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Independent Predictors of Cognitive Decline in Healthy Elderly Persons
Scott Marquis, BS;
M. Milar Moore, BS;
Diane B. Howieson, PhD;
Gary Sexton, PhD;
Haydeh Payami, PhD;
Jeffrey A. Kaye, MD;
Richard Camicioli, MD
Arch Neurol. 2002;59:601-606.
ABSTRACT
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Background Several studies have shown that individually memory, hippocampal volume,
and motor measures presage the onset of dementia. It is unclear if these independently
contribute to the prediction of mild cognitive impairment.
Objective To determine the ability of memory, hippocampal volume, and a gait speed
to independently predict cognitive decline in healthy elderly persons.
Design A prospective, longitudinal, observational cohort study with a mean
follow-up of 6 years.
Participants One hundred eight optimally healthy elderly cognitively intact subjects.
Main Outcome Measures Any cognitive impairment noted on the Clinical Dementia Rating Scale
(score = 0.5) or persistent or progressive cognitive impairment. Cox modeling
determined if time to onset of cognitive impairment was associated with baseline
logical memory II test score (a measure of delayed recall), hippocampal volume
(magnetic resonance imaging), or gait speed (time to walk 30 ft [9 m]) independent
of age, sex, depression, or the allele producing the  4 type of apolipoprotein
E (APOE 4).
Results Questionable dementia occurred in 48 participants in a mean (SD) of
3.7 (2.4) years. This progressed to persistent cognitive impairment in 38
of these participants in a mean (SD) of 4.4 (2.4) years. Logical memory II
test performance and hippocampal volume each predicted onset of questionable
dementia, independent of age and sex. Time to walk 30 ft additionally contributed
independently to the prediction of time to onset of persistent cognitive impairment.
Possessing the APOE 4 allele and depression
did not enter either model significantly.
Conclusions Models combining multiple risk factors should refine the prediction
of questionable dementia and persistent cognitive impairment, harbingers of
dementia. Individuals at risk for cognitive impairment may represent a high-risk
group for intervention.
INTRODUCTION
ALZHEIMER DISEASE (AD) is a formidable public health issue, affecting
an estimated 12% of the population over the age of 65 years in the United
States.1 Approaches that allow better anticipation
of progression to dementia in healthy individuals would enhance current efforts
aimed at preventing or slowing AD onset.2
Several risk factors have been identified that predict the onset of
AD and cognitive impairment in elderly populations. The strongest include
age, sex, educational level,3 genetic makeup
(family history of dementia or allele producing the 4 type of apolipoprotein
E [APOE 4]),4
mild cognitive impairment (MCI) (especially memory loss),2, 5-6
parkinsonism,7 gait impairment,8
and hippocampal or medial temporal volume measures.9-13
The present study was aimed at integrating several individually validated
predictors of cognitive decline to determine if they independently predict
decline in a group of initially healthy elderly persons. We examined clinical
measures of memory,6 timed gait,8
and hippocampal volume.12 We hypothesized that
models combining these measures could refine our ability to forecast the likelihood
of progression to questionable dementia (QD) or persistent cognitive impairment
(PCI), harbingers of AD, and candidates for clinical trials aimed at preventing
the onset of AD.
PARTICIPANTS AND METHODS
PARTICIPANTS
The Oregon Brain Aging Study is a prospective study of neurologic function
in the optimally healthy elderly population. Subjects were 65 years or older
at the initial assessment, without comorbid conditions, mentally healthy (normal)
by mental status examination, and without memory impairment by self-report
or proxy.14 None of the cohort had had a history
of significant head trauma, risk factors for vascular disease, or abuse of
alcohol or other substances based on medical history or medical record review.
Clinical examination findings and laboratory study results that included a
complete blood cell count, chemistry profile, vitamin B12 and folate
levels, chest x-ray film, and electrocardiogram were additionally used to
exclude covert medical conditions that might contribute to cognitive impairment.
At the time of recruitment, participants were taking only vitamins, hormone
replacement therapy, and/or nonsteroidal anti-inflammatory drugs. Use of drugs
that might affect cognitive function, including ascorbic acid and vitamin
E, coenzyme Q, nonsteroidal anti-inflammatory agents, and gingko biloba was
recorded. Each participant underwent evaluation at 6-month intervals using
standardized assessment tools and annual neurologic and neuropsychological
assessments, and magnetic resonance imaging using previously described
protocols.6, 12 Participants who had at least one
volumetrically analyzed magnetic resonance imaging scan at the time of enrollment
were entered into the current analysis.
