Impact of cognitive reserve on the
relationship of lead exposure and
M.L. Bleecker, MD,
PhD
D.P. Ford, MD, MPH
M.A. Celio, BA
C.G. Vaughan, MA
K.N. Lindgren, PhD
Address correspondence and
reprint requests to Dr. Margit
L. Bleecker, Center for
Occupational and
Environmental Neurology,
2 Hamill Road, Suite 225,
Baltimore, MD 21210
coen@msn.com
Supplemental data at
www.neurology.org
470
neurobehavioral performance
ABSTRACT Background: Cognitive reserve (CR)—a construct studied in many neurologic disor-
ders—refers to the maintenance of cognitive performance in spite of ongoing underlying brain
pathology. Objective: We hypothesized that a dose-effect relationship would exist between
chronic occupational lead exposure and cognitive effects in workers with low CR but not in work-
ers with high CR and identical lead exposure, and that level of CR would not influence the relation-
ship between lead exposure and motor performance. Methods: We stratified currently employed
lead smelter workers by Wide Range Achievement Test-R for reading (WRAT), a recognized mea-
sure of CR, into loCR and hiCR groups. From these two groups we matched 56 pairs on working
lifetime weighted blood lead (TWA). We performed a factor analysis on 14 neuropsychological
outcome variables. Within each CR group regression analyses after adjusting for age, alcohol use,
and depression scale score tested for dose-effect relationships between TWA and outcome vari-
ables. Results: Both CR groups had comparable age, years employed, alcohol use, and current
blood lead levels. Factor analysis provided three factors and five tests used in the regression
analyses. Significant dose-effect relationships between TWA and cognitive tests present only in
the loCR group included Attention Factor and Digit Symbol. Both CR groups demonstrated signif-
icant dose-effect relationships on the Motor Factor. Conclusion: This study found that cognitive
reserve protects against the effect of chronic lead exposure on select measures of cognitive
performance but not on motor performance. NEUROLOGY 2007;69:470–476
The theory of cognitive reserve (CR) is premised on the maintenance of cognitive perfor-
mance in spite of ongoing underlying brain pathology.1,2 Factors which may contribute to
CR include genetics,3 childhood cognitive ability,4 head size,1,5 education,4-6 linguistic
ability,7 reading achievement,8,9 lifestyle,10,11 and occupational attainment.5,6,12 While the
concept of CR evolved out of the Alzheimer disease (AD) literature,6,12-15 it is relevant in a
variety of other dementias8,16 and in brain dysfunction associated with cerebrovascular
disease,17,18 HIV-1 infection,19 sleep apnea,20 closed head injury,21 Parkinson disease
(PD),22 multiple sclerosis (MS),23 temporal lobe epilepsy,24 and electroconvulsive thera-
py.25 Even those at risk for AD have increased use of CR during memory tasks as sug-
gested by different activation patterns when compared to controls on functional MRI.26
The neural basis of CR has been demonstrated in a normal aging population27 using
functional MRI28 and PET.29
CR in the setting of brain insult secondary to neurotoxic exposure has received little
attention to date. The protective effects of CR were suggested in a study of lead smelter
workers where a dose-effect relationship between cumulative lead exposure and Mini-
Mental State Examination was present only in those workers with a measure of low CR
but not in their counterparts with high CR, despite comparable lead exposure in the two
groups.30
Surrogates of CR most commonly seen in the literature include years of education and
measures of occupational attainment.6 Measures of reading achievement are considered
better indicators of CR because they are less likely to be influenced by opportunity.8,9,30
