community-based cohort,
minimizing the selection bias associated with studying patients and controls
in clinical research settings.
In our sample, cognitive decline in presymptomatic AD was not uniform
across cognitive domains. Memory functions (Word List learning trial, delayed
recall, and delayed recognition) and executive functions (Trail-Making Tests
A and B) declined the most prominently. Because memory deficit is a cardinal
diagnostic feature of AD, it was confirmatory rather than surprising to find
in our own study, as in those of others,19, 20, 21
that early memory impairment was associated with subsequent onset of AD. However,
consensus is lacking on the sequence of the cognitive deficits that follow,
precede, or coexist with memory impairment during progression of the disease,
particularly early in its course. A few previous studies of patients already
diagnosed as having early AD have found memory and frontal/executive functions
to be the most frequently impaired.7, 8, 9
In the MoVIES cohort described herein, we11
previously reported that at a single assessment point 1.5 years before onset,
memory (delayed recall) and executive functions (Trail-Making Tests) distinguished
best between presymptomatic cases and those who would remain nondemented.
We now report that decline on the same tests during the 2 preceding years
(3.5 years to 1.5 years before onset) predicted the development of symptoms
of AD. In the Framingham cohort,20 although
cognitive decline was not examined, cross-sectional measures of memory (retention)
and abstract reasoning (similarities and differences) were the strongest preclinical
predictors of incident AD 5 and 10 years before onset. Taken together, these
findings suggest that executive dysfunction is among the earliest manifestations
of AD, consistent with the hypothesis of Lafleche and Albert8
that "the partial degeneration of an intracortical projection system early
in the course of disease could produce difficulties in tasks that require
the rapid and simultaneous integration of multiple types of information."
Early executive dysfunction might not be specific to AD, but there were
too few cases of non-AD dementias (such as frontotemporal dementia)41 in our community sample to allow us to study them.
Furthermore, conditions affecting visuomotor speed and attention might affect
performance on the Trail-Making Test. In post hoc analyses to control for
possible variation from this source, a hybrid measure, the difference between
Trail-Making Tests B and A, had a rate ratio of 3.34, only slightly lower
than the rate ratio of 3.72 on Trail-Making Test B alone. Thus, our findings
are most likely explained by the additional cognitive complexity and working
memory "load" of Trail-Making Test B rather than the speed or visual components
common to both parts A and B.
We observed small but significant presymptomatic declines in a few tasks
sensitive to other cognitive changes in AD. Category Fluency is more sensitive
to AD than Initial Letter Fluency, presumably because it is more affected
by deterioration in the structure of semantic knowledge in AD.42
Average performance in the CERAD Praxis test, a largely constructional task,
declined 0.7 SD in 2 years, whereas Clock Drawing, involving construction
and planning, declined 0.4 SD in 2 years. The case-control difference in orientation
decline might be related to memory and might foreshadow the more marked disorientation
characteristic of clinically evident AD.
Despite their advantages, some of our study's design features might
have introduced other sources of bias. Our requirement that subjects have
complete cognitive test data at multiple points might have led to our selecting
a relatively "successfully aging" cohort, although cases' and controls' mean
T1 MMSE scores of 26.7 and 27.8, respectively, do not suggest a substantial
healthy survivor bias.11 Because the same test
battery was used at each wave, we cannot discount the possibility of practice
effects, as demonstrated by slightly improved cognitive performance in controls
on some measures. Because a true age-related improvement in cognitive function
is not expected, our results might in fact underestimate any normal age-related
cognitive decline, ie, practice effects might counteract age effects in nondemented
elderly persons.43
Our findings highlight the importance of executive dysfunction early
in the disease process and might facilitate detection and monitoring of early
AD. They might also help explain the temporal evolution of cognitive decline
in preclinical AD and prompt further study on the underlying mechanisms.
AUTHOR INFORMATION
Accepted for publication February 5, 2001.
This work was supported in part by research grants AG07562 and AG05133
and by training grant T32 AG00181 from the National Institute on Aging, National
Institutes of Health, US Department of Health and Human Services, Bethesda,
Md.