ASSESSMENTS
The standardized neurologic assessment included a patient interview,
mental status evaluation, and standardized neurologic examination. Dementia
status was graded using the Clinical Dementia Rating Scale (CDR),15 based on subject or informant report of cognitive
or functional decline and confirmed by cognitive testing using the Mini-Mental
State Examination (score <24)16 and the
Neurobehavioral Cognitive Status Examinations,17
as previously described.3 Depressive symptoms
were rated using the Geriatric Depression Scale.18
Socioeconomic status was assessed at baseline using the Hollingshead scale.19 Other indicators of cognitive performance were part
of a standardized neuropsychological battery (including parts of the Wechsler
Memory Scale–Revised and the Wechsler Adult Intelligence Scale–Revised)
that was administered annually but was not used to determine dementia status.14 The logical memory (LM) test from the Wechsler Memory
Scale–Revised, in particular, included a brief story that was read to
the subject and then scored for recall both immediately (LM I) and again 25
to 30 minutes later (LM II). Gait was evaluated annually by a neurologist
(J.A.K., R.C., or colleagues) as part of a comprehensive neurologic examination
and was quantified by having the participant walk at a self-selected pace
15 ft (4.5 m) out to a marker on the ground, turn, and walk back to the starting
point. The time (seconds) and the number of steps (excluding steps taken to
turn) were recorded.20
Magnetic resonance imaging scans were obtained near the time of enrollment
using a 1.5-T scanner (GE Medical Systems, Milwaukee, Wis), with the following
image parameters: multiecho multiplanar, 4-mm coronal slices; field of view,
24 cm2; acquisition matrix, 256 x 256 pixels; number of excitations,
0.5; repetition time, 3000 milliseconds; and echo times, 30 and 80 milliseconds.
Image analysis was performed by semiautomated recursive segmentation using
the program REGION (Oregon Aging and Alzheimer Disease Center, Portland) and
by manual tracing using the National Institutes of Health Image (Version 1.5;
National Institutes of Health, Bethesda, Md) on Macintosh computers (Apple
Computers, Cupertino, Calif).12 Total pixel
counts for each region (intracranial and hippocampal areas) were summed for
each slice and multiplied by the slice thickness to convert areas to volumes.
Hippocampal volumes were measured by manually tracing the area between the
red nucleus and the superior colliculus on serial slices using the National
Institutes of Health Image. These analysis techniques have been previously
shown to be reliable: for hippocampal volume, intraclass correlation = 0.90;
for the measurement of intracranial volume, intraclass correlation = 0.98.12
DATA ANALYSIS
Baseline characteristics were compared using t
or  2 tests. Survival analyses were done using the Cox proportional
hazards model to determine if individual traits at study baseline could predict
the earliest signs of cognitive decline or persistent impairment. Age, sex,
educational level, depressive symptoms, APOE status
(any 4 allele), neuropsychological measures
of memory and hippocampal volume, and gait measures were considered as potential
explanatory variables. Length of follow-up was determined for all participants
and each individual was classified as having attained 1 of the 3 study end
points—QD, PCI, or censored status:
- Questionable dementia was identified in any subject who demonstrated
a CDR score of 0.5 or more at any visit after the initial assessment irrespective
of their ultimate outcome. We considered this a marker of increased risk of
subsequent decline to PCI.
- Persistent cognitive impairment was defined as a conversion to
a CDR score of 0.5 or more without a subsequent reestablishment of normal
cognitive function (CDR = 0). If subjects died following conversion, they
were retained in this group.
- Those who did not demonstrate progression toward cognitive impairment
(CDR score remained at 0) or either died or withdrew from the study prior
to measurable progression were included in the analysis as censored cases.
Two regression analyses were run to model QD and PCI. The effects of
age and sex were controlled for by entering them into the model at the first
step. Hippocampal volumetric measures, memory scores, APOE 4 level status, depressive symptoms, and motor measures were
added by forward stepwise regression. With the exception of sex and age, variables
are only reported if the survival model–calculated P values were less than .05 in 1 of the models examined. The interdependence
of the predictor variables (age, LM II test score, time to walk 30 ft [9 m],
and hippocampal volume) was further examined by calculating the partial correlation
coefficients among these 4 variables.