Compared with years of education, reading achievement was shown to be a more accu-
From the Center for Occupational and Environmental Neurology, Baltimore, MD.
Supported by the New Brunswick Occupational and Safety Commission.
Disclosure: The authors report no conflicts of interest.
Copyright © 2007 by AAN Enterprises, Inc.
rate measure of educational experience and
predictor of performance on neuropsycho-
logical testing in the elderly.9 A reading test
identifies those self-educated individuals
that left school early for a variety of socio-
cultural reasons and those individuals who
graduated high school but are functionally
illiterate.31
Occupational lead exposure is associated
with impaired performance on tasks of both
cognition and of motor speed and dexterity.32
Because CR has only been shown to be rele-
vant to cognitive tasks we hypothesized that
in the setting of chronic lead exposure CR
should be protective against cognitive effects
but not motor effects.
METHODS Subjects. Participants included 256 currently
employed, English-speaking lead smelter workers character-
ized in previous publications.30,33 An extensive neurobehav-
ioral battery was administered as part of a larger study of
lead effects in French and English speaking smelter workers.
All participants volunteered for the study and signed an in-
formed consent form approved by a combined government
regulatory agency-management-labor oversight committee.
Cognitive reserve. The Wide Range Achievement Test–
Revised for reading (WRAT)34 score provides a measure of
reading achievement and premorbid intelligence,35,36 and is
unlikely to be influenced by occupational neurotoxic insult.
The WRAT, a measure of CR,30 is a word recognition test
for 75 words. The words are of increasing complexity but
only correct pronunciation not comprehension is required.
When 10 consecutive words are mispronounced the test is
terminated. Raw scores are then converted to an equivalent
reading grade level. For the purpose of this study, a partici-
pant was classified as loCR if his performance on the WRAT
was at a reading grade level of 11th grade or lower; hiCR
participants had an equivalent reading grade level of 12th
grade or higher.
Lead exposure. Blood lead levels were determined at least
quarterly since hire of each participant in compliance with
applicable occupational health standards. Samples were ana-
lyzed using atomic absorption spectroscopy with a graphite
furnace in a laboratory that maintained acceptable perfor-
mance in the Centers for Disease Control round-robin profi-
ciency testing program for blood lead measurement. High
ambient lead exposure occurred for the first 14 years of the
smelter operation followed by much lower exposure in the
calculated working-lifetime average blood lead level (TWA).
In order to calculate TWA, we used the results of all blood
lead testing to calculate an integrated blood lead level (IBL),
a measure of cumulative blood lead. IBL was calculated as
the sum— over each participant’s working lifetime— of the
products of each blood lead level and one-half of the time
interval from the preceding blood lead to the subsequent
blood lead measure. For TWA the IBL is divided by total
years employed. This provided the average intensity of expo-
sure over the time of employment.
Neuropsychological variables. We chose 14 tests from a
larger neuropsychological battery as outcome variables
based upon the strength of their association with lead expo-
sure as reported in the literature.32 The variables included
Wechsler Adult Intelligence Scale (WAIS) Digit Span For-
ward, Backward, and Total (DS Forward, DS Backward,
and DS Total), Block Design and Digit Symbol, Wechsler
Memory Scale (WMS-R) Logical Memory I and II (LM I and
