Impacto de La Reserva Cognoscitiva en El Desempeño Neuroconductual

8/10/2019 Impacto de La Reserva Cognoscitiva en El Desempeo Neuroconductual

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Impact of cognitive reserve on therelationship of lead exposure andneurobehavioral performance

M.L. Bleecker, MD,

PhD

D.P. Ford, MD, MPH

M.A. Celio, BA

C.G. Vaughan, MA

K.N. Lindgren, PhD

ABSTRACT Background: Cognitive reserve (CR)a construct studied in many neurologic disor-

dersrefers 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 currentblood 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;69:470476

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.

Supplemental data atwww.neurology.org

Address correspondence and

reprint requests to Dr. Margit

L. Bleecker, Center for

Occupational and

Environmental Neurology,2 Hamill Road, Suite 225,

Baltimore, MD 21210

[email protected]

470 Copyright 2007 by AAN Enterprises, Inc.


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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 associatedwith 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.

METHODSSubjects.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 sumover each participants working lifetimeof 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

StudiesDepression 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 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 interestin this case TWAto 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


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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 ap 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 similarin 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 factorStroop 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-

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 classicallyexamined groups with uniform diagnoses or

exposurenormal aging,27 AD,6,12-15 PD,22 depres-

sion,25 sleep apnea,20 MS,23 cerebrovascular dis-

ease,17,18 closed head trauma21that 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 TWAto 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 1 Descriptives for 112 current smelter workers

Variable LoCR HiCR p Value

Age, y 38.5 (9.87; 2161) 38.3 (9.10; 2159) 0.87*

WRAT(raw score) 46.2 (10.93; 1562) 70.3 (4.91; 6384) 0.00

Education,y 12.0 (118) 12.0 (518) 0.00

MMSE 28.0 (2230) 30.0 (2730) 0.00

CES-D 10.9 (9.56; 044) 7.3 (7.56; 034) 0.02

Years employed 14.5 (8.56; 126) 14.1 (8.13; 226) 0.81

Blood lead (g/dL) 26.3 (7.45; 648) 25.9 (10.69; 662) 0.81

TWA (g/dL) 34.2 (11.92; 758) 34.0 (12.04; 958) 0.99

Current drinkers, % 76.7 76.7 1.00

Current smokers, % 12.5 16.1 0.59

Current management, % 17.9 32.1 0.08

*Independent samplesttest used (p 0.05, two-tailed): mean (SD; minmax) presented unless otherwise specified.

Nonparametric Mann-WhitneyUtest used (p 0.05, two-tailed): median (minmax) 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 TestRevised for Reading; MMSE Mini-Mental State Examina-

tion; CES-D Center for Epidemiological StudiesDepression scale; blood lead blood lead level at the time of testing;

TWA working-lifetime weighted average blood lead.

472 Neurology 69 July 31, 2007


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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 toprocess 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 2 Neuropsychologicaltest data for 112 currentsmelter workers

Variable LoCR HiCR p Value

Stroop CW 37.6 (8.01; 2056) 43.0 (11.11; 2172) 0.00*

Trails A 35.4 (13.06; 1776) 30.6 (10.62; 1460) 0.03

Trails B 89.2 (31.82; 42164) 63.9 (20.06; 28122) 0.00

DigitSymbol 45.1 (12.48; 2270) 51.7 (11.75; 3181) 0.01

BlockDesign 28.8 (10.40; 648) 32.6 (8.66; 1446) 0.04

DS Forward 7.1 (2.25; 213) 9.0 (2.24; 414) 0.00

DS Backward 5.9 (1.73; 210) 7.6 (2.17; 412) 0.00

DS Total 12.9 (3.29; 720) 16.6 (3.62; 924) 0.00

LM I 10.8 (3.74; 421) 13.8 (4.08; 222) 0.00

LMII 8.4 (4.05; 021) 12.2 (3.88; 420) 0.00

RAVLT Trial V 11.1 (2.45; 615) 11.6 (2.16; 715) 0.22

RAVLT Delayed 8.4 (3.40; 015) 9.9 (3.03; 315) 0.01

Purdue DH 14.1 (1.44; 1117) 14.6 (1.94; 919) 0.11

Purdue NDH 13.9 (1.63; 1018) 14.4 (1.65; 1019) 0.13

*Independent samplesttest used (p 0.05, two-tailed): mean (SD; minmax) 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.

Table 3 Relation of TWAto 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

DigitSymbol 0.367 (0.145); 6.4% 0.02 0.148 (0.122); 1.9% 0.23

MotorFactor 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

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

TrailsB 0.203 (0.406); 0.3% 0.62 0.073 (0.215); 0.2% 0.75

BlockDesign 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 StudiesDepression scale, and current alcohol use.

Significant (p 0.05, one sided test) dose-effect relationship.TWA working lifetime weighted blood lead; CR cognitive

reserve.



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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 revealedvisuomotor 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

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 causalinferences 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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Impacto de La Reserva Cognoscitiva en El Desempeño Neuroconductual

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