Logical memory II test scores were determined for the time of the latest
available examination or after achieving QD or PCI status. The proportion
of participants achieving an LM II test score of less than 5 recalled items
at follow-up (corresponding to 1.5 SDs below the normative value for persons
older than 70 years) was also examined to determine the relationship among
QD, PCI, and MCI.2, 21
RESULTS
Outcomes of 108 participants (68 women and 40 men) followed up for a
mean of 6 years from the Oregon Brain Aging Study were examined. Ninety-seven
percent were white, 2% Hispanic, and 1% Native American. At the time of the
analysis, 20 of the 108 subjects were dead and 2 had withdrawn from the study.
As given in Table 1, 48 subjects
had a rating of QD, while 38 had subsequently developed PCI. Patients with
QD and PCI were older than those whose cognition remained intact. There was
no difference between groups in the use of drugs that might affect cognitive
function (P>.10 for all drugs), including ascorbic
acid, vitamin E, coenzyme Q10, nonsteroidal anti-inflammatory agents, and
gingko biloba. The Mini-Mental State Examination and Neurobehavioral Cognitive
Status Examinations scores were higher at baseline in those whose cognition
remained intact. Sex, educational level, vocabulary, socioeconomic class, APOE status, Geriatric Depression Scale score, and duration
of follow-up did not differ between those whose cognition became impaired
and those whose cognition remained intact.
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Table 1. Characteristics of Participants at Baseline and at the Time
Questionable Dementia (QD) or Persistent Cognitive Impairment (PCI) Developed*
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Participants whose cognition became impaired had poorer recall on the
LM II test, smaller hippocampal volumes, and took longer to walk 30 ft. Participants
whose cognition became impaired (data not available for 3 QD and 3 PCI participants)
with follow-up declined on the LM II test, while those whose cognition remained
intact improved (data not available for 1 participant). The proportion of
participants remaining intact who achieved a score of less than 5 (1.5 SDs)
on the LM II test was 3 of 59, while 18 of the 45 participants with QD and
18 of the 35 participants with PCI showed this degree of impairment. Total
brain, but not total intracranial volumes, were smaller in participants who
became impaired (Table 2); however,
these were not entered into the models.
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Table 2. Mean Values for Predictor Variables*
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Coefficients in the multivariable Cox models are listed in Table 3. Older age, a worse LM II test
score, and decreased hippocampal volume were significant predictors of QD.
A 1-year increase in age yielded an increased risk (hazard ratio) of 1.07
times, while a 1-point increase in LM II test score yielded a decreased risk
of 0.90, and a 1-cm3 increase in hippocampal volume yielded a decreased
risk of 0.027. The LM II test score, hippocampal volume, and time to walk
30 ft were significant in the model for the development of PCI. A 1-point
increase in the LM II test score yielded a decreased risk of 0.85 and a 1-cm3 increase in the hippocampal volume yielded a decreased risk of 0.036.
A 1-second increase in time to walk 30 ft yielded an increased risk of 1.14
times of developing PCI. Age only approached statistical significance in this
model and sex was not a significant predictor in either model.
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Table 3. Predictive Factors in Cox Proportionate Hazards Models Including
All of the Indicated Variables for Questionable Dementia (QD) or Persistent
Cognitive Impairment (PCI)*
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Age was negatively correlated with hippocampal volume (partial r = -0.44) and LM II test score (partial r = -0.23) and positively correlated with time to walk 30 ft
(partial r = 0.25). The correlation between the other
variables was weak (partial r<0.1), except for
a negative correlation between hippocampal volume and time to walk 30 ft (r = -0.12).
COMMENT
Our study combined memory performance, neuroimaging, and physical findings
in one predictive model. Logical memory II test score, hippocampal volume,
and time to walk 30 ft forecast cognitive decline, independent of age and
sex, in this cohort of initially healthy elderly participants. Age was a significant
risk for the development of QD only. Time to walk 30 ft only entered the model
for the development of PCI.