LM II), Rey Auditory Verbal Learning Test Trial Five and
30-minute delayed recall (RAVLT Trial V and RAVLT De-
layed), Trail Making Test A and B (Trails A and Trails B),
Stroop Color-Word (Stroop CW), and Purdue Pegboard
dominant and nondominant hands (Purdue DH and Purdue
NDH).37 As depression may affect neuropsychological per-
formance, symptoms were obtained by a self-reported ques-
tionnaire on depression from the Center for Epidemiologic
Studies–Depression Scale (CES-D).38
Statistical analyses. We used SPSS-PC v12.0.1 for all data
analyses. The participants were stratified according to WRAT
performance into a loCR group (WRAT raw score ⬍ 63; n ⫽
200) and a hiCR group (WRAT raw score ⱖ 63; n ⫽ 56).
Visual inspection of the TWA distributions of the two CR
groups showed a relative absence of loCR individuals with
low TWAs and of hiCR individuals with high TWAs. This
difference in the TWA distributions was reflected in the sig-
nificant difference between loCR TWA (mean ⫾ SD), 40.2
␮g/dL ⫾ 12.07 and hiCR TWA, 34.3 ␮g/dL ⫾ 12.12 (p ⬍
0.00). With such an imbalance between CR groups for lead
exposure it was clear that multivariable adjustment would
not be sufficient to disentangle the effects of these two vari-
ables on the neuropsychological outcomes. In this setting,
matching is recommended39 to force the distribution of the
variable of interest—in this case TWA—to be comparable.
Consequently, matched pairs were created using TWA with
no more than 2 ␮/dL difference between the pairs. For each
member of the hiCR group the matching procedure con-
sisted of the identification of all potential loCR matches.
From this group of potential loCR matches one was ran-
domly selected. Fifty-six pairs were identified for the analy-
ses. We were unable to successfully match the remaining
loCR individuals on a second round of matching resulting in
their exclusion from further analyses.
Descriptive statistics and graphics were performed on the
demographic variables and the lead exposure terms to check
for gross violations of assumptions for parametric analyses.
CES-D was skewed toward low scores (less depressive symp-
toms) and therefore a square root transformation was em-
ployed to convert the depression variable to better
approximate a normal distribution. Parametric independent
sample t tests and nonparametric chi squared and Mann-
Whitney U test were used for group mean comparison be-
tween the loCR and hiCR groups.
Principle component factor analysis was performed on
the 14 neurobehavioral variables to statistically identify sim-
ilar tests within neuropsychological constructs. Variables
were considered part of a factor if their varimax rotated fac-
tor loading was 0.70 or higher (table E-1 on the Neurology
Web site at www.neurology.org). Averaging test z-scores
created composite scores for each factor. Variables that did
not clearly load onto one domain (factor loadings ⬍ 0.70)
were analyzed separately.
In separate linear models each factor composite score
and the remaining individual tests were regressed on TWA
Neurology 69 July 31, 2007 471
 Table 1 Descriptives for 112 current smelter workers
Variable LoCR
Age, y 38.5 (9.87; 21–61)
WRAT (raw score) 46.2 (10.93; 15–62)
Education, y 12.0 (1–18)
MMSE 28.0 (22–30)
CES-D 10.9 (9.56; 0–44)
Years employed 14.5 (8.56; 1–26)
Blood lead (␮g/dL) 26.3 (7.45; 6–48)
TWA (␮g/dL) 34.2 (11.92; 7–58)
Current drinkers, % 76.7
Current smokers, % 12.5
Current management, % 17.9
*Independent samples t test used (p ⫽ 0.05, two-tailed): mean (SD; min–max) presented unless otherwise specified.
†Nonparametric Mann-Whitney U test used (p ⫽ 0.05, two-tailed): median (min–max) presented.
‡Square root transformation of CES-D raw score used for group comparison.
§
Nonparametric chi squared test used (p ⫽ 0.05, two-tailed).