This work was based in part on a doctoral dissertation by Dr Chen.
We thank Rajesh Pandav for assistance with the manuscript and the participants
and staff of the MoVIES project, without whom this work would not have been
accomplished.
From the Department of Epidemiology, University of Pittsburgh Graduate
School of Public Health (Drs Chen, Belle, Cauley, and Ganguli), HealthSouth
Harmarville Rehabilitation Hospital (Dr Ratcliff), and the Departments of
Psychiatry (Drs Ratcliff, DeKosky, and Ganguli) and Neurology (Dr DeKosky)
and the Alzheimer's Disease Research Center (Drs DeKosky and Ganguli), University
of Pittsburgh School of Medicine, Pittsburgh, Pa. Dr Chen is now with the
Department of Psychiatry, University of Michigan, Ann Arbor.
Corresponding author: Mary Ganguli, MD, MPH, Western Psychiatric
Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213-2593 (e-mail:
gangulim{at}msx.upmc.edu).
REFERENCES
| |
1. Morris JC, Storandt M, McKeel DW Jr, Rubin EH, Price JL, Grant EA, Berg L. Cerebral amyloid deposition and diffuse plaques in "normal" aging:
evidence for presymptomatic and very mild Alzheimer's disease. Neurology. 1996;46:707-719.
FREE FULL TEXT
2. Small BJ, Herlitz A, Fratiglioni L, Almkvist O, Backman L. Cognitive predictors of incident Alzheimer's disease: a prospective
longitudinal study. Neuropsychology. 1997;11:413-420.
FULL TEXT
|
ISI
| PUBMED
3. Bondi MW, Monsch AU, Galasko D, Butters N, Salmon DP, Delis DC. Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology. 1994;8:374-384.
FULL TEXT
4. La Rue A, Jarvik LF. Cognitive function and prediction of dementia in old age. Int J Aging Hum Dev. 1987;25:79-89.
ISI
| PUBMED
5. Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L. Clinico-pathologic studies in dementia: nondemented subjects with pathologically
confirmed Alzheimer's disease. Neurology. 1988;38:1682-1687.
FREE FULL TEXT
6. Green MS, Kaye JA, Ball MJ. The Oregon Brain Aging Study: neuropathology accompanying healthy aging
in the oldest old. Neurology. 2000;54:105-113.
FREE FULL TEXT
7. Reid W, Broe G, Creasey H, Grayson D, McCusker E, Bennett H, Longley W, Sulway MR. Age at onset and pattern of neuropsychological impairment in mild early-stage
Alzheimer disease: a study of a community-based population. Arch Neurol. 1996;53:1056-1061.
ABSTRACT
8. Lafleche G, Albert MS. Executive function deficits in mild Alzheimer's disease. Neuropsychology. 1995;9:313-320.
FULL TEXT
9. Grady CL, Haxby JV, Horwitz B, Sundaram G, Schapiro BM, Friedland RP, Rapoport SI. Longitudinal study of the early neuropsychological and cerebral metabolic
changes in dementia of the Alzheimer type. J Clin Exp Neuropsychol. 1988;10:576-596.
ISI
| PUBMED
10. Ganguli M, Ratcliff G, DeKosky S. Cognitive test scores in community-based rural elderly with and without
dementia. Aging Mental Health. 1997;1:176-180.
11. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M. Cognitive tests which best discriminate between presymptomatic AD and
those who remain non-demented. Neurology. 2000;55:1847-1853.
FREE FULL TEXT
12. 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 under the auspices of Department of Health and Human Services Task
Force on Alzheimer's Disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
13. Nagy Z, Hindley NJ, Braak H, Braak E, Yilmazer-Hanke DM, Schultz C, Barnetson L, King EM, Jobst KA, Smith AD. The progression of Alzheimer's disease from limbic regions to the neocortex:
clinical, radiological and pathological relationships. Dement Geriatr Cogn Disord. 1999;10:115-120.