A previous population-based study found that global cognitive function,
age, and family report of memory loss were associated with subsequent cognitive
decline.22 In another study, neuropsychological variables did not
contribute to the prediction of dementia in subjects with reported memory
losses.23 Memory measures combined with medial temporal volumes presaged
dementia in elderly persons younger than 85 years.24 That memory
performance and hippocampal volume independently contributed to the model
in our study supports the observation that hippocampal atrophy does not serve
as a surrogate for memory loss.25 This proposal is supported by the
weak correlation between the predictor variables. In a study of younger elderly
persons, memory measures and APOE genotype did not
predict the development of AD, whereas the fusiform, middle, and inferior
temporal gyral volumes had a sensitivity of 93%.26 Progressive brain
atrophy,27-28 or functional imaging
have also been examined in other studies.29
Impaired gait independent of significant medical, orthopedic, or rheumatologic
disease was a significant predictor only for the development of PCI, a persistent
state of cognitive decline, which may be closer to dementia than QD. Another
study has shown that a change in brain magnetic resonance imaging and APOE4 both predicted cognitive
and lower extremity functional decline in an elderly male cohort.30
The presence of the APOE4 allele did not contribute significantly to our multivariable model,
possibly reflecting the older age of the participants.31 That depressive
symptoms were not significant predictors in our cohort (data not shown) might
be related to the exclusion of participants with severe depressive symptoms
at baseline, or to other selection criteria.32
The identification of QD in this cohort puts individuals at risk for
subsequent evolution to PCI at a rate consistent with the conversion to dementia
reported in other studies.33 With longer follow-up, these individuals
may progress to dementia.34-35
Questionable dementia represents a clinically definable end point that is
independent of psychometric testing, unlike MCI. Both are precursors to dementia,
but MCI was not examined in the current study since LM II test performance
was examined as a predictor. It would be inappropriate to use the same psychological
predictor as an end point since poor performance on memory testing at baseline
would be expected to lead to poor subsequent memory performance.
Only a small portion (5%) of intact elderly persons achieved impairment
on the LM II test of 1.5 SDs below norms for that age group, corresponding
to MCI, with longitudinal follow-up. A higher proportion of QD (40%) and PCI
(51%) showed this degree of impairment. These proportions are conservative
because appropriate norms for longitudinally presented memory tests in this
highly educated, very elderly population are unavailable. Nevertheless, these
findings highlight the incomplete overlap between categories of cognitive
impairment in elderly persons and point to the need to better define their
significance in longitudinal cohort studies.36
Gait impairment, which was a predictor of PCI, may indicate more widespread
pathologic change, or the coexistence of vascular disease, either of which
might accelerate the development of a more persistent state of cognitive impairment.37
We believe that the latter category merited definition as an irreversible
state. Motor impairment has previously been described in association with
cognitive impairment, but our data suggest that it can be observed prior to
the development of cognitive decline in the oldest old.38
By focusing on exceptionally healthy, very elderly volunteers, we were
able to identify intrinsic characteristics associated with dementia risk without
confounding medical conditions. The participants in our study represent the
upper 1% to 3% of the elderly population in terms of health and, hence, our
results cannot be generalized.39 Among the strengths of our study
are its prospective design with biannual clinical assessments, and a small
dropout rate, that allowed impairment to be reliably identified at an early
stage. Despite optimal health, our participants exhibited cognitive decline
and decreased survival at rates similar to previous
studies.40-43
Nevertheless, a broader age range of participants with representative medical
conditions (eg, hypertension, diabetes mellitus) should be examined in future
investigations to confirm our findings. Another strength is that most of our
participants have agreed to brain autopsy, which will ultimately clarify the
cause(s) of cognitive impairment. To date, patients with cognitive impairment
(both QD and PCI) have met criteria for AD at autopsy, consistent with the
experience of other investigators,44-45
and suggesting that these end points are clinically meaningful.
Logical memory II test scores at baseline, in our study, were well above
published criteria for MCI suggesting that our subjects were in a presymptomatic
state rather than at an early phase of dementia.2 Others have provided
evidence for a long preclinical phase for dementia.46-47
Future studies will examine the transition between QD to PCI and progression
to subsequent dementia.
CONCLUSIONS
Assessment of risk factors for the development of cognitive impairment
in elderly persons will need to include cognitive and motor measures as well
as neuroimaging. A combined approach will be useful for studies targeting
preventive therapies for those at highest risk prior to the onset of AD.
AUTHOR INFORMATION
Accepted for publication December 19, 2001.