CR ⫽ cognitive reserve; WRAT ⫽ Wide Range Achievement Test–Revised for Reading; MMSE ⫽ Mini-Mental State Examina-
tion; CES-D ⫽ Center for Epidemiological Studies–Depression scale; blood lead ⫽ blood lead level at the time of testing;
TWA ⫽ working-lifetime weighted average blood lead.
after controlling for age, current alcohol use, and depression
scale score. We defined a dose-effect relationship within each
WRAT group to be significant when the corresponding beta
coefficient had a p ⬍ 0.1. Collinearity diagnostics and resid-
ual plots were examined for each multiple linear regression
to assess for model violations (e.g., multicollinearity, nonlin-
earity, and heteroscedasticity). Individuals with residuals
greater than three standard deviations were examined as
possible univariate outliers. Multivariate outliers were ex-
amined using Mahalanobis distance. No individuals were
identified as univariate or as multivariate outliers.
RESULTS The demographics of the 112 smelter
workers stratified by WRAT and matched on
TWA exposure are presented in table 1. Age,
years employed, current blood lead levels, and
percentage of current alcohol users, smokers, and
salaried employees were comparable in the two
groups. Mini-Mental State Examination
(MMSE), not used in the analyses, is included for
descriptive purposes. Table 2 presents the mean
scores on the neuropsychological tests with most
scores on cognitive tasks better in the hiCR group
as expected, while motor task scores were similar
in the two groups.
Principal component factor analysis of the 14
neurobehavioral tests resulted in three factors: at-
tention/executive (DS Forward, DS Backward,
DS Total), verbal memory (LM I, LM II, RAVLT
Trial V, RAVLT Delayed), and motor speed and
dexterity (Purdue DH, Purdue NDH)—and five
tests that did not load on a factor—Stroop CW,
Digit Symbol, Trails A, Trails B, and Block De-
sign. Results of the regression analyses of these
factors and the five tests on TWA after control-
472 Neurology 69 July 31, 2007
HiCR p Value
38.3 (9.10; 21–59) 0.87*
70.3 (4.91; 63–84) 0.00
12.0 (5–18) 0.00†
30.0 (27–30) 0.00†
7.3 (7.56; 0–34) 0.02‡
14.1 (8.13; 2–26) 0.81
25.9 (10.69; 6–62) 0.81
34.0 (12.04; 9–58) 0.99
76.7 1.00§
16.1 0.59§
32.1 0.08§
ling for the covariates are presented in table 3. A
dose-effect relationship was present in the loCR
group for attention/executive factor, Digit Sym-
bol, and motor speed and dexterity factor. In the
hiCR group no dose-effect relationship was found
on cognitive performance but a significant dose-
effect relationship was present for the motor
speed and dexterity factor, a domain not expected
to be influenced by CR.
DISCUSSION Studies of CR have classically
examined groups with uniform diagnoses or
exposure—normal aging,27 AD,6,12-15 PD,22 depres-
sion,25 sleep apnea,20 MS,23 cerebrovascular dis-
ease,17,18 closed head trauma21—that are stratified
based upon a surrogate for CR and then differ-
ences in neurobehavioral performance examined.
In these smelter workers those with low CR had
jobs with more potential for lead exposure com-
pared to those workers with high CR. To address
this bias we chose a study design whereby work-
ers with low and high CR were matched on TWA
to force the same distribution of chronic lead ex-
posure in both groups.
We identified significant dose-effect relation-
ships between TWA and performance on cogni-
tive tests only in the loCR group despite
comparable lead exposure in both CR groups.
The absence of any dose-effect relationship in the
hiCR group suggests that CR served as an effect
modifier and allowed performance to be main-
tained even though lead did affect the nervous
system in this group as witnessed by its effect on
 Table 2 Neuropsychological test data for 112 current smelter workers