FULL TEXT
|
ISI
| PUBMED
14. Touchon J, Ritchie K. Prodromal cognitive disorder in Alzheimer's disease. Int J Geriatr Psychiatry. 1999;14:556-563.
FULL TEXT
|
ISI
| PUBMED
15. Katzman R. The aging brain: limitations in our knowledge and future approaches. Arch Neurol. 1997;54:1201-1205.
ISI
| PUBMED
16. Perry RJ, Hodges JR. Spectrum of memory dysfunction in degenerative disease. Curr Opin Neurol. 1996;9:281-285.
ISI
| PUBMED
17. Locascio JJ, Growdon JH, Corkin S. Cognitive test performance in detecting, staging, and tracking Alzheimer's
disease. Arch Neurol. 1995;52:1087-1099.
ABSTRACT
18. Braak H, Braak E. Evolution of the neuropathology of Alzheimer's disease. Acta Neurol Scand Suppl. 1996;165(suppl):3-12.
19. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L. The course of cognitive impariment in preclinical Alzheimer's disease:
three- and 6-year follow-up of a population-based sample. Arch Neurol. 2000;57:839-844.
FREE FULL TEXT
20. Elias MF, Beiser A, Wolf PA, Au R, White RF, D'Agostino RB. The preclinical phase of Alzheimer's disease: a 22-year prospective
study of the Framingham cohort. Arch Neurol. 2000;57:808-813.
FREE FULL TEXT
21. Rubin EH, Storandt M, Miller JP, Kinscherf DA, Grant EA, Morris JC, Berg L. A prospective study of cognitive function and onset of dementia in
cognitively healthy elders. Arch Neurol. 1998;55:395-401.
FREE FULL TEXT
22. Ganguli M, Dodge HH, Chen P, Belle S, DeKosky ST. Ten-year incidence of dementia in a rural elderly U.S. community population:
the MoVIES project. Neurology. 2000;54:1109-1116.
FREE FULL TEXT
23. Szklo M. Population-based cohort studies. Epidemiol Rev. 1998;20:81-90.
FREE FULL TEXT
24. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos E, Kokmen E. Mild cognitive impairment: clinical characteristics and outcome. Arch Neurol. 1999;56:303-308.
FREE FULL TEXT
25. Ganguli M, Ratcliff G, Huff FJ, Bells S, Kancel MJ, Fischer L, Seaberg E, Kuller LH. Effects of age, gender, and education on cognitive tests in a rural
elderly community sample: norms from the Monongahela Valley Independent Elders
Survey. Neuroepidemiology. 1991;10:42-52.
ISI
| PUBMED
26. Ganguli M, Belle S, Ratcliff G, Seaberg E, Huff FJ, von der Porten K, Kuller LH. Sensitivity and specificity for dementia of population-based criteria
for cognitive impairment: the MoVIES project. J Gerontol. 1993;48:M152-M161.
27. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD),
part I: clinical and neuropsychological assessment of Alzheimer's disease. Neurology. 1989;39:1159-1165.
FREE FULL TEXT
28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
29. Hughes CP, Berg L, Danziger WL, Coben L, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140:566-572.
FREE FULL TEXT
30. Becker JT, Boller F, Saxton J, McGonigle-Gibson KL. Normal rates of forgetting of verbal and non-verbal material in Alzheimer's
disease. Cortex. 1987;23:59-72.
ISI
| PUBMED
31. Reitan RM. The relation of the Trailmaking Test to organic brain damage. J Consult Psychol. 1955;19:393-394.
FULL TEXT
| PUBMED
32. Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia. 1967;5:135-140.
33. Benton AL, Hamsher K. Multilingual Aphasia Examination. Iowa City: University of Iowa; 1976.
34. Kaplan EF, Goodglass GH, Weintraub S. The Boston Naming Test. Philadelphia, Pa: Lea & Febiger; 1983.
35. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-1364.
FREE FULL TEXT
36. Freedman M, Leach L, Kaplan EF, et al. Clock Drawing: A Neuropsychological Analysis. New York, NY: Oxford University Press; 1994.