Author contributions: Study concept and design (Mr Marquis and Drs Howieson, Kaye, and Camicioli); acquisition
of data (Ms Moore and Drs Howieson, Payami, Kaye, and Camicioli); analysis and interpretation of data (Mr Marquis,
Ms Moore, and Drs Sexton and Camicioli); drafting of the manuscript (Mr Marquis and Drs Kaye and Camicioli); critical revision
of the manuscript for important intellectual content (Mr
Marquis, Ms Moore, and Drs Sexton, Payami, Kaye, Howieson, and Camicioli); statistical expertise (Mr Marquis, Ms Moore, and
Drs Sexton, Payami, and Kaye); obtained funding (Drs Payami, Kaye, and Camicioli); administrative, technical, and material
support (Dr Kaye); study supervision (Drs Kaye and Camicioli).
The Oregon Brain Bank and the Oregon Aging and Alzheimer Disease Center
are supported by grants AG08017 and 5M01RR0034 from the National Institutes
of Health; the Alzheimer Research Alliance of Oregon, Portland; the Medical
Research Foundation of Oregon, Portland; and donations from individuals. The
Oregon Brain Aging Study is additionally supported by a Merit Review Grant
from the Department of Veterans Affairs, Washington, DC (Dr Kaye).
We thank the staff of the Oregon Aging and Alzheimer Disease Center
and the Oregon Brain Aging Study.
Corresponding author: Richard Camicioli, MD, Department of Medicine
(Neurology), University of Alberta, 2E3.08, 8440 112th St, Edmonton, Alberta,
Canada T6G 2B7 (e-mail: richard.camicioli{at}ualberta.ca).
From the Department of Neurology, Oregon Health Sciences University
(Drs Howieson, Sexton, Payami, and Kaye, Mr Marquis, and Ms Moore), and the
Portland Veterans Affairs Medical Center (Dr Kaye), Portland, Ore; and the
Department of Medicine, University of Alberta, Edmonton (Dr Camicioli).
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Guest Editorial: Linking Thinking, Walking, and Falling
Alexander and Hausdorff
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2008;63:1325-1328.
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Healthy Cognitive Aging and Leisure Activities Among the Oldest Old in Japan: Takashima Study
Dodge et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2008;63:1193-1200.
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Atrophy rates accelerate in amnestic mild cognitive impairment
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Neurology 2008;70:1740-1752.
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Quantitative gait dysfunction and risk of cognitive decline and dementia
Verghese et al.
J. Neurol. Neurosurg. Psychiatry 2007;78:929-935.
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Impaired Attention Predicts Motor Performance Decline in Older Community-Dwellers With Normal Baseline Mobility: Results From the Italian Longitudinal Study on Aging (ILSA)
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Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2007;62:837-843.
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Frailty: An Emerging Research and Clinical Paradigm Issues and Controversies
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Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2007;62:731-737.
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Improvements in Speed-Based Gait Classifications Are Meaningful
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Stroke 2007;38:2096-2100.
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Performance-based physical function and future dementia in older people.
Wang et al.
Arch Intern Med 2006;166:1115-1120.
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Neuropsychological Markers of Progression From Mild Cognitive Impairment to Alzheimer's Disease
Marcos et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2006;21:189-196.
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Familial risk for Alzheimer's disease alters fMRI activation patterns
Bassett et al.
Brain 2006;129:1229-1239.
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Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia: A Critical Review and Meta-Analysis
Perkins et al.
Am. J. Psychiatry 2005;162:1785-1804.
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Implicit memory and Alzheimer's disease neuropathology
Fleischman et al.
Brain 2005;128:2006-2015.
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Early Event-Related Potential Changes During Working Memory Activation Predict Rapid Decline in Mild Cognitive Impairment
Missonnier et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:660-666.
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Apolipoprotein E {varepsilon}4 Allele and Lorazepam Effects on Memory in High-Functioning Older Adults
Pomara et al.
Arch Gen Psychiatry 2005;62:209-216.
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Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia
DeCarli et al.
Neurology 2004;63:220-227.
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Predicting the rate of cognitive decline in aging and early Alzheimer disease
Adak et al.
Neurology 2004;63:108-114.
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Mild cognitive impairment: Directions for future research
Luis et al.
Neurology 2003;61:438-444.
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Natural history of cognitive decline in the old old
Howieson et al.
Neurology 2003;60:1489-1494.
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