Variable LoCR HiCR p Value

Stroop CW 37.6 (8.01; 20–56) 43.0 (11.11; 21–72) 0.00*

Trails A† 35.4 (13.06; 17–76) 30.6 (10.62; 14–60) 0.03

Trails B† 89.2 (31.82; 42–164) 63.9 (20.06; 28–122) 0.00

Digit Symbol 45.1 (12.48; 22–70) 51.7 (11.75; 31–81) 0.01

Block Design 28.8 (10.40; 6–48) 32.6 (8.66; 14–46) 0.04

DS Forward 7.1 (2.25; 2–13) 9.0 (2.24; 4–14) 0.00

DS Backward 5.9 (1.73; 2–10) 7.6 (2.17; 4–12) 0.00

DS Total 12.9 (3.29; 7–20) 16.6 (3.62; 9–24) 0.00

LM I 10.8 (3.74; 4–21) 13.8 (4.08; 2–22) 0.00

LM II 8.4 (4.05; 0–21) 12.2 (3.88; 4–20) 0.00

RAVLT Trial V 11.1 (2.45; 6–15) 11.6 (2.16; 7–15) 0.22

RAVLT Delayed 8.4 (3.40; 0–15) 9.9 (3.03; 3–15) 0.01

Purdue DH 14.1 (1.44; 11–17) 14.6 (1.94; 9–19) 0.11

Purdue NDH 13.9 (1.63; 10–18) 14.4 (1.65; 10–19) 0.13

*Independent samples t test used (p ⫽ 0.05, two-tailed): mean (SD; min–max) presented unless otherwise specified.
†Higher score indicates worse performance.
CR ⫽ cognitive reserve; Stroop CW ⫽ Stroop Color-Word; Trails A ⫽ Trail Making Test A; Trails B ⫽ Trail Making Test B; DS
Forward ⫽ Wechsler Adult Intelligence Scale (WAIS)-R Digit Span Forward; DS Backward ⫽ WAIS-R Digit Span Backward;
DS Total ⫽ WAIS-R Digit Span Total; LM I ⫽ Wechsler Memory Scale (WMS-R) Logical Memory I; LM II ⫽ WMS-R Logical
Memory II; RAVLT Trial V ⫽ Rey Auditory Verbal Learning Test Trial Five; RAVLT Delayed ⫽ Rey Auditory Verbal Learning
Test 30-minute delayed recall; Purdue DH ⫽ Purdue Pegboard dominant hand; Purdue NDH ⫽ Purdue Pegboard nondomi-
nant hand.

motor performance. There are multiple theories
on how CR is protective against insults to the
brain. These include an increased concentration
of cortical synapses in larger brains that provide
more brain reserve capacity,1 a greater ease of us-
ing alternative brain circuits,2 and the ability to
process tasks more efficiently in presently used
brain circuits.2
Surrogates for CR include measures of read-
ing achievement, 8,9,28,29 years of education, 4-6
occupational attainment,6,12 and leisure activi-
ties.10,11 In the current study the loCR group
had a median education of 12.0 years with a
range of 1 to 18 years. This suggests that
WRAT was a better measure of educational
achievement than years attending school as
WRAT may reflect variability in academic
standards such as an emphasis on the acquisi-
tion of mechanical skills rather than book
learning. In the hiCR group, the median educa-
tion was 12.0 years with a range of 5 to 18 years
suggesting self-education through reading in
those with low years of education. Occupa-
tional attainment, another marker of CR, was

Table 3 Relation of TWA to neuropsychological outcomes in loCR and hiCR

Variable loCR p Value hiCR p Value

Attention Factor –0.027 (0.012); 9.5%*† 0.02† 0.014 (0.010); 3.1% 0.18

Digit Symbol –0.367 (0.145); 6.4%† 0.02† –0.148 (0.122); 1.9% 0.23

Motor Factor –0.022 (0.010); 5.3%† 0.04† –0.020 (0.012); 4.8%† 0.09†

Verbal Memory Factor –0.015 (0.010); 2.7% 0.15 –0.008 (0.009); 1.2% 0.38

Stroop CW –0.053 (0.122); 0.3% 0.66 –0.112 (0.120); 1.2% 0.36

Trails A 0.180 (0.177); 1.4% 0.31 0.111 (0.118); 1.3% 0.35

Trails B 0.203 (0.406); 0.3% 0.62 –0.073 (0.215); 0.2% 0.75

Block Design –0.162 (0.149); 1.8% 0.28 –0.150 (0.094); 3.5% 0.12

*Parameter estimates (␤) (standard error); R2 change presented for TWA after controlling for the covariates age, Center for
Epidemiological Studies–Depression scale, and current alcohol use.
†Significant (p⬍ 0.05, one sided test) dose-effect relationship.TWA ⫽ working lifetime weighted blood lead; CR ⫽ cognitive
reserve.