37. Folstein M, Folstein S, McHugh PR. "Mini-Mental State": a practical method of grading the cognitive state
of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
38. SAS/STAT User's Guide, Version 6.12. 4th ed. Cary, NC: SAS Institute Inc; 1996.
39. Huff FJ, Becker JT, Belle SH, Nebes RD, Holland AL, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology. 1987;37:1119-1124.
FREE FULL TEXT
40. Becker JT, Huff J, Nebes RD, Holland A, Boller F. Neuropsychological function in Alzheimer's disease: pattern of impairment
and rates of progression. Arch Neurol. 1988;45:263-268.
ABSTRACT
41. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. Frontotemporal lobar degeneration: a consensus on clinical diagnostic
criteria. Neurology. 1998;51:1546-1554.
FREE FULL TEXT
42. Martin A, Fedio P. Word production and comprehension in Alzheimer's disease: the breakdown
of semantic knowledge. Brain Lang. 1983;19:124-141.
FULL TEXT
|
ISI
| PUBMED
43. Ratcliff G, Dodge H, Birzescu M, Ganguli M. Tracking cognitive functioning over time: ten-year longitudinal data
from a community-based study. J Clin Geropsychol. In press.
RELATED ARTICLE
Canaries in a Coal Mine: Cognitive Markers of Preclinical Alzheimer Disease
Brent J. Small, Laura Fratiglioni, and Lars Bäckman
Arch Gen Psychiatry. 2001;58(9):859-860.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Independent Cognitive Effects of Atrophy and Diffuse Subcortical and Thalamico-Cortical Cerebrovascular Disease in Dementia
Swartz et al.
Stroke 2008;39:822-830.
ABSTRACT
| FULL TEXT
A Randomized Trial of Beta Carotene Supplementation and Cognitive Function in Men: The Physicians' Health Study II
Grodstein et al.
Arch Intern Med 2007;167:2184-2190.
ABSTRACT
| FULL TEXT
A plateau in pre-Alzheimer memory decline: Evidence for compensatory mechanisms?
Smith et al.
Neurology 2007;69:133-139.
ABSTRACT
| FULL TEXT
Neuropsychological Measures in Normal Individuals That Predict Subsequent Cognitive Decline
Blacker et al.
Arch Neurol 2007;64:862-871.
ABSTRACT
| FULL TEXT
Plasma C-Peptide and Cognitive Performance in Older Men Without Diabetes
Okereke et al.
AJGP 2006;14:1041-1050.
ABSTRACT
| FULL TEXT
Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men
Okereke et al.
J. Clin. Endocrinol. Metab. 2006;91:4306-4312.
ABSTRACT
| FULL TEXT
Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment.
Tabert et al.
Arch Gen Psychiatry 2006;63:916-924.
ABSTRACT
| FULL TEXT
Apolipoprotein epsilon-4 allele and the two-year progression of cognitive function in Chinese subjects with late-onset Alzheimer's disease
Lam et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2006;21:92-99.
ABSTRACT
Depressive Symptoms and Cognitive Decline in Late Life: A Prospective Epidemiological Study
Ganguli et al.
Arch Gen Psychiatry 2006;63:153-160.
ABSTRACT
| FULL TEXT
Similar Neurocognitive Performance of Adults With and Without a History of Parental Alzheimer's Disease: A Pilot Study
Ercoli et al.
J Geriatr Psychiatry Neurol 2005;18:208-212.
ABSTRACT
What the Study of Persons At Risk for Familial Alzheimer's Disease Can Tell Us About the Earliest Stages of the Disorder: A Review
Ringman
J Geriatr Psychiatry Neurol 2005;18:228-233.
ABSTRACT
Longitudinal Models of Growth and Survival Applied to the Early Detection of Alzheimer's Disease
McArdle et al.
J Geriatr Psychiatry Neurol 2005;18:234-241.
ABSTRACT
Prevalence and Natural Course of Aging-Associated Cognitive Decline in a Population-Based Sample of Young-Old Subjects
Schonknecht et al.
Am. J. Psychiatry 2005;162:2071-2077.
ABSTRACT
| |