Neurology 69 July 31, 2007 473

 not useful in these smelter workers. Supervisor
positions were awarded based upon perfor-
mance on the job and not necessarily on tradi-
tional managerial skills. Consistent with this
interpretation, 17.9% of the loCR group were
supervisors and 67.9% of the hiCR group were
hourly laborers.
Cognitive performance is maintained follow-
ing a variety of insults to the brain in those indi-
viduals with greater CR. In a study of normal
aging5 the CR surrogates of education, occupa-
tional attainment, and brain size were compared
on measures of verbal memory and nonverbal
reasoning after adjusting for childhood cognition
and burden of white matter hyperintensities as
seen on brain MRI. Education and occupational
attainment but not brain size contributed signifi-
cant variance to cognitive performance. This
finding would not support the passive brain re-
serve hypothesis that proposes a larger brain is
able to tolerate more insult before clinical expres-
sion of impairment. In another study perfor-
mance on a memory test was similar in patients
prior to treatment with electroconvulsive therapy
and significantly worse afterwards in those with
low CR as defined by education and occupational
attainment.25 Another approach examined closed
head injury patients with similar education, occu-
pational attainment, or pre-injury IQ stratified on
the presence or absence of a premorbid history of
a neuropsychiatric condition including alcohol-
ism or drug abuse. Even though the group with no
premorbid history had more severe head injuries
their neuropsychological performance was better
than the group with a premorbid history and less
severe head injuries. Diminished CR from the ag-
gregate effects of the insults sustained during the
premorbid history was the explanation provided
for these results.21
Inorganic lead exposure in adults classically
affects motor speed, psychomotor speed, atten-
tion/executive function, and visual/verbal mem-
ory. Extensive review of the occupational lead
exposure and psychometric performance revealed
visuomotor tasks were the most frequent domain
associated with lead exposure.32 Visuomotor
tasks include tests of motor speed and dexterity
that involve manipulation of pegs requiring pre-
cise finger movement and an intact corticospinal
tract40 and peripheral nervous system. As expo-
sure to lead affects both the central and peripheral
nervous system there is the opportunity to alter
motor performance at multiple locations possibly
accounting for its frequent association with lead
exposure.32,33,41-46 A study with similar findings to
474 Neurology 69 July 31, 2007
the present one reported Taiwanese lead workers
had better performance on cognitive tests com-
pared to the referent group, a finding attributed
to their higher years of education; however finger
tapping in these workers was significantly associ-
ated with blood lead.43 In fact the authors suggest
that simple visuomotor dysfunction is an early
sign of chronic lead intoxicaton.43 In another Tai-
wanese study of lead workers finger tapping
again associated with blood lead and perfor-
mance improved as blood lead levels decreased on
subsequent examinations.41 In Korean lead ex-
posed workers blood lead was the best predictor
for significant decrements in Purdue Pegboard
and Pursuit Aiming, another visuomotor task.44
Following repeat examination of this group
longitudinal blood lead was only associated
with poorer performance in Purdue Pegboard.45
Differences in Grooved pegboard performance
were found in lead workers with ␦-aminole-
vulinic acid dehydratase (ALAD) polymor-
phism such that workers with ALAD1 genotype
were significantly slower than workers with
ALAD1-2/2-2 genotypes. 46 Visuomotor tasks
lack sociocultural bias potentially present in
cognitive tasks and are less influenced by CR
that may also contribute to their frequent asso-
ciation with lead exposure.
This study was cross-sectional in design and
therefore subject to the limitations of that de-
sign. The lead exposure term of interest, TWA,
was calculated based on data points collected at
various times in the past, thus making causal
inferences drawn from our results more likely
to be valid. Use of a matched sampling proce-
dure was necessary to address the study hy-
pothesis however the resulting decrease in the
number of subjects included in the analyses re-
duced the statistical power, thereby limiting the
ability to reproduce some of the findings previ-
ously reported in the occupational lead expo-
sure literature. Despite the methodologic
limitations our findings are biologically plausi-
ble. The ability to generalize the results of this
study could be limited by features unique to
this smelter population; for this reason these
results should be replicated in other exposed
populations.
Received May 23, 2006. Accepted in final form March 7,
2007.
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M. L. Bleecker, D. P. Ford, M. A. Celio, et al.
Neurology 2007;69;470-476
DOI 10.1212/01.wnl.0000266628.43760.8c